penetration of anti infective agents into.3

Penetration of Anti-Infective Agents intoPulmonary Epithelial Lining FluidFocus on Antibacterial Agents

Keith A. Rodvold,1 Jomy M. George2 and Liz Yoo1

1 University of Illinois at Chicago, Chicago, IL, USA

2 Philadelphia College of Pharmacy, Philadelphia, PA, USA

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

1. Epithelial Lining Fluid (ELF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638

1.1 Collection of ELF and Limitations of Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639

1.2 Factors Influencing Penetration of Antimicrobials into ELF and Comparison with Plasma Concentrations . . . . . . . . . . . . . . . . . 640

1.3 Pharmacokinetic-Pharmacodynamic Parameters of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640

2. b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641

2.1 Oral Penicillins and Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641

2.2 Parenteral Penicillins and Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

2.3 Carbapenems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

3. Macrolides, Azalides and Ketolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645

3.1 Erythromycin, Roxithromycin, Dirithromycin and Modithromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645

3.2 Clarithromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649

3.3 Azithromycin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649

3.4 Ketolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650

4. Fluoroquinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650

4.1 Ciprofloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650

4.2 Moxifloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651

4.3 Levofloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652

5. Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652

6. Glycopeptides and Lipoglycopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654

6.1 Vancomycin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654

6.2 Teicoplanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655

6.3 Telavancin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655

6.4 Oritavancin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656

7. Miscellaneous Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656

7.1 Linezolid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657

7.2 Tigecycline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658

7.3 Iclaprim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658

8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658

Abstract The exposure-response relationship of anti-infective agents at the site of infection is currently being re-

examined. Epithelial lining fluid (ELF) has been suggested as the site (compartment) of antimicrobial

activity against lung infections caused by extracellular pathogens. There have been an extensive number of

studies conducted during the past 20 years to determine drug penetration into ELF and to compare plasma

REVIEW ARTICLEClin Pharmacokinet 2011; 50 (10): 637-664

0312-5963/11/0010-0637/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

and ELF concentrations of anti-infective agents. The majority of these studies estimated ELF drug con-

centrations by the method of urea dilution and involved either healthy adult subjects or patients undergoing

diagnostic bronchoscopy. Antibacterial agents such as macrolides, ketolides, newer fluoroquinolones and

oxazolidinones have ELF to plasma concentration ratios of >1. In comparison, b-lactams, aminoglycosides

and glycopeptides have ELF to plasma concentration ratios of £1. Potential explanations (e.g. drug

transporters, overestimation of the ELF volume, lysis of cells) for why these differences in ELF penetration

occur among antibacterial classes need further investigation. The relationship between ELF concentrations

and clinical outcomes has been under-studied. In vitro pharmacodynamic models, using simulated ELF and

plasma concentrations, have been used to examine the eradication rates of resistant and susceptible pa-

thogens and to explainwhy selected anti-infective agents (e.g. thosewith ELF to plasma concentration ratios

of >1) are less likely to be associated with clinical treatment failures. Population pharmacokinetic modelling

and Monte Carlo simulations have recently been used and permit ELF and plasma concentrations to be

evaluated with regard to achievement of target attainment rates. These mathematical modelling techniques

have also allowed further examination of drug doses and differences in the time courses of ELF and plasma

concentrations as potential explanations for clinical and microbiological effects seen in clinical trials.

Further studies are warranted in patients with lower respiratory tract infections to confirm and explore the

relationships between ELF concentrations, clinical and microbiological outcomes, and pharmacodynamic

parameters.

Plasma drug concentrations in relation to the minimum in-

hibitory concentration (MIC) for the bacterial pathogen of

interest have traditionally been used as a predictive marker of

the efficacy of antibacterial agents.[1] In vitro models and clin-

ical trials during the past two decades have dramatically ex-

panded our knowledge of exposure-effect relationships and

have established pharmacokinetic-pharmacodynamic indices

for many antibacterial agents.[2-4] Hence more attention has

been placed on the importance of anti-infective concentrations,

not only in plasma but also at the site of infection.[5-7]

Pulmonary epithelial lining fluid (ELF) and alveolar

macrophages (AMs) have been advocated as important sites of

infection with common extracellular and intracellular respira-

tory pathogens, respectively. For community-acquired pneu-

monia, Streptococcus pneumoniae, Moraxella catarrhalis and

Haemophilus influenzae are the predominant extracellular pa-

thogens, and Mycoplasma pneumoniae, Chlamydophila (Chla-

mydia) pneumoniae andLegionella pneumophila are the primary

intracellular pathogens. Thus knowledge of the location of the

respective pathogens, drug penetration and drug concentra-

tions in different compartments of the lung should assist in

selection of appropriate antibacterial therapy and design of

dosing regimens to effectively treat lower respiratory tract

infections.[8-11]

The aim of this review is to provide a comprehensive sum-

mary of the concentrations of antibacterial agents in ELF and

the extent of their penetration. A brief overview has been in-

cluded to describe the common methodologies that are used in

collecting samples from ELF, the limitations associated with

these methods and interpretation of the data that are obtained.

Also discussed are the physicochemical and host-related factors

that may influence penetration of anti-infective agents at the

site of lung infections, comparison of ELF to plasma (or

serum) concentration ratios, and correlation of pharmacokinetic-

pharmacodynamic parameters that are specific for each class of

antibacterial agents.

1. Epithelial Lining Fluid (ELF)

Awide variety of different methodologies have been used for

measuring concentrations of anti-infective agents and drug dis-

tribution patterns within the lungs. Commonly employedmethods

have included whole-tissue homogenates, sputum, respiratory

secretions, bronchial mucosa, pleural fluid, bronchoalveolar

lavage (BAL), ELF, microdialysis, positron emission tomo-

graphy and magnetic resonance spectroscopy.[12] It remains

unclear which of these techniques is the most appropriate.[11-15]

Historically, anti-infective drug concentrations were mea-

sured by obtaining lung tissue during a surgical procedure.

Although this is one of the oldest methods for measuring drug

concentrations in the lung, whole-tissue concentrations are

no longer recommended.[14] In addition, methods that include

measurement of antibacterial concentrations in sputum or bron-

chial secretions have been considered less than optimal.[11,12,16]

For example, the shortcomings of using sputum concentrations

as an indicator of lung penetration include the possibility of

falsely low saliva drug concentrations (indicating poor lung

penetration) because of a dilutional effect caused by saliva, or

638 Rodvold et al.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (10)

falsely elevated saliva drug concentrations (suggesting high

lung penetration) if the antibacterial is extensively distributed

into saliva but not into other pulmonary fluids or tissues. The

major drawback of drug concentrations reported from whole

lung tissue, bronchial tissues and/or secretions is the assump-

tion that anti-infective agents are uniformly distributed across

all lung compartments (e.g. extracellular, intracellular). Thus

the reported drug concentration represents a mixture from all

compartments versus a value for a specific site of activity.

Methods that measure concentrations of anti-infective agents

in specific compartments of the lung (e.g. ELF, interstitial fluid,

AMs) are currently preferred and are considered to provide

further insight into the significance of drug concentrations at

the site of pulmonary infections.[5,11-14,16] ELF has been con-

sidered the likely site of extracellular respiratory micro-organisms

in bacterial pneumonia and acute bacterial exacerbation of

chronic bronchitis. However, one must understand that no

method or sampling site is perfect, and each has its advantages,

potential limitations and methodological issues.[11-16]

1.1 Collection of ELF and Limitations of Methodology

Currently, the combination of bronchoscopy and BAL has

become a safe and effective method for obtaining samples from

the bronchoalveolar surface of the lower respiratory tract. The

procedure involves a fibre-optic bronchoscope being passed

and wedged into a subsegment of the middle or lower lung lobe.

BAL is performed by instillations of three or four aliquots of

sterile 0.9% normal saline solution into the lung lobe, with the

fluid being immediately aspirated and placed on ice after each

aliquot. The aspirate from the first instillation is usually col-

lected separately and discarded because of significant con-

tamination with cells from the proximal airways. The aspirates

recovered from the subsequent instillations are pooled, the

volume is measured and recorded, and removal of a sample for

other testing (e.g. a total cell count and a differential cell count)

is sent to the laboratory. The remaining volume of BAL is

immediately centrifuged, the supernatant and cell pellet are

separated, and samples from the supernatant for determining

urea and drug concentrations are collected and frozen until the

assays can be performed. A blood sample to determine urea and

drug concentrations is also obtained at the time of the sched-

uled bronchoscopy and BAL procedure.

The recovered BAL fluid is a mixture of saline, ELF and

cellular components of the ELF. In order to determine the anti-

infective drug concentration, the ‘apparent’ volume of ELF

must be estimated. Urea (or albumin or creatinine) has been

commonly used as an endogenous marker to estimate the vol-

ume of ELF.[17] Urea concentrations are normally the same in

plasma and in ELF, since urea is non-polar and has a low

molecular weight that allows it to rapidly diffuse and establish

an equilibrium across the capillary-alveolar membrane. By

measuring the urea in BAL aspirate and plasma, a ratio can be

calculated and the dilution of the apparent volume of ELF can

be estimated (equation 1):

ELF volume¼Volume aspirated � Urea ðBAL aspirateÞ

Urea ðplasmaÞ

(Eq: 1Þ

Using the calculated value of the ELF volume, the drug

concentration in ELF (CELF) can be estimated as follows

(equation 2):

CELF¼Volume of BAL

ELF volume� CBAL (Eq. 2)

where CBAL is the drug concentration measured in BAL.

The techniques of bronchoscopy and BAL are associated

with a low level of technical complexity.[12] However, our re-

view of the literature indicates that the technique for perform-

ing BAL differs among investigators, with the main variations

being the dwell time, the aspiration pressure, the volume of fluid

injected and the number of BAL aspirates collected.[11,15,16,18] In

addition, different assay methodologies and analytical kits are

used to measure urea in BAL and plasma. Each of these vari-

ables may influence the correction for ELF dilution and the

apparent volume of ELF. It has been suggested by some re-

searchers that overestimation of the ELF volume (and thus

underestimation of drug concentrations) can range from 100%to 300%.[9,11,13,16] It has also been suggested that lysis of cells

(e.g. AMs) in the collected BAL fluid increases the measured

concentrations of anti-infective agents in ELF.[12,13,15] Finally,

alterations in the ELF volume, cell counts and protein con-

centrations in BAL have been associated with subjects who

smoke and/or have interstitial lung disease.[19,20] Therefore it isrecommended that a standardized BAL procedure be estab-

lished and used consistently to ensure that technical errors are

minimized and that distal ELF samples are obtained. The as-

says for urea in plasma and BAL need to be precise and reliable.

Subject recruitment needs to be carefully considered in order to

minimize unexpected variability. Accurate understanding of

the methodology and strict adherence to the procedures are

crucial to minimize known sources of error.

Other shortcomings include the difficulty of obtaining

multiple ELF samples from the same subject at several sam-

pling timepoints, because of the nature of the BAL proce-

dure.[12,13] As a result, clinical studies require a larger number of

subjects who are randomized to a single BAL sampling time.

Penetration of Antibacterial Agents into Pulmonary ELF 639


Several studies from Japan have been able to overcome this

issue by using bronchoscopy with bronchoscopic microsampl-

ing (BMS) probes.[21-25] This technique obtains samples of ELF

from the bronchial space (whereas BAL samples are obtained

from the alveolar space) and does not require measurement of

urea concentrations. Differences in methodology and sampling

sites explain, in part, why anti-infective drug concentrations

have not always been similar when BMS and BAL were per-

formed in the same subjects.

1.2 Factors Influencing Penetration of Antimicrobials into

ELF and Comparison with Plasma Concentrations

There are many factors that influence antimicrobial pene-

tration into the pulmonary compartments.[8,9,11-13,15,16] Anti-

infective agents must cross the blood-bronchus barrier to reach

the alveolar ELF and the lung interstitium in order to achieve

adequate concentrations. This barrier is composed of an

alveolar-capillary membrane. The capillary endothelium is re-

latively permeable; however, the alveolar membrane is virtually

impermeable because of the presence of tight junctions. The

major mode of transport between membranes occurs through

passive diffusion. Protein binding determines the amount of the

unbound drug that is present to diffuse through membranes,

explaining why antimicrobials with a high degree of protein

binding do not penetrate well into lung tissue. The degree of

lipophilicity, as well as administration of the drug in an un-

ionized form, determine how well the antimicrobial will pene-

trate tissue.[8,9,11-13,15,16] Other factors that favour penetration

include the pHat the site of infection and other dynamic processes

such as bronchial inflammation at the site of infection.[5,8,11]

Concentrations of anti-infective agents in ELF are con-

sidered to provide useful and accurate estimates for determin-

ing extracellular drug penetration in the lungs. Various methods

have been suggested to compare plasma and ELF concentra-

tions of anti-infective agents. Nearly all studies report com-

parisons of concentrations (e.g. ELF and plasma concentrations)

that were simultaneously obtained at both sites. In fact, that is

how the data are reported in our tables for the various classes of

antibacterial agents. However, since the concentration-time

profiles of drugs in plasma and ELF can increase and decrease

at different paces from each other (known as system hysteresis),

penetration ratios will vary in magnitude with the sampling

time(s) chosen. To overcome this issue, it is recommended that

research studies determine penetration ratios from estimates of

the area under the concentration-time curve (AUC) values of

plasma and ELF data.[26,27] Accurate estimates of the AUC can

be obtained even when drug concentrations are only sparsely

sampled. Where ratios based on AUC estimates have been re-

ported, we have incorporated them into the text of our review.

1.3 Pharmacokinetic-Pharmacodynamic Parameters

of Efficacy

Our knowledge and understanding of the pharmacokinetic-

pharmacodynamic parameters of anti-infective agents have

grown substantially over the past 30 years.[2-4]Application of these

parameters has had a major influence on the dose selection, the

dosing interval and/or mode of administration, development of

in vivo susceptibility breakpoint determinations, assessment of

bacterial resistance and the clinical drug development process.

This information has had an impact on how anti-infective agents

are used at the bedside and developed in research.

Pharmacokinetic-pharmacodynamic parameters that cor-

relate with the efficacy of specific anti-infective agents include

(i) the percentage of time during which unbound (free) drug

concentrations remain above the MIC of an infecting micro-

organism (fT>MIC) [in the case of b-lactams (e.g. penicillins,

cephalosporins, carbapenems, monobactams), linezolid or ori-

tavancin];[2-4,7] (ii) the ratio of the maximum unbound con-

centration (fCmax) to the MIC of an infecting micro-organism

(fCmax/MIC) [in the case of aminoglycosides, fluoroquinolones,

daptomycin, oritavancin ormetronidazole];[2-4,7] and (iii) the ratio

of the unbound AUC during a 24-hour time period (fAUC24)

to the MIC of an infecting micro-organism (fAUC24/MIC) [in

the case of fluoroquinolones, aminoglycosides, azithromycin,

clarithromycin, telithromycin, doxycycline, tigecycline, van-

comycin, daptomycin, telavancin, linezolid, clindamycin or

quinupristin/dalfopristin].[2-4,6,7]

The concepts and categorization of the pharmacokinetic-

pharmacodynamic parameters of anti-infective agents have

been based on relationships established from plasma or serum

concentrations.[2-4] We are unaware of any clinical studies that

have evaluated and documented similar correlations with con-

centrations at the site of infection (e.g. ELF) for community- or

hospital-acquired lower respiratory tract infections.[6,7] While

many of the reports that are included in this review have de-

scribed pharmacokinetic-pharmacodynamic parameters by

using ELF concentration-time data, caution must be applied in

presuming that the magnitude of exposure required in ELF

and/or the relationship between parameters and outcomes are

the same or even similar to those observed in plasma. Studies

are needed in patients with lower respiratory tract infections to

confirm and explore the relationships between ELF con-

centrations, clinical and microbiological outcomes, and phar-

macodynamic parameters.

640 Rodvold et al.


2. b-Lactams

Intrapulmonary penetration studies have been conducted with

b-lactam agents since the early 1990s. Oral and intravenous

cephalosporins have accounted for the majority of these studies

(tables I and II).[28-41] b-lactam–b-lactamase inhibitor combina-

tions (e.g. amoxicillin/clavulanic acid, piperacillin/tazobactam)

have been evaluated for the penicillin class. Several carbapenem

agents (e.g. meropenem, ertapenem, biapenam) have been studied.

NoELF data have been reported for themonobactam aztreonam.

2.1 Oral Penicillins and Cephalosporins

Intrapulmonary studies of oral penicillins and cephalo-

sporins have usually been conducted after a single oral dose

(table I). The concentrations of amoxicillin and clavulanic acid

in ELFwere found to be similar to each other (mean values 0.89

and 0.96 mg/mL, respectively); however, these values were less

than 20% of the total plasma concentrations.[28] The con-

centrations of oral cephalosporins in ELF were commonly

observed to be less than 1 mg/mL and were often reported as

Table I. Plasma and epithelial lining fluid (ELF) concentrations of oral penicillins and cephalosporins

Antibacterial agent Dosage regimen Subjects

(n)

Sampling time (h)a Plasma concentration

(mg/mL)bELF concentration

(mg/mL)bELF/plasma

penetration ratiob

Reference

Amoxicillin/clavulanic acid

(AMO/CLA)

500 mg

AMO + 250 mg

CLA · 1 dose

15 1–2 AMO: 6.90 [1.2–9.8]c AMO: 0.89 [0–3.48]c,d NR 28

CLA: 5.25 [0.7–9.95]c CLA: 0.96 [0–8.36]c,d NR

Cefuroxime axetil 500 mg · 1 dose 14 0.9–6.8e 3.9 – 0.5 0.7 – 0.2 0.15 29

500 mg · 1 dose 4 6 1.1 – 0.3 <LLQ NA 30

4 12 0.06 – 0.12 <LLQ NA

4 24 <LLQ <LLQ NA

Cefpodoxime

proxetil

200 mg · 1 dosef 6 3 1.85 – 0.82 0.22 – 0.13 0.108 – 0.044 31

6 6 1.40 – 1.25 0.12 – 0.14 0.0605 – 0.0479

Ceftibuten 400 mg · 1 dose 7 1.9 [1.38–2.67]g 15.2 [2.4–23.2]g 1.6 [0–2.8]g 0.13 32

4 6.5 [4.08–8.08]g 14.0 [7.8–17.6]g 1.6 [0.76–2.1]g 0.12

3 13.3 [12.25–15.0]g,h 4.1 [2.5–5.6]g,h 1.2 [0.4–2.2]g,h 0.38

Cefdinir 300 mg · 1 dose 9 4 2.0 [1.4–8.0]c 0.29 [0–.4.73]c,i 0.15 [0–.3.26]c,i 33

600 mg · 1 dose 8 4 4.2 [3.05–6.4]c 0.49 [0–.0.59]c 0.12 [0–.0.14]c

Cefaclor 750 mg bid · 7

dosesj

6 4 3.08 – 1.7 2.71 – 0.87 0.88 34

6 6 0.68 – 0.70 2.16 – 1.70 3.2

6 12 0.23 – 0.1 0.6 – 0.3 2.6

Cefditoren 400 mg · 1 dose 8 1.0–2.0k 1.78 – 1.27 0.39 – 0.21 0.381 – 0.501 35

8 2.01–3.0k 1.33 – 0.95 0.34 – 0.25 0.232 – 0.181

8 3.01–4.0k 1.03 – 0.51 0.30 – 0.18 0.318 – 0.192

a Sampling time after the last dose.

b Values are expressed as mean – SD unless specified otherwise.

c Values are expressed as median [range].

d Fourteen ELF samples were measured in 15 patients.

e Values are expressed as range.

f Two tablets of cefpodoxime proxetil (130 mg per tablet; equivalent to 200 mg of cefpodoxime).

g Values are expressed as mean [range].

h Samples at 20.25 h were not included because both plasma and ELF samples were <LLQ.

i Seven ELF samples were measured in nine patients.

j Modified-release formulation.

k Collection interval.

bid = twice daily; LLQ = lower limit of quantification; NA = not applicable; NR = not reported; SD = standard deviation.



undetectable.[29-35,42] The ratios of ELF concentrations to total

plasma concentrations ranged from 0.1 to 0.38, suggesting low

to moderate penetration into the ELF. The exception to this oc-

curred followingmultiple doses of a modified-release formulation

of cefaclor 750mg.[34] The ELF concentrations of cefaclor were

similar to the total plasma concentrations (mean values 2.71 and

3.08mg/mL, respectively, at 4 hours) or exceeded the total plasma

concentrations (mean values 2.16 and 0.68mg/mL, respectively, at

6 hours; and 0.60 and 0.23mg/mL, respectively, at 12 hours).

Several methodological limitations of the intrapulmonary

studies of oral penicillins and cephalosporins should be noted.

Sampling times were often restricted in number and were often

limited to the first few hours after antimicrobial administration,

thus they did not include the entire dosing interval. The ratios of

ELF concentrations to plasma concentrations were based on

concentrations at these specific sampling times as opposed to a

more accurate comparison being made by estimating AUCs for

ELF and plasma. These issues probably contributed to the

large difference between plasma and ELF concentrations,

secondary to system hysteresis (e.g. concentrations in plasma

and ELF often increase and decrease at different paces from

each other). In addition, the ratios of ELF to plasma con-

centrations were based on total (versus unbound) plasma drug

concentrations. Finally, the lower level of detection for mea-

suring drug concentrations was limited, since two-thirds of the

studies used microbiological assays. While a few recent studies

Table II. Plasma and epithelial lining fluid (ELF) concentrations of parenteral penicillins and cephalosporins

Antibacterial

agent

Dosage regimen Subjects

(n)

Sampling

time (h)aPlasma concentration


(mg/mL)bELF/plasma

penetration ratiob

Reference

Piperacillin/tazobactam

(PIP/TAZ)

4 g PIP + 500 mg TAZ IV

0.5 h infusion q8h

10 Steady statec PIP: 24.0 – 13.8 PIP: 13.6 – 9.4 PIP: 0.568 – 0.336 36

TAZ: 2.4 – 1.2 TAZ: 2.1 – 1.1 TAZ: 0.913 – 0.277

Cefpirome 1 g IV 0.5 h infusion · 1 dose 37 0.5–7d 34.5 – 3.3e 7.2 – 1.1e,f 0.359 – 0.074e,f 37

Ceftazidime 1 g IM · 1 dose 5 1 39.89 – 10.42 2.71 – 0.88 NR 38

5 2 36.04 – 9.21 2.66 – 0.64 NR

5 4 13.34 – 4.12 1.32 – 0.64 NR

5 8 6.08 – 1.71 0.66 – 0.36 NR

5 12 1.07 – 0.45 0.12 – 0.15 NR

2 g 0.5 h IV infusion · 1 dose

then continuous IV infusion

of 4 g/d

15 8, 12, 18g 39.6 – 15.2 8.2 – 4.8 0.206 – 0.089 39

Cefepime 2 g IV 0.5 h infusion · 1 dose

then continuous IV infusion

of 4 g/d

7 8g 13.5 – 3.2h 13.7 – 3.0 1.01 40

7 12g 13.7 – 3.5h 13.5 – 3.3 0.99

6 18g 13.3 – 3.6h 14.9 – 2.3 1.12

Ceftobiprole 500 mg IV 2 h infusion

q8h · 4 doses

6 2.5 17.68 – 4.48 2.55 – 0.99 0.255 – 0.366i 41

6 4 12.77 – 2.26 2.00 – 1.07

6 6 6.91 – 4.58 4.58 – 5.82

6 8 3.65 – 1.05 1.51 – 0.39

a Sampling time after the start of the infusion unless specified otherwise.


c Samples were collected at steady state after 2 d of therapy and at 5 h after a dose.

d Values are expressed as range.

e Values are expressed as mean – SEM.

f Eight samples were available.

g Serum and ELF concentrations were sampled after 2 d of therapy at 8, 12 and 18 h during a continuous infusion.

h Twenty concentrations were available at each sampling time.

i The penetration ratio was calculated from AUC values for ELF and plasma.

AUC = area under the concentration-time curve; IM = intramuscularly; IV = intravenous; NR = not reported; q8h = every 8 h; SD = standard deviation;

SEM = standard error of the mean.

642 Rodvold et al.


have overcome most of these limitations, the ELF concentra-

tions of cefuroxime were still undetectable throughout the en-

tire dosing interval, and the percentages of penetration by

ceftibuten and cefdinir into ELFwere still less than 40%.[30,32,33]

2.2 Parenteral Penicillins and Cephalosporins

Intrapulmonary studies of parenteral penicillins and ceph-

alosporins have included a variety of subject types, modes of

drug administration and differences in BAL collection tech-

niques (table II). In critically ill patients with severe nosocomial

pneumonia, three studies have been conducted using micro-

lavage to determine ELF and plasma concentrations of

piperacillin-tazobactam, ceftazidime and cefepime.[36,38,39] The

mean (– standard deviation [SD]) concentrations of piperacillin

and tazobactam following at least 2 days of therapy with an

intravenous dosage regimen of 4 and 0.5 g every 8 hours were

13.6 – 9.4 and 2.1 – 1.1 mg/mL, respectively, which were ap-

proximately 57% and 91%, respectively, of the total plasma

concentrations.[36] The same researchers used a similar study

design and methods to evaluate the intrapulmonary penetra-

tion of ceftazidime and cefepime in critically ill patients re-

ceiving continuous intravenous infusions of 4 g/day.[38,39] Themean (– SD) concentrations of ceftazidime and cefepime were

8.2 – 4.8 and 14.1 – 2.8 mg/mL, respectively. However, the re-

spective ratios of ELF to total plasma concentrations were

0.21 and 1.04. Unlike those of other parenteral cephalosporins

whose ELF to total plasma concentration ratios range between

7% and 36%, the concentrations of cefepime in ELF were

similar to or exceeded the total and unbound plasma con-

centrations (protein binding of cefepime is approximately

20%).[40,43] The discordance in penetration among the par-

enteral cephalosporins does not seem to be related to differ-

ences in structure or protein binding (range 10–20%).

A novel study design was used to evaluate drug exposure in

ELF of ceftobiprole for the treatment of pneumonia caused by

meticillin (methicllin)-resistant Staphylococcus aureus.[41] Pop-

ulation pharmacokinetic modelling of ELF and plasma con-

centrations from both animal and human data were used in

Monte Carlo simulations to evaluate the probabilities of achiev-

ing a desired target attainment based on bacterial killing rates

obtained from a preclinical pneumonia model in neutropenic

mice.[44] For a dosage regimen of ceftobiprole 500mg every

8 hours as a 2-hour intravenous infusion, the probabilities of

achieving 1-log and 2-log cell kill rates were 85.6% and 79.7%,

respectively, over the MIC distribution of 4958 isolates. This

study provided a logical approach for evaluating dosage regi-

mens for the treatment of lower respiratory tract infections,

based on preclinical infection models, the pharmacokinetic-

pharmacodynamic characteristics of the agent being studied

and drug exposure information at the site of infection (e.g. the

lung). In addition, this study allowed differences in ELF pe-

netration in mice versus man (68.8% vs 25.5%) to be accounted

for and dosage selection in humans to be evaluated.[41,44]

2.3 Carbapenems

Single- and multiple-dose studies have evaluated the in-

trapulmonary penetration of meropenem and ertapenem

(table III).[45-48] The mean concentrations of meropenem in

ELF and the penetration ratios ranged from 7.07 to 0.59 mg/mL

and from 0.51 to 1.04, respectively, in 30 subjects administered

a single 1 g dose intravenously over 30 minutes.[45] A similar

range of ELF and plasma concentrations was observed fol-

lowing multiple doses of 1 g every 8 hours in healthy adult

subjects.[46] In both studies, concentrations of meropenem in

ELF at 8 hours were undetectable or extremely low (mean

0.03 mg/mL). While plasma concentrations increased pro-

portionally as doses of meropenem were increased, concentra-

tions in ELF tended to decrease as meropenem doses increased.

The ratios of ELF concentrations to total plasma concentra-

tions ranged from 0.49 to 0.80 for the 500mg dose, from 0.32 to

0.53 for the 1 g dose and from 0.048 to 0.219 for the 2 g dose.[46]

It is unclear why this disproportionate percentage change in

ELF concentrations occurred. In contrast to these findings, a

mean penetration ratio (based on ratios of the AUC) of 0.72%was observed in critically ill patients with ventilator-associated

pneumonia receiving 3-hour infusions of meropenem 2 g ad-

ministered every 8 hours.[49] Subsequently, pharmacokinetic

simulations based on the mean parameter vector of these data

suggested that ELF concentrations of meropenem are main-

tained aboveMICvalues of£1mg/mL for nearly 30%of the dosing

interval.[50] Similar median penetration ratios were observed with

Bayesian parameter estimates of patients with ELF sampling

(0.264) and a 9999-subject Monte Carlo simulation (0.254).

Two studies have evaluated the penetration of ertapenem

into ELF.[47,48] In 15 adult patients undergoing thoracotomy,

the mean ELF concentrations of ertapenem ranged from 2.11

to 4.06 mg/mL during the first 5 hours after a single periopera-

tive dose of 1 g.[47] The mean ratios of ELF concentrations to

total plasma concentrations ranged from 0.062 to 0.094. In

comparison, adult patients treated for early-onset ventilator-

associated pneumonia had median ELF concentrations of

9.4 and 0.3 mg/mL at 1 and 24 hours, respectively, after multiple

doses of ertapenem 1 g once daily.[48] The ratios of ELF con-

centrations to total plasma concentrations ranged from 0.21 to



Table III. Plasma and epithelial lining fluid (ELF) concentrations of carbapenems

Antibacterial

agent

Dosage regimen Subjects (n) Sampling



(mg/mL)bELF/plasma

penetration ratiob

Reference

Meropenem 1 g IV 0.5 h infusion · 1 dose 30c 0.5 25.96 – 22.16 5.04 – 3.33 0.19 – 0.11 45

1 14.98 – 5.30 7.07 – 2.87 0.51 – 0.24

2 12.01 – 3.48 3.86 – 2.74 0.33 – 0.20

4 2.51 – 0.68 2.20 – 2.29 1.04 – 1.20

6 0.57 – 0.27 0.59 – 1.09 0.82 – 1.18

8 0.29 – 0.24 NR NA

500 mg IV 0.5 h infusion

q8h · 4 doses

4 1 10.9 – 1.3 5.3 – 2.5 0.49–0.80d 46

4 2 5.2 – 1.6 2.7 – 1.8

4 3 2.4 – 0.9 1.9 – 0.9

4 5 0.3 – 0.4 0.7 – 0.4

4 8 0.0 – 0.0 0.2 – 0.1

1 g IV 0.5 h infusion q8h · 4

doses

4 1 19.0 – 7.6 7.7 – 3.1 0.32–0.53d

4 2 7.5 – 1.3 4.0 – 1.1

4 3 5.3 – 1.5 1.7 – 1.4

4 5 2.0 – 1.3 0.8 – 0.4

4 8 0.0 – 0.0 0.03 – 0.05

2 g IV 0.5 h infusion q8h · 4

doses

4 1 60.9 – 8.0 2.9 – 1.0 0.048

4 3 12.8 – 2.7 2.8 – 1.5 0.219

Ertapenem 1 g IV 0.5 h infusion · 1 dose 15e 1 63.1 – 16.9 4.06 – 6.64 0.0619 – 0.1100 47

3 39.7 – 15.2 2.59 – 2.33 0.0685 – 0.0645

5 27.2 – 15.5 2.11 – 1.80 0.0940 – 0.1070

1 g IV 1 h infusion q24h 15f 1g 30.3 [27.1–37.8]h,i 9.4 [8.0–10.7]j 0.32 [0.28–0.46]k 48

12g 4.8 [3.9–6.4]h,i 2.0 [1.1–2.5]j

24g 0.8 [0.5–1.2]h,i 0.3 [0.2–0.4]j

Biapenem 300 mg IV 0.5 h infusion · 1

dose

6l 0.5 18.1 – 2.8 3.48 – 1.20 0.20 – 0.08 22

300 mg IV 3 h infusion · 1

dose

3 6.8 – 1.2 1.33 – 0.26 0.20 – 0.06

a Sampling time after the start of the infusion unless specified otherwise.


c Thirty subjects were assigned to one bronchoscopy sampling time (the number of subjects per sampling time was NR).

d Range for all sampling timepoints.

e Fifteen subjects were enrolled, and samples were collected at each sampling time.

f Fifteen subjects were assigned to one bronchoscopy sampling time.

g Samples were collected after 2 d of therapy.

h Unbound serum concentration.

i Values are expressed as median [IQR] for 15 samples.

j Values are expressed as median [IQR] for five samples.

k Values are expressed as median [IQR] for 15 matching sample pairs.

l Each subject received both dosage regimens in a crossover study design.

IQR = interquartile range; IV = intravenous; NA = not applicable; NR = not reported; qxh = every x h; SD = standard deviation.

644 Rodvold et al.


0.64 (median 0.32). Since ertapenem is highly protein bound

(e.g. 96% at 10 mg/mL and 84% at 300 mg/mL), the penetration

ratios in both studies are closer to or greater than 1 if unbound

plasma concentrations are considered.

Kikuchi et al.[22] compared ELF concentrations in six healthy

adult subjects administered a single dose of biapenem 300mg as

0.5-hour and 3-hour intravenous infusions. Themean (– SD)ELF

concentrations were 3.48– 1.20mg/mL at the end of the 0.5-hour

infusion and 1.33– 0.26mg/mL at the end of the 3-hour infusion.

The mean penetration ratios of ELF concentrations to total

plasma concentrations were 0.20 for both infusion periods. These

authors also evaluated a BMS technique, which used a polyester

fibre rod probe to repeatedly obtain ELF concentrations at the

surface of a bronchus (termed ‘bronchial ELF’). In contrast to the

BAL sampling technique, bronchial ELF concentrations were

higher with the 3-hour infusion (4.36– 2.07mg/mL) than with the

0.5-hour infusion (2.35– 1.06mg/mL). No explanations were

provided for the discrepancies between the two techniques.

3. Macrolides, Azalides and Ketolides

Intrapulmonary studies have been commonly conducted for

agents from the antibacterial classes of macrolides, azalides and

ketolides (tables IV–VII).[23,24,30,51-68] The majority of reported

studies have evaluated clarithromycin, azithromycin and teli-

thromycin. Although the number of studies is small, data are

available for older macrolide agents such as erythromycin,

roxithromycin and dirithromycin, as well as the investigational

ketolide cethromycin.

3.1 Erythromycin, Roxithromycin, Dirithromycin and

Modithromycin

Intrapulmonary concentrations of erythromycin were first

reported in 1995 from a multiple-dose study in 12 healthy adult

subjects.[51] The mean (– SD) plasma concentrations and ELF

concentrations at 4 hours after nine doses of oral erythromycin

Table IV. Plasma and epithelial lining fluid (ELF) concentrations of oral erythromycin, roxithromycin, dirithromycin and modithromycin

Antibacterial

agent


(n)

Sampling



(mg/mL)bELF/plasma

penetration ratiob

Reference

Erythromycin 250 mg q6h · 9 doses 4 4 0.7 – 0.2 0.8 – 0.1 NR 51

4 8 0.1 – 0.1 <LLQ

4 12 0.04 – 0.05 <LLQ

Roxithromycin 300 mg q12h · 10

doses

8 2 11.4 – 5.7 2.0 – 1.7c 0.17 52

300 mg q12hd 7 NR 3.74 – 1.16 0.90 – 0.68e NR 53

Dirithromycin 500 mg q24h · 5

doses

5 24 0.44 2.21 5.023 54

5 48 0.31 2.25 7.258

5 72 0.33 1.57 4.758

5 96 0.12 0.22 1.833

5 120 0.11 0.15 1.364

Modithromycin 400 mg · 1 dose 4 2 0.646 – 0.088 16.7 – 3.0 26.3 55

4 4 0.575 – 0.075 13.7 – 4.9 24.8

4 6 0.540 – 0.131 15.1 – 6.6 27.0

4 8 0.441 – 0.070 11.4 – 1.9 25.9

4 10 0.429 – 0.091 10.0 – 3.0 23.2

4 12 0.424 – 0.088 5.8 – 2.0 13.8

4 24 0.315 – 0.116 6.5 – 2.6 21.3


b Values are expressed as mean – SD.

c Two of eight subjects had ELF concentrations <LLQ (<0.2 mg/mL).

d The duration of therapy was 3 mo.

e Five of seven subjects had ELF concentrations <LLQ; a value of 0 was included to determine the mean (– SD).

LLQ = lower limit of quantification; NR = not reported; qxh = every x h; SD = standard deviation.



250mg every 6 hours were similar: 0.7 – 0.2 and 0.8 – 0.1 mg/mL,

respectively. Unfortunately, the two other sampling times

(8 and 12 hours) in this study were outside the dosing interval,

and the concentrations of erythromycin were reported as un-

detectable (assay sensitivity = 0.05 mg/mL). Patients treated

with oral erythromycin 250mg every 6 hours for 28 days had

measurable ELF concentrations at 2, 4 and 8 hours after the last

dose administration.[69] Themean 2-hour ELF concentration of

erythromycin was 0.97 mg/mL, and a similar 4-hour concen-

tration was observed in the healthy subject study.

In eight patients with mild chronic bronchitis treated with

oral roxithromycin 300mg every 12 hours for 5 days, the ELF

concentration (mean –SD 2.0 – 1.7 mg/mL) was only 17% of

the simultaneously measured plasma concentration (mean–SD 8.1 – 4.0 mg/mL).[52] In comparison, the concentration of

roxithromycin in AMs was significantly higher (mean– SD

Table V. Plasma and epithelial lining fluid (ELF) concentrations of oral clarithromycin

Dosage regimen Subjects (n) Sampling time (h)a Plasma concentration


(mg/mL)bELF/plasma

penetration ratiob

Reference

200 mg · 1 dose 5 3 0.36 – 0.07 4.84 – 3.39 14 23

500 mg · 1 dose 4 6 1.0 – 0.6 39.6 – 41.1 NR 30

4 12 0.25 – 0.21 <LLQ NR

4 24 0.07 – 0.05 <LLQ NR

4 48 <LLQ <LLQ NR

500 mg bid · 7 doses 10 4.25 – 0.27c 3.96 – 1.19c 20.46 – 6.7c NR 56

500 mg q12h · 9 doses 3 4 2.2 – 0.9 29.3 – 12.4 NR 51

4 8 2.6 – 0.5 72.1 – 73.0 NR

4 12 0.8 – 0.3 48.6 – 46.8 NR

3 24 0.5 – 0.07 11.9 – 3.6 NR

4 48 0.01 – 0.03 23.4 – 19.2 NR

500 mg q12h · 9 doses 5 4 3.29 – 0.94 34.02 – 5.16 11 57

5 8 1.58 – 0.50 20.36 – 4.49 14

5 12 0.91 – 0.59 23.01 – 11.90 28

5 24 0.19 – 0.09 4.17 – 0.29d 31

500 mg q12h · 9 doses 5 4 2.00 – 0.60 34.5 – 29.3 NR 58

5 8 1.55 – 0.42 26.1 – 7.2 NR

5 12 1.22 – 0.35 15.1 – 11.1 NR

5 24 0.23 – 0.11 4.6 – 3.7 NR

1000 mg q24h · 5 dosese 7 3 1.54 – 0.60 6.38 – 3.92 NR 59

7 6 1.43 – 0.42 6.89 – 4.19 NR

7 9 2.22 – 0.60 11.50 – 6.65 NR

7 12 1.04 – 0.42 7.14 – 7.29 NR

7 24 0.75 – 0.35 6.80 – 3.39f NR

7 48 0.156g 6.08g NR



c Values are expressed as mean – SEM.

d Three of five subjects had concentrations <LLQ.

e The clarithromycin formulation used in this study was an extended-release tablet.

f Five of seven subjects had concentrations <LLQ.

g Six of seven subjects had concentrations <LLQ.

bid = twice daily; LLQ = lower limit of quantification; NR = not reported; qxh = every x h; SD = standard deviation; SEM = standard error of the mean.

646 Rodvold et al.


Table VI. Plasma and epithelial lining fluid (ELF) concentrations of azithromycin




(mg/mL)bELF/plasma

penetration ratio

Reference

500 mg PO · 1 dose 4 12 0.13 – 0.05c NR NR 60

4 24 NR NR NR

4 48 NR 2.18 NR

6 72 NR NR NR

4 96 0.01 NR NR

500 mg PO · 1 dose 4 6 0.13 – 0.07 <LLQ NR 30

4 12 <LLQ <LLQ NR

4 24 <LLQ <LLQ NR

4 48 <LLQ <LLQ NR

4 120 <LLQ <LLQ NR

4 240 <LLQ <LLQ NR

500 mg PO first dose and then

250 mg PO q24h · 4 doses

5 4 0.09 – 0.05 <LLQ NR 57

5 8 0.06 – 0.05d 1.93e NR

5 12 0.04 – 0.02d 1.75e NR

5 24 0.03 – 0.03d <LLQ NR



6 4f 0.178 – 0.05 0.45 – 0.15 NR 61

5 28f 0.122 – 0.055 1.53 – 0.31 NR

5 76f 0.093 – 0.036 2.67 – 0.85 NR

5 124f 0.054 – 0.008 3.12 – 0.93 NR

6 172f 0.031 – 0.055 0.61 – 0.23 NR

6 244f 0.015 – 0.005 <LLQ NR

6 340f <LLQ <LLQ NR

5 508f <LLQ <LLQ NR



5 4 0.08 – 0.05 1.01 – 0.45g NR 58

5 8 0.09 – 0.04 2.18 – 0.25d NR

5 12 0.04 – 0.02 0.95 – 0.40d NR

5 24 0.05 – 0.03 1.22 – 0.59g NR



4 4 0.10 – 0.02 0.64 – 0.35 NR 62

4 8 0.05 – 0.02 0.66 – 0.42 NR

4 12 0.07 – 0.86 0.88 – 0.46 NR

4 24 0.03 – 0.02 0.94 – 0.68 NR

500 mg IV 60 min infusion

q24h · 5 doses

4 4 0.37 – 0.10 1.70 – 0.74 NR 63

4 12 0.25 – 0.04 1.27 – 0.47h NR

4 24 0.14 – 0.04 2.86 – 1.75 NR

a Sampling time after the last dose unless specified otherwise.



d One of five subjects had concentrations <LLQ.

e Four of five subjects had concentrations <LLQ.

f Sampling time after the first dose (500 mg).

g Two of five subjects had concentrations <LLQ.

h One of four subjects had concentrations <LLQ.

IV = intravenous; LLQ = lower limit of quantification; NR = not reported; PO = orally; q24h = every 24h; SD = standard deviation; SEM = standard error of the mean.



21.0– 10.0mg/mL). In a study evaluating the immunoregulatory

effects of roxithromycin in patients with chronic respiratory

tract infections, the ELF concentrations were measurable in

only two of seven patients (1.56 and 4.77 mg/mL) who had re-

ceived 3 months of oral roxithromycin 300mg every 12 hours.[53]

The plasma concentrations in these two patients were 2.55 and

8.78 mg/mL, respectively.

Dirithromycin was one of the first macrolide agents for

which ELF concentrations were reported to be significantly

higher than concurrent plasma concentrations.[54] In 25 patients

Table VII. Plasma and epithelial lining fluid (ELF) concentrations of oral ketolides

Antibacterial agent Dosage regimen Subjects (n) Sampling



(mg/mL)bELF/plasma

penetration ratiob

Reference

Telithromycin 600 mg · 1 dose 5 3 0.36 – 0.19 2.94 – 2.64 NR 24

600 mg od · 5 doses 5 3 0.63 – 0.11 7.51 – 4.54 12 24

600 mg od · 5 doses 6 2 NR 4.91 – 4.00 NR 64

6 8 NR 2.26 – 1.17 NR

800 mg od · 5 doses 6 2 NR 4.24 – 3.14 NR 64

6 8 NR 4.31 – 1.87 NR

800 mg od · 5 doses 7 2 1.86 – 0.31 14.89 – 11.35c 8.57 65

6 12 0.23 – 0.05d 3.27 – 1.68d 13.58

7 24 0.08 – 0.03 0.97 – 0.60c 16.77

800 mg od · 5 doses 6 2 1.97 – 1.64e 5.22 – 2.79 3 66

1 8 0.48 1.09 2

5 12 0.70 – 0.55 3.47 – 3.88 5

5 24 0.14 – 0.06 0.84 – 0.54 7

800 mg od · 5 doses 5 2 1.14f 5.5f NR 67

6 8 0.63f 3.7f 6.4

6 24 0.055f 0.82d,f 12.7

6 48 <0.03 0.17f,g NA

Cethromycin 150 mg od · 5 doses 5 2 0.12 – 0.08 0.9 – 1.0 NR 68

5 4 0.09 – 0.06 0.9 – 0.2 NR

5 8 0.04 – 0.02 0.8 – 0.5 NR

5 12 0.02 – 0.01 0.3 – 0.3 NR

5 24 0.01 – 0.11 0.1 – 0.1 NR

300 mg od · 5 doses 5 2 0.25 – 0.15 2.5 – 1.6 NR 68

5 4 0.38 – 0.21 2.7 – 2.0 NR

5 6 0.18 – 0.07 1.6 – 0.8 NR

5 8 0.09 – 0.03 0.9 – 0.8 NR

5 12 0.10 – 0.06 0.8 – 0.4 NR

5 24 0.01 – 0.01 0.1 – 0.1 NR

5 48 0.00 – 0.00 0.0 – 0.0 NR



c One of seven subjects had concentrations <LLQ.

d One of six subjects had concentrations <LLQ.

e Five of six subjects had plasma samples available.

f Values are expressed as median.

g Three of six subjects had concentrations <LLQ.

LLQ = lower limit of quantification; NA = not applicable; NR = not reported; od = once daily; SD = standard deviation.

648 Rodvold et al.


treated for acute exacerbation of chronic bronchitis, the mean

ELF concentrations during the first 24–72 hours after five oral

doses of dirithromycin 500mg once daily ranged from 1.57

to 2.25 mg/mL. Subsequent mean ELF concentrations were

0.22 mg/mL at 96 hours and 0.15 mg/mL at 120 hours. In com-

parison, the mean plasma concentrations ranged from

0.44 mg/mL at 24 hours to 0.11 mg/mL at 120 hours. A similar

range of ELF concentrations was observed between 2 and

24 hours (approximately 2.37 mg/mL) after the last oral dose of

dirithromycin 500mg once daily in 20 patients treated for acute

exacerbation of mild chronic obstructive pulmonary disease.[69]

The investigational bridged bicyclic macrolide (bicyclolide)

modithromycin (also known as S-013420 and EDP-420) has

recently been studied in healthy Japanese subjects.[55] Follow-

ing a single oral dose of 400mg, the mean concentrations

of modithromycin in ELF between 2 and 24 hours ranged from

5.8 to 16.7 mg/mL. The mean plasma concentrations during this

same time period ranged from 0.315 to 0.646 mg/mL. As with

other newer agents, themean concentrations ofmodithromycin

in AMs (range 61–176 mg/mL) were well above those observed

in plasma and ELF.

3.2 Clarithromycin

Two single-dose studies of clarithromycin have suggested

that ELF concentrations are measurable only within the first

6 hours after administration of oral doses of 200 and 500mg

(table V).[23,30] Four multiple-dose studies of the immediate-

release formulation of clarithromycin have reported plasma

and intrapulmonary concentrations following the oral dosage

regimen of 500mg twice daily.[51,56-58] Themean concentrations

of clarithromycin in ELF ranged between 20.46 and 32.4 mg/mL

at 4 hours and between 15.1 and 48.6 mg/mLat 12 hours. Plasma

concentrations were 10- to 60-fold lower and ranged between

2.0 and 3.96 mg/mL at 4 hours and between 0.8 and 1.22 mg/mL

at 12 hours. The reported concentrations were fairly consistent

between studies. Plasma and ELF concentrations of the active

metabolite, 14-hydroxy-clarithromycin, were also reported in

two studies. Concentrations of 14-hydroxy-clarithromycin in

ELF (range 1.2–15.09 mg/mL) were greater than concurrent

plasma concentrations (0.4–6.41mg/mL), but the difference (1.1-

to 7.45-fold) was less than that observed with clarithromycin.

One study evaluated the intrapulmonary disposition of the

extended-release formulation of clarithromycin 1000mg once

daily.[59] Following five doses, the mean concentrations in ELF

were 11.50 mg/mL at 9 hours and 6.80 mg/mL at 24 hours, and

they remained constant throughout the 24-hour dosing inter-

val. The mean plasma concentrations were 2.22 mg/mL at

9 hours and 0.75 mg/mL at 24 hours. The concentrations of

clarithromycin in AMs ranged between 43 and 1087 mg/mL

(mean 303 mg/mL) andwere comparable to values reportedwith

the immediate-release formulation of clarithromycin. Maximum

concentration (Cmax) values in plasma, ELF andAMsoccurred at

9 hours with the extended-release formulation, which was later

than with the immediate-release formulation.

In vitro and in vivo murine pharmacodynamic models have

made use of clinically observed plasma andELF concentrations

to evaluate the bactericidal activity and/or postantibacterial

effect of clarithromycin against isolates ofH. influenzae and/orS. pneumoniae.[70-73] In addition,Monte Carlo simulations have

been used to assess the ability of pharmacodynamic parameters

(e.g. an AUC/MIC ratio of ‡25) to determine susceptibility

breakpoints and target attainment rates against penicillin-

susceptible and -resistant strains of S. pneumoniae.[74,75] Over-

all, these studies support the concept that the higher concen-

trations of clarithromycin in ELF contribute to the potential

efficacy of clarithromycin against S. pneumoniae strains with

MIC values up to 8 mg/mL.

3.3 Azithromycin

Six studies (two single-dose studies and four multiple-dose

studies) have evaluated the intrapulmonary disposition of oral

azithromycin (table VI). Interestingly, the single-dose studies

provided minimal information, since most plasma and ELF

samples had undetectable concentrations.[30,60] The multiple-

dose studies indicated that the mean ELF concentrations

ranged between 0.64 and 3.12 mg/mL during the first 24 hours

after the last dose of the standard oral dosing regimen of azi-

thromycin.[57,58,61,62] The concentrations of azithromycin in

ELF were fairly stable and demonstrated minimal fluctuations

throughout the 24-hour dosing interval. The mean plasma

concentrations during this same time period ranged from 0.03

to 0.1 mg/mL. No study has reported ELF to plasma concen-

tration ratios. However, the ELF concentrations were ap-

proximately 10- to 20-fold higher than the concurrent plasma

concentrations.

Single oral doses of azithromycin in the immediate-release

and extended-release formulations were compared in 64 pa-

tients who had been diagnosed with lung cancer and required

open-chest surgery for lung resection.[76] For the immediate-

release formulation, a single 500mg dose resulted in AUC from

0 to 24 hours (AUC24) values in serum and ELF of 3.1 and

2.3mg�h/mL, respectively. Following a 2g dose of the extended-

release formulation, the AUC24 values in serum and ELF were

10.0 and 17.6 mg�h/mL, respectively. Higher exposure was also



observed in AMs and whole lung tissues with the extended-

release formulation.

Only one study has reported plasma and ELF concentra-

tions following multiple intravenous doses of azithromycin

500mg once daily.[63] The plasma concentrations at the time of

bronchoscopy were comparable (range 0.09–0.49 mg/mL) to

those associated with oral dosing once the differences in the

dose and oral bioavailability were taken into account. Con-

centrations in ELF ranged from 0.79 to 5.86 mg/mL and were

slightly higher than the values associated with oral dosing. The

estimated AUC24 of azithromycin in ELF (45.8 mg�h/mL) was

approximately 5.6-fold higher than the AUC24 in plasma

(8.2 mg�h/mL) following intravenous dosing.

The observed azithromycin concentrations in ELF and

plasma have been used to investigate in vitro bactericidal ac-

tivity and pharmacodynamic target attainment rates against

clinical isolates of S. pneumoniae and H. influenzae. In ELF,

azithromycin demonstrated greater potency, killing rates and

postantibacterial effects than clarithromycin against H. influ-

enzae and tended to be adequate for eradication of macrolide-

susceptible S. pneumoniae (suggested susceptibility breakpoint

£2mg/mL).[73,74,77-80] The probability of achieving target attainment

rates was lower with azithromycin than with clarithromycin.[74]

3.4 Ketolides

Several intrapulmonary studies have reported ELF con-

centrations for oral telithromycin dosage regimens of 600 and

800mg once daily (table VII).[24,64-68] Like clarithromycin and

azithromycin, telithromycin achieves higher and sustained ex-

tracellular concentrations (2- to 17-fold) in ELF than in plas-

ma. The mean ELF concentrations following telithromycin

800mg once daily for 5 days were approximately 5.0 and

0.9mg/mL at 2 hours and 24 hours, respectively. The total plasma

concentrations at these same sampling times averaged 1.9 and

0.1 mg/mL, respectively. The reported mean ratios for ELF to

total plasma concentrations at individual sampling times

ranged from 2 to 14.9. A mean penetration ratio of 7.95 (with

AUC values of 83.73 and 10.53 mg�h/mL for ELF and plasma,

respectively) has been reported, based on a population phar-

macokinetic analysis and a 10 000-subject Monte Carlo simu-

lation.[81] These ratios would be greater if unbound plasma

concentrations are considered (telithromycin plasma protein

binding: 60–70%). Intracellular concentrations of telithromycin

are even higher in AMs than in ELF and can range from 50- to

>500-fold greater than total plasma concentrations.[64-67]

For the investigational ketolide antibacterial cethromycin,

the ELF concentrations between 2 and 24 hours ranged from

0.1 to 0.9 mg/mL after the 150mg once-daily dosage regimen

and from 0.1 to 2.7 mg/mL after the 300mg once-daily dosage

regimen (table VII).[68] In comparison, the plasma concentra-

tions were approximately 10-fold lower than the ELF concen-

trations, whereas the AM concentrations were 10-fold higher

than the ELF concentrations.

Several pharmacodynamic studies have evaluated the in vitro

activity and target attainment potential of telithromycin against

pathogens commonly associated with community-acquired pneu-

monia (e.g. macrolide-susceptible and -resistant S. pneumoniae,

and b-lactamase-positive and -negative H. influenzae).[73,82-85]

Using simulated total and unbound serum and ELF concen-

trations of telithromycin, these studies have provided recom-

mendations for potential pharmacokinetic-pharmacodynamic

parameter values of the Cmax/MIC and AUC24/MIC ratios

associated with bacteriostatic and bactericidal activity, as

well as no regrowth of telithromycin-susceptible bacteria over

24–48 hours.[73,82,83]

4. Fluoroquinolones

Most fluoroquinolones that have been developed during the

past 25 years have been studied to determine the degree of lung

penetration. Ciprofloxacin, moxifloxacin and levofloxacin are

currently the most commonly recommended fluoroquinolones

for the treatment of lower respiratory tract infections.With that

in mind, our review focuses on intrapulmonary penetration

studies of those three fluoroquinolones only. However, a list of

references has been provided for those readers who have an

interest in similar studies of other fluoroquinolones.[86-100]

4.1 Ciprofloxacin

Several single- and multiple-dose studies have evaluated in-

trapulmonary penetration of oral ciprofloxacin in healthy adult

subjects and patients undergoing diagnostic bronchoscopy

(table VIII).[96,98-101] The concentration-time profile following

a single oral dose of 500mg suggests that ciprofloxacin does not

achieve adequate ELF concentrations throughout the dosing

interval. Although the mean plasma and ELF concentrations

were similar (2.33 and 2.13 mg/mL, respectively) at 2.5 hours,

subsequent ELF concentrations (range 5–48 hours) were below

the lower limit of quantification (LLQ).[99,100] When multiple

oral doses of ciprofloxacin 500mg were administered every

12 hours, the mean concentrations were slightly lower in ELF

than in plasma throughout the dosing interval (2.11 vs 1.87mg/mL

at 4 hours and 0.55 vs 0.41 mg/mL at 12 hours).[101] Two studies

that measured ELF concentrations of ciprofloxacin between

650 Rodvold et al.


3 and 6 hours after multiple doses of an oral regimen of 250mg

every 12 hours reported that ELF concentrations (2.0 and

3.0 mg/mL at 3 and 6 hours, respectively) were higher than

concurrent plasma concentrations (1.1 and 1.19 mg/mL at 3 and

6 hours, respectively).[96,98]

4.2 Moxifloxacin

Concentrations of moxifloxacin in ELF have been reported

in two studies involving oral administration (table VIII).[62,102]

After a single oral dose of moxifloxacin 400mg, the mean

concentrations in ELF ranged from 20.7 mg/mL at 2.2 hours

to 3.57 mg/mL at 24.1 hours.[102] The mean ratios of ELF

concentrations to total plasma concentrations ranged from

5.19 to 6.95. Similarly, after multiple oral doses of moxifloxacin

400mg every 24 hours in older adult subjects (mean age

67 – 10 years), the mean plasma concentrations ranged from

3.23 mg/mL at 4 hours to 0.78 mg/mL at 24 hours and the mean

ELF concentrations ranged from 11.66 mg/mL at 4 hours to

5.71 mg/mL at 24 hours.[62] Even if protein binding (approxi-

mately 50%) is taken into account, ELF concentrations remain

2.5- to 3.5-fold higher than unbound plasma concentrations

throughout a 24-hour dosing interval. A recent study using a

Calu-3 lung epithelial cell model suggested that P-glycoprotein-

mediated active transport mechanisms influence the secre-

tion of moxifloxacin into the lung and may explain, in part,

why higher concentrations are observed in ELF than in

plasma.[103]

Table VIII. Plasma and epithelial lining fluid (ELF) concentrations of oral ciprofloxacin and moxifloxacin

Antibacterial

agent


(n)

Sampling time

(h)aPlasma concentration


(mg/mL)bELF/plasma

penetration ratiob

Reference

Ciprofloxacin 250 mg bid · 4 d 11 3–6c 1.1 – 0.2d 2.0 – 1.7d 1.85 – 0.47d 96

250 mg bid · 4 d 13 3–6c 1.19 – 0.16d 3.0 – 1.05d 2.13 – 0.5d 98

500 mg · 1 dose 4 6 0.95 – 0.32 <LLQ NA 99

4 12 0.23 – 0.07 <LLQ NA

4 24 0.03 – 0.01 <LLQ NA

4 48 <LLQ <LLQ NA

500 mg · 1 dose 5 2.5 2.33e 2.13e,f NR 100

5 5 1.13e <LLQ NA

5 12 0.43e <LLQf NA

500 mg q12h · 9

doses

4 4 2.11 – 0.35 1.87 – 0.91 NR 101

4 12 0.55 – 0.09 0.41 – 0.10 NR

4 24 0.08 – 0.03 <LLQ NA

Moxifloxacin 400 mg · 1 dose 19g 2.2 3.22 – 1.25 20.7 – 1.92 6.78 – 2.29 102

11.8 1.14 – 1.42 5.90 – 2.20 5.19 – 1.90

24.1 0.51 – 1.19 3.57 – 1.58 6.95 – 1.43

400 mg q24h · 5

doses

4 4 3.23 – 0.88 11.66 – 11.86 NR 62

4 8 2.21 – 0.59 7.80 – 5.08 NR

4 12 1.68 – 0.53 10.52 – 3.66 NR

4 24 0.78 – 0.39 5.71 – 6.28 NR



c Values are expressed as range.

d Values are expressed as mean – SEM.

e Values are expressed as median.

f Values measured in four subjects.

g A total of 19 subjects were studied, but information on how many subjects were assigned to each sampling time was not provided in the study.

bid = twice daily; LLQ = lower limit of quantification; NA = not applicable; NR = not reported; qxh = every x h; SD = standard deviation; SEM = standard error of

the mean.



The intrapulmonary data generated from these two studies

have been used in numerous evaluations to compare the

pharmacodynamic characteristics of moxifloxacin with those

of other antibacterial agents that are commonly used in lower

respiratory tract infections.[77,79,104-110] Most investigations

have used simulated plasma and ELF concentrations in vivo

to link in vitro bactericidal killing activity, eradication rates

against various genotypes and/or resistant patterns of

S. pneumoniae and S. aureus, prevention of selection or emer-

gence of resistance, and achievement of AUC/MIC target at-

tainment rates. These studies have provided further support for

the concept that ELF concentrations contribute to the efficacy

of moxifloxacin against pathogens associated with lower res-

piratory tract infections.

4.3 Levofloxacin

Concentrations of levofloxacin in ELF have been in-

vestigated extensively (table IX).[25,62,63,101,111-115] Studies have

included single and multiple doses of levofloxacin administered

both orally and intravenously at a wide range of dosages (e.g.

100–1000mg). The individuals who were studied included

healthy adult subjects, patients undergoing diagnostic fibre-

optic bronchoscopy, critically ill patients with severe community-

acquired pneumonia and outpatients with a clinical diagnosis of

mild to moderate chronic bronchitis, chronic obstructive pul-

monary disease or lower respiratory tract infection.

Eleven of 13 studies used plasma and ELF sampling over a

24-hour interval.[62,63,101,111-115] The mean ratios of ELF con-

centrations to total plasma concentrations at individual sam-

pling times ranged from 1.0 to 4.9 when the samples were

obtained between 4 and 24 hours after dosing. Several studies

reported AUC24 values in plasma and in ELF. For the

500mg dose, the mean AUC24 values ranged from 34.5 to

180 mg�h/mL in ELF, compared with 50.1–86.7 mg�h/mL in

plasma.[62,63,112] For the 750mg dose, the mean AUC24 values

in ELF and in plasma were 151.4 and 95.4 mg�h/mL, respec-

tively.[63] A 1000mg dose resulted in mean AUC24 values of

260–279.1 mg�h/mL in ELF and 103.6–130 mg�h/mL in plas-

ma.[114,115] The ratios of ELF concentrations to plasma con-

centrations that were estimated from these AUC values ranged

from 1.59 to 2.69.

Drusano et al.[116] performed population pharmacokinetic

modelling and Monte Carlo simulations based on steady-state

concentrations in plasma and ELF after oral doses of levo-

floxacin 500 and 750mg were administered to healthy adult

subjects. The penetration ratio based on the AUC values in

ELF and in plasma, derived from the mean parameter vector,

was 1.16. The mean and median ratios were 3.18 (SD 5.71) and

1.43 (95% confidence interval [CI] 0.143, 19.12), respectively,

when calculations were based on 1000-subject Monte Carlo

simulations. The penetration ratio was greater than 1 in 61% of

simulations.

Other investigators have also evaluated pharmacodynamic

target attainment rates using estimates of ELF concentrations

of levofloxacin in hospitalized patients with community-

acquired pneumonia and in a murine pneumonia model of

Pseudomonas aeruginosa infection.[117,118]

5. Aminoglycosides

Aminoglycosides such as gentamicin, tobramycin and ne-

tilmicin are most often used intravenously or via inhalation for

the treatment of serious respiratory infections involving Gram-

negative organisms. Aminoglycosides are known for poor lung

penetration and varied concentrations in the lung tissue de-

pending on the anatomical site that is sampled. Intrapulmonary

penetration and ELF concentrations of aminoglycosides in

critically ill patients with lower respiratory tract infections have

been evaluated following intravenous and intramuscular ad-

ministration of single and multiple doses (table X).[119-124]

Sampling of ELF concentrations in aminoglycoside studies

has been limited to the first 8 hours after drug administration,

and no estimation of exposure throughout the dosing interval

has been provided. In general, concentrations of aminoglyco-

sides in ELF are significantly lower than plasma concentrations

during the first 1.5 hours after administration. Subsequently,

the concentrations in ELF become similar to those in plasma at

approximately 2 or 3 hours after administration. For example,

the mean concentrations of tobramycin in ELF were 2.7 mg/mL

(approximately 12% of the plasma concentration [22.4 mg/mL])

at 0.5 hours following a 30-minute intravenous infusion of

7–10mg/kg.[122] Similar ELF concentrations (e.g. <3 mg/mL)

were observed at 1 hour after a single dose of gentamicin 240mg

(mean– SD 3.5 – 0.1mg/kg) and during the first 2 hours of

adjusted doses of tobramycin.[119,121] Although the mean con-

centrations of netilmicin in ELF were higher at 1 and 1.5 hours

(7.5 and 9.6 mg/mL, respectively) after a single dose of 450mg,

these ELF concentrations were only 35% and 62% of the con-

current mean plasma concentrations (21.4 and 15.3 mg/mL,

respectively).[124] Once the Cmax values of gentamicin and ne-

tilmicin in ELF occurred at 2 hours (4.24 and 14.7 mg/mL, re-

spectively), the ELF to plasma concentration ratios were 0.85

and >1, respectively.[119,124] Subsequently, ELF and plasma

concentrations of the aminoglycosides became similar to each

other. Thus system hysteresis has greatly influenced the large

652 Rodvold et al.


Table IX. Plasma and epithelial lining fluid (ELF) concentrations of levofloxacin




(mg/mL)bELF/plasma

penetration ratiob

Reference

100 mg PO · 1 dose 5 2 NR 1.41 – 0.32 NA 25

500 mg PO · 1 dose 35c 0.5 4.73 4.74 1.0 111

1 6.6 10.8 1.7

2 4.9 9.0 0.8

4 4.1 10.9 3.0

6–8d 4.0 10.1 2.7

12–24d 1.2 NR NA

500 mg PO · 1 dose 8 1 3.34 – 3.00 3.44 – 3.69 0.788 112

8 4 4.06 – 1.90 2.35 – 1.97 NR

8 8 2.12 – 1.11 1.64 – 1.51 NR

8 12 1.90 – 0.64 0.95 – 0.93 NR

8 24 0.93 – 0.61 0.87 – 0.72 1.043

500 mg PO q24h · 5 doses 4 4 5.29 – 1.23 9.94 – 2.74 NR 101

4 12 3.07 – 0.93 6.46 – 2.48 NR

4 24 0.60 – 0.10 0.70 – 0.40 NR

500 mg PO q24h · 5 doses 4 4 5.08 – 2.31 15.23 – 4.53 NR 62

3 8 4.37 – 0.71 10.18 – 6,74 NR

4 12 4.60 – 4.58 6.85 – 4.36 NR

4 24 1.52 – 1.42 2.94 – 1.74 NR

500 mg IV 1 h infusion q24h · 5 doses 4 4 4.74 – 1.37 11.01 – 4.52 NR 63

4 12 1.63 – 0.59 2.50 – 0.97 NR

4 24 0.48 – 0.16 1.24 – 0.55 NR

500 mg IV 1 h infusion q24h 12e 1 12.6f,g 11.9f,g 1.31 – 0.31 113

24 3.0f,g 3.9f,g 1.18 – 0.36

500 mg IV 1 h infusion q12h 12e 1 19.7f,g 17.8f,g 1.27 – 0.46 113

12 7.7f,g 11.8f,g 1.12 – 0.40

750 mg PO q24h · 5 doses 4 4 11.98 – 2.99 22.12 – 14.92 NR 101

4 12 4.06 – 0.51 9.17 – 5.34 NR

4 24 1.69 – 1.14 1.45 – 0.75 NR

750 mg IV 1.5 h infusion q24h · 5 doses 4 4 6.55 – 1.65 12.94 – 0.74 NR 63

4 12 3.52 – 0.77 6.04 – 0.47h NR

4 24 0.84 – 0.20 1.73 – 0.78 NR

750 mg IV 2 h infusion q24h · 3 doses 4 4 5.7 – 0.4 28.0 – 23.6 4.9 114


4 4 7.5 – 1.4 24.8 – 10.2 NR

4 8 6.0 – 1.1 15.7 – 4.5 NR

4 12 4.8 – 1.7 9.6 – 4.7 2.0

4 24 1.2 – 0.4 4.3 – 1.8 3.6

Continued next page



variability associated with reported ELF to plasma penetration

ratios that have been observed in the limited number of in-

trapulmonary studies.

6. Glycopeptides and Lipoglycopeptides

6.1 Vancomycin

Vancomycin has been used for over 50 years to treat serious

Gram-positive infections, including meticllin-resistant S. aureus.

A great deal of attention has recently been paid to appropriate

dosing of vancomycin, particularly in lower respiratory tract

infections.[125,126] However, only a limited number of studies have

evaluated ELF concentrations of vancomycin and assessed its

plasma and intrapulmonary disposition (table XI).[127-131]

Lamer et al.[127] investigated plasma and ELF concentra-

tions of vancomycin in 14 critically ill adult patients (mean–SD Acute Physiology and Chronic Health Evaluation II

[APACHE II] score 18.7 – 6) who were mechanically ventilated

and had signs and symptoms of lower respiratory tract infection.

The patients received an initial dose of intravenous vancomycin

15mg/kg, and subsequent doses were adjusted to achieve a

trough plasma concentration between 15 and 20 mg/mL. Blood

and BAL samples were collected at an average of 6.6 days

(range 5–11 days) after starting treatment with a cumulative

dose of 9.4 g (range 3–17.5 g). Concentrations of vancomycin in

ELF ranged from 0.4 to 8.1 mg/mL, and a significant linear

correlation (r = 0.64; p< 0.02) was observed between plasma

and ELF concentrations. Patients with lung inflammation

(ELF albumin concentration ‡3.4mg/mL; n= 7) had a sig-

nificantly higher (p < 0.02) vancomycin ELF to plasma con-

centration ratio (mean 0.246; range 0.192–0.426) than patients

without inflammation (mean 0.14; range 0.023–0.285) and a

normal ELF albumin concentration (<3.4mg/mL; n= 7).

Georges et al.[128] also evaluated vancomycin plasma and ELF

concentrations in ten critically ill adult patients (mean–SD age

65.5– 8.4 years) with meticillin-resistant S. aureus pneumonia re-

quiringmechanical ventilation. Plasma andELFconcentrations of

vancomycin were measured 24 hours after starting intravenous

vancomycin 7.5mg/kg every 6 hours, infused over 1 hour. Four of

ten patients hadmeasurable concentrations of vancomycin in ELF

(range 1.38–2.77mg/mL), and the concomitant trough plasma

concentrations ranged from 20.9 to 23.2mg/mL. In the six patients

with undetectable concentrations of vancomycin in ELF, the

trough plasma concentrations ranged from 7.7 to 18.1mg/mL. The

authors of both studies[127,128] recommended that trough plasma

concentrations of vancomycin should be approximately 20mg/mL

to ensure that adequate ELF concentrations are achieved.

Plasma and intrapulmonary concentrations of vancomycin

in ten healthy adult subjects were measured at 4 and 12 hours

after the start of the ninth dose of intravenous vancomycin

1000mg every 12 hours (tableXI).[129] In addition, a population

pharmacokinetic analysis and Monte Carlo simulations were

conducted.[132] The ratio of ELF to total plasma concentrations

was 0.5, based upon AUC values for each matrix. If protein

binding of vancomycin in healthy adult subjects is assumed to

be approximately 50%, ELF and unbound plasma vancomycin

concentrations were essentially of the same magnitude.

An in vitro model evaluated the effects of simulated ELF

concentrations and penetration ratios on bacterial killing of

Table IX. Contd




(mg/mL)bELF/plasma

penetration ratiob

Reference


4 8 8.1 – 1.6 10.5 – 4.3 NR

4 12 4.1 – 0.8 9.4 – 3.8 NR

4 24 2.0 – 0.4 2.8 – 1.0 NR

a Sampling time after the last dose or after the start of the last IV infusion, as applicable.


c A total of 35 subjects were studied, but information on how many subjects were assigned to each sampling time was not provided in the study.

d Values are expressed as range.

e 12 subjects had two bronchoscopies after administration of the final dose (e.g. at 1 h and 12 h or at 1 h and 24 h).

f Samples were collected after 2 d of therapy.

g Values are expressed as median.

h One of four subjects had concentrations <LLQ.

IV = intravenous; LLQ = lower limit of quantification; NA = not applicable; NR = not reported; PO = orally; qxh = every x h; SD = standard deviation.

654 Rodvold et al.


meticillin-resistant S. aureus and development of resistance.[133]

Bactericidal activity could not be demonstrated for dosage re-

gimens that achieved an unbound AUC24/MIC ratio of 350

with a penetration ratio of 1.0. Development of resistance was

suppressedwhen the unboundAUC24/MIC ratiowas ‡280witha penetration ratio of ‡0.8. These findings suggest that currentdosage regimens, which recommend trough plasma vancomy-

cin concentrations of 15–20 mg/mL, are not adequate for bac-

tericidal activity, even when the ELF penetration ratio is equal

to 1.0. Development of resistance (e.g. heterogeneous) is likely

to occur ifMIC values are >1 mg/mL, the unboundAUC24/MIC

ratio is <280 and/or the ELF penetration ratio is <0.8.

6.2 Teicoplanin

Teicoplanin is another glycopeptide that is commercially

available in many countries other than the US. One study

compared steady-state serum and ELF concentrations of in-

travenous teicoplanin in 13 critically ill patients with ventilator-

associated pneumonia who received 12mg/kg twice daily for

2 days followed by 12mg/kg once daily (table XI).[130] The total

and unbound serum concentrations ranged from 8.8 to

29.9 mg/mL and from 2.0 to 5.4 mg/mL, respectively. The con-

centrations of teicoplanin in ELF ranged from 2.0 to

11.8 mg/mL, and the ratio of ELF to unbound serum con-

centrations ranged from 0.48 to 3.32 (median 1.46).

6.3 Telavancin

Telavancin is a lipoglycopeptide developed for the treatment

of serious Gram-positive infections, including meticillin-

resistant S. aureus. Steady-state plasma and intrapulmonary

concentrations of telavancin were evaluated in 20 healthy adult

subjects who were administrated 10mg/kg intravenously once

daily for 3 days (table XI).[131] The mean concentrations of

telavancin in ELF at 8 and 24 hours after the last dose were 3.73

and 0.89 mg/mL, respectively. The mean plasma concentrations

at 12 and 24 hours were 22.9 and 7.28 mg/mL, respectively.

Table X. Plasma and epithelial lining fluid (ELF) concentrations of aminoglycosides

Antibacterial

agent


(n)

Sampling



(mg/mL)bELF/plasma

penetration ratiob

Reference

Gentamicin 240 mg IV 30 min infusion · 1

dose

6 1 8.79 – 0.64c 2.95 – 0.37c 0.30 – 0.05c 119

6 2 6.37 – 0.50c 4.24 – 0.42c 0.85 – 0.10c

6 4 4.70 – 0.49c 3.10 – 0.39c 1.14 – 0.26c

6 6 4.70 – 0.57c 2.65 – 0.35c 0.74 – 0.18c

Tobramycin 150 mg IM · 1 or more doses 5 6 4.1 – 1.5 5.3 – 2.9 1.4 – 0.8 120

300 mg IM · 1 or more doses 5 6 4.3 – 2.4 5.5 – 2.1 1.6 – 0.6 120

IV doses adjusted to achieve

serum Cmax ~8 mg/mL and Cmin

<2 mg/mL while maintaining

q8h dosing intervald

4 0.5e 6.90 – 1.44 2.33 – 0.50 0.30 – 0.03 121

4 2e 4.08 – 1.30 1.67 – 0.60 0.42 – 0.16

4 4e 2.14 – 0.85 1.62 – 1.19 0.64 – 0.37

4 8e 0.79 – 0.38 0.77 – 0.38 1.53 – 0.76

7–10 mg/kg IV 30 min infusion

q24he

12 1 22.4 – 5.9 2.7 – 0.7 0.119 – 0.019 122

300 mg inhalation · 1 dose 12 NA NA 90 – 54 NA 123

Netilmicin 450 mg IV 30 min infusion · 1

dose

5 1 21.4 – 1.19c 7.5 – 1.0c NR 124

5 1.5 15.3 – 0.85c 9.6 – 0.3c NR

5 2 12.0 – 0.71c 14.7 – 2.2c NR

5 3 8.3 – 0.64c 9.3 – 0.6c NR

a Sampling time after the last dose or after the start of the last IV infusion, as applicable.



d The mean number of doses (– SD) administered before BAL fluid collection was 21.25 – 6.42.

e Samples were collected at steady state after 2 d of therapy.

BAL = bronchoalveolar lavage; Cmax = maximum concentration; Cmin = minimum concentration; IM = intramuscularly; IV = intravenous; NA = not applicable;

NR = not reported; qxh = every x h; SD = standard deviation; SEM = standard error of the mean.



The plasma protein binding of telavancin is approximately

90%. A subsequent population pharmacokinetic analysis and

Monte Carlo simulation study reported mean and median va-

lues for the ratio between the ELF AUC and the unbound

plasma AUC of 1.01 and 0.73, respectively.[134] The large

variability (SD 0.96) of the ELFAUC from time zero to infinity

(AUCp) skewed the mean value towards 1.

6.4 Oritavancin

Oritavancin is an investigational lipoglycopeptide being

developed for the treatment of serious Gram-positive infec-

tions, including meticillin-resistant S. aureus. Plasma and

bronchopulmonary concentrations of oritavancin were col-

lected in 20 healthy adult subjects for up to 168 hours after the

fifth intravenous dose of 800mg every 24 hours.[127] The mean

concentrations of oritavancin in ELF (range 3.1 mg/mL at

4 hours to 1.7 mg/mL at 168 hours) were lower than the total

plasma concentrations (range 119.6–10.4 mg/mL) [table XI]. If

protein binding for oritavancin in healthy adult subjects is as-

sumed to be approximately 90%, the ELF and unbound plasma

oritavancin concentrations were similar.

7. Miscellaneous Antibacterial Agents

Several studies have reported intrapulmonary concentrations

of agents from other antibacterial classes (table XII).[135-139]

Currently, linezolid and tigecycline are available for clinical

Table XI. Plasma and epithelial lining fluid (ELF) concentrations of glycopeptides and lipoglycopeptides

Antibacterial

agent


(n)

Sampling



(mg/mL)bELF/plasma

penetration ratiob

Reference

Vancomycin 15 mg/kg IV 2 h infusion · 5

for 11 dc,d

14 18.4 – 11 24 – 19 4.5 – 2.3e 0.18 127

7.5 mg/kg IV 1 h infusion q6hf 4 6f 22.19 – 0.83 2.03 – 0.49 NR 128

6 6f 12.45 – 3.56 NDg NR

1000 mg IV 1 h infusion

q12h · 9 doses

5 4 19.8 – 3.7 5.3 – 1.5 NR 129

5 12 5.1 – 1.7 2.4 – 0.7 NR

Teicoplanin 12 mg/kg IV 30 min infusion

q12h · 2 d, then 12 mg/kg IV

30 min infusion q24h

13 18–24h,i 15.9 4.9 1.46j 130

Telavancin 10 mg/kg IV 1 h infusion

q24h · 3 doses

5 4 NR NR NR 131

5 8 NR 3.73 – 1.28 NR

5 12 22.9 NR NR

5 24 7.28 0.89 – 1.03 NR

Oritavancin 800 mg IV 1–2 h infusion

q24h · 5 doses

5 4 119.6 – 24.6 3.1 – 1.1 NR 129

5 12 75.7 – 16.3 3.7 – 2.5 NR

5 24 73.7 – 28.2 6.3 – 1.5 NR

5 168 10.4 – 3.0 1.7 – 0.8 NR



c Subsequent doses were adjusted in order to obtain a trough plasma concentration of 15–20mg/mL.

d The mean (– SD) duration of therapy was 6.6 – 1.75 d.

e No drug was detected in BAL fluid from one patient, therefore, the LLQ (10 ng/mL) was used in the analysis.

f Sampling was performed 24 h after the start of vancomycin therapy.

g Concentrations in BAL fluid were undetectable (assay LLQ 0.5 mg/mL).

h Samples were collected 4 to 6 d after the start of teicoplanin therapy.

i Values are expressed as range.

j The ratio represents the ELF to unbound serum concentration (median unbound fraction 22% [range 8–42%]).

BAL = bronchoalveolar lavage; IV = intravenous; LLQ = lower limit of quantification; ND = not detected; NR = not reported; qxh = every x h; SD = standard

deviation.

656 Rodvold et al.


use and have been approved for the treatment of lower res-

piratory tract infections. Iclaprim is an investigational agent

that is undergoing clinical development.

7.1 Linezolid

Linezolid is an oral and parenteral antibacterial agent that is

representative of the oxazolidinone class. Linezolid is used in

the treatment of serious lower respiratory tract infections

caused by Gram-positive pathogens such as meticillin-resistant

S. aureus. The intrapulmonary disposition of linezolid has been

investigated in healthy adult subjects, patients with chronic ob-

structive pulmonary disease and critically ill patients requiring

mechanical ventilation.

Plasma and bronchopulmonary concentrations of linezolid

were measured in 25 healthy adult subjects for up to 48 hours

after the fifth oral dose of 600mg every 12 hours.[135] The mean

concentrations and systemic exposure of linezolid in ELF

(range 64.3 mg/mL at 4 hours to 0.7 mg/mL at 48 hours; AUC24

672mg�h/mL) exceeded those in plasma (range 15.5–0.2mg/mL;

AUC24 204.2 mg�h/mL) and in AMs (range 2.2 mg/mL to below

the LLQ; AUC24 30.0 mg�h/mL) [table XII]. For ELF, the

AUC24/MIC ratio was 168 and the T>MIC was 100% for a

12-hour dosing interval at an MIC required to inhibit the

growth of 90% of organisms (MIC90) of 4 mg/mL for S. aureus.

Plasma and intrapulmonary concentrations of linezolid were

measured between 2.9 and 7.5 hours following the sixth oral

dose of 600mg every 12 hours in ten subjects undergoing di-

agnostic bronchoscopy and BAL.[136] Concentrations of line-

zolid in ELF were detectable in nine subjects and ranged from

13.1 to 52.4 mg/mL (table XII). The concomitant plasma and

AM concentrations ranged from 8.6 to 19.6 mg/mL and from

0.5 to 23.7 mg/mL, respectively. The mean –SD ELF to plasma

concentration ratio was 8.35 – 11.69 and quite variable over the

ten sampling times.

Plasma and ELF concentrations of linezolid were de-

termined at steady state in 16 critically ill adult patients with

ventilator-associated pneumonia.[137] Following 2 days of in-

travenous therapy with linezolid 600mg every 12 hours,

bronchoalveolar microlavage (with 40mL of sterile 0.9% nor-

mal saline solution) was performed twice in each subject at 1

and 12 hours after the start of the last dose. Concentrations of

Table XII. Plasma and epithelial lining fluid (ELF) concentrations of linezolid, tigecycline and iclaprim

Antibacterial

agent




(mg/mL)bELF/plasma

penetration ratiob

Reference

Linezolid 600 mg PO bid · 5 doses 5 4 15.5 – 4.9 64.3 – 33.1 4.2 – 1.4 135

5 8 8.9 – 3.2 31.4 – 33.0 3.1 – 2.2

5 12 10.2 – 2.3 24.3 – 13.3 2.4 – 1.2

5 24 1.8 – 0.6 7.6 – 6.0 3.9 – 2.3

5 48 0.2 – 0.2 0.7 – 0.8 2.3 – 1.6

600 mg PO bid · 6 doses 10 5.10 – 2.01b 13.40 – 3.92 25.09 – 14.59 8.35 – 11.69 136

600 mg IV 1 h infusion · 2 d 16 2c 17.7 – 4.0 14.4 – 5.6 1.05 – 0.34 137

16 12c 2.4 – 1.2 2.6 – 1.7 1.04 – 0.28

Tigecycline 100 mg IV 30 min

infusion · 1 dose, then

50 mg IV 30 min infusion

q12h · 7 doses

5 2c 0.19 – 0.06 0.19 – 0.15 NR 138

5 3c 0.15 – 0.05 0.12 – 0.21 NR

5 4c 0.16 – 0.07 0.06 – 0.13 NR

5 6c 0.12 – 0.06 0.37 – 0.36 NR

5 12c 0.10 – 0.09 0.10 – 0.17 NR

5 24c 0.05 – 0.01 0.00 – 0.00 NR

Iclaprim 1.6 mg/kg IV 1 h infusion · 1

dose

8 1.97 – 0.08b,c 0.59 – 0.18 12.61 – 7.33 21.29 – 11.18 139

8 3.57 – 0.30b,c 0.24 – 0.05 6.38 – 5.17 24.93 – 16.53

8 6.50 – 0.29b,c 0.14 – 0.05 2.66 – 2.08 20.57 – 17.31



c Sampling time after the start of the last IV infusion.

bid = twice daily; IV = intravenous; NR = not reported; PO = orally; q12h = every 12 h; SD = standard deviation.



linezolid in ELF ranged from 4.5 to 25.4 mg/mL (mean

14.4 mg/mL) at 1 hour and from 0.3 to 5.8 mg/mL (mean

2.6 mg/mL) at 12 hours (table XII). The ELF to plasma con-

centration ratio was approximately 1 at both sampling times,

and the mean AUC24 in plasma was 154.6 mg�h/mL.

7.2 Tigecycline

Tigecycline is a parenteral glycylcycline and belongs to the

tetracycline class of anti-infective agents. Tigecycline has shown

activity against a wide spectrum of pathogens, including Gram-

positive, Gram-negative, atypical and anaerobic pathogens.

Steady-state plasma and intrapulmonary concentrations of

tigecycline weremeasured in 30 healthy adult subjects following

the last dose of an intravenous regimen, which included a

loading dose of 100mg followed by 50mg every 12 hours for a

total of seven doses.[138] The mean concentrations of tigecycline

in serum andELFwere similar during the entire 12-hour dosing

interval and ranged from 0.10 to 0.19 mg/mL and from 0.06 to

0.37 mg/mL, respectively (table XII). In contrast, the mean

concentrations in AMs were significantly higher (p < 0.05)

and ranged from 10.7 to 15.2 mg/mL. A population phar-

macokinetic analysis and Monte Carlo simulations were sub-

sequently conducted to determine systemic exposure (based on

AUC24 values) and penetration ratios.[140] The median ELF

to serum concentration ratio was 1.15 and was associated

with wide variability (5th and 95th percentiles 0.561 and 5.23,

respectively).

It is worth noting that the protein binding of tigecycline in

humans ranges from 71% to 89%, and the data reported above

used total serum concentrations from uninfected subjects. Two

recent studies in animal models have suggested that (i) a sig-

nificantly higher penetration ratio is seen when protein binding

is accounted for and unbound serum concentrations are used;

(ii) ELF to unbound serum concentration ratios are sig-

nificantly higher in mice with a pulmonary infection (12.9 and

23.3 at doses of 25 and 50mg/kg, respectively) than in those

without a pulmonary infection (6.2 and 8.1 at doses of 25 and

50mg/kg, respectively); and (iii) the penetration ratio is dose

dependent and tends to increase with larger doses.[141,142]

Further studies are needed to confirm these observations in

patients with lower respiratory tract infections.

7.3 Iclaprim

Iclaprim is a dihydrofolate reductase inhibitor and a mem-

ber of the diaminopyrimidine class of anti-infective agents.

Iclaprim has potent in vitro activity against Gram-positive pa-

thogens, including meticillin-resistant S. aureus and Strepto-

coccus species.

Plasma and intrapulmonary concentrations of iclaprim were

measured in 24 healthy male subjects from 1.8 to 7.08 hours

after the start of a 1-hour intravenous infusion of 1.6mg/kg of

bodyweight.[139] The concentrations of iclaprim in ELF (range

0.5–25.3 mg/mL) exceeded the concomitant plasma concentra-

tions at all sampling times with the ratios of ELF to total

plasma concentrations ranging from 6 to 51.2 (table XII). The

MIC90 values for Gram-positive pathogens such as penicillin-

susceptible and -intermediate S. pneumoniae (0.06 and 2 mg/mL,

respectively) and meticillin-resistant S. aureus (0.12 mg/mL)

were exceeded by the concentrations of iclaprim in ELF for up

to 7 hours. The concentrations of iclaprim in AMs were similar

to or higher than those in ELF.

8. Conclusions

The penetration of antibacterial agents into the ELF of the

lung has been extensively evaluated during the past 20 years.

This review includes more than 80 studies that have reported

ELF concentrations and extracellular penetration ratios of

antibacterial agents that are used to treat lower respiratory

tract infections. More studies (e.g. >100) would have been in-

cluded in the review if we had elected to include all reports on

fluoroquinolones instead of just those on ciprofloxacin, moxi-

floxacin and levofloxacin.[25,62,63,86-102,111-115] In spite of this,

fluoroquinolones still accounted for approximately 25% of the

studies that we reviewed.

A wide variety of penetration ratios and patterns of ELF

disposition have been observed for agents from various anti-

bacterial classes. Aminoglycosides, b-lactams and glycopep-

tides tend to have ELF to total plasma concentration ratios of

£1. Aminoglycosides tend to have ELF concentrations that are

fairly constant and significantly lower than plasma concentra-

tions in the first few hours after drug administration, with

subsequent ELF concentrations being similar to or slightly

lower than plasma concentrations during the last half of the

dosing interval. A wide range of penetration ratios has been

reported for b-lactam agents. Even when protein binding

and differences in the characteristics of the molecule are taken

into account, the discordance in penetration could not be pre-

dicted for various agents from the b-lactam classes. Although

the number of studies of glycopeptide or lipoglycopeptide agents

(e.g. vancomycin, telavancin, oritavancin) is limited, once protein

binding is accounted for, the pattern of disposition and the

ratios of ELF to unbound plasma concentrations are similar

and approach values closer to 1.

658 Rodvold et al.


In comparison, antibacterial agents such as macrolides, ke-

tolides, fluoroquinolones (e.g. levofloxacin and moxifloxacin)

and linezolid have ELF to total plasma concentration ratios of

>1. Why agents from these antibacterial classes tend to have

higher concentrations in ELF than in plasma remains un-

known. Recent studies have suggested that active transporter

systems in epithelial cells may be involved and may influence

the secretion of these agents in the lung.[103,143-145] On the other

hand, technical issues associated with the collection of BAL

samples and measurement of ELF concentrations have been

raised as other potential explanations for these observa-

tions.[12,13,15] Some authors have provided rationales as to why

these confounding variables may not explain the higher ob-

served ELF concentrations. Obviously, more research is needed

to understand the underlying mechanisms of drug transporters

in the lung, and strict adherence to sample collection proce-

dures is required in order to minimize known sources of error.

The majority of studies have been conducted in adults

who were healthy or outpatients undergoing an elective diag-

nostic fibre-optic bronchoscopy. The BAL procedure has

usually consisted of 150–200mL of 0.9% normal saline solution

being instilled as three or four aliquots. A few recent studies

have targeted older outpatients or patients with a clinical

diagnosis of mild to moderate chronic bronchitis, chronic ob-

structive pulmonary disease or lower respiratory tract infec-

tion.[53,54,62,69,112,115] The reported ELF concentrations were

similar to or slightly higher than those observed in healthy

subjects. An increasing number of studies have provided ELF

data in critically ill patients who were in an intensive care unit,

receiving mechanical ventilation and being treated for severe

pneumonia.[36,39,40,49,113,118,119,121,122,124,126-128,130,137] In these

patients, microlavage or minilavage (e.g. 20mL of 0.9% nor-

mal saline solution instilled as one or two aliquots per sampl-

ing time) has commonly been used for the BAL procedure.[18]

Despite differences in study procedures and patient popula-

tions, the data on the antibacterial agents that have been

studied so far (e.g. piperacillin/tazobactam, ceftazidime, cefe-

pime, meropenem, levofloxacin, aminoglycosides, vancomycin,

teicoplanin, linezolid) have shown that ELF concentrations

were similar to those observed in healthy subjects and out-

patients. Thus antibacterial concentrations in ELF from non-

infected subjects tend to serve as conservative estimates of

the likely drug concentrations at extracellular sites of lung in-

fection. However, further studies are still warranted in pa-

tients with pulmonary infections to explore the importance

of intrapulmonary concentrations with respect to establish-

ing relationships between pharmacokinetic-pharmacodynamic

parameters and clinical or microbiological outcomes.

The interpretation of antibacterial concentrations in ELF is

greatly influenced by the study design, sample collection and

timing, analytical methods and data analysis. Our review of the

literature and our work as investigators in these types of studies

have provided us with an appreciation of the following key

issues that need to be considered when reviewing and/or de-

signing intrapulmonary penetration studies: (i) multiple-dose

studies are more likely to provide meaningful information

and measurable ELF concentrations; (ii) serial sampling times

should be spaced throughout a dosing interval in order to

provide accurate estimates of AUCs in plasma and in ELF;

(iii) procedures for collection, handling and storage of BAL

samples are required, including careful separation of ELF and

cell components; (iv) studies should involve experienced per-

sonnel using established bronchoscopy and BAL procedures

that are individualized to the type of subjects being studied;

(v) analytical methodologies must be sensitive and specific

for measurement of urea and drug concentrations in plasma

and in ELF; and (vi) pharmacokinetic-pharmacodynamic data

analysis and mathematical modelling should take into account

protein binding, systemic exposure, simulations of drug con-

centration profiles and evaluation of target attainment rates.

Ideally, a logical approach for evaluating dosage regimens –

based on preclinical infection models, the pharmacokinetic-

pharmacodynamic characteristics of the agent being studied

and drug exposure information at the site of infection (e.g. ELF

in the lung) – should be incorporated into the study design.[41]

All of these considerations are important to the understanding

of ELF penetration and appropriate decision-making to guide

dosage regimen designs for patients with lower respiratory tract

infections.[7]

This review has focused on human studies that have mea-

sured ELF concentrations of antibacterial agents. An increas-

ing number of intrapulmonary penetration studies have been

conducted in animals. Antibacterial agents that have and have

not been studied in humans have been evaluated for applica-

tions in veterinary medicine for foals, horses and dogs.[146-155]

In addition, animal studies evaluating different modes of ad-

ministration or formulations of current and investigational

antibacterial agents have been reported.[156-160] These studies

are also providing further insights into the penetration of an-

tibacterial agents into ELF.

Acknowledgements

No sources of funding were used in the preparation of this review. The

authors have no conflicts of interest that are directly relevant to the content

of this review.



References1. Siegel RE. The significance of serum versus tissue concentrations of anti-

biotics in the treatment of penicillin-resistant Streptococcus pneumoniae and

community-acquired pneumonia: are we looking in the wrong place? Chest

1999; 116: 535-8

2. Craig WA. Pharmacokinetic-pharmacodynamic parameters: rationale for

antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1-10

3. Rodvold KA. Pharmacodynamics of antiinfective therapy: taking what we

know to the patient’s bedside. Pharmacotherapy 2001; 11 (Pt 2): 319S-330S

4. Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics-

pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore.

Clin Infect Dis 2007; 44: 78-86

5. Muller ML, dela Pena A, Derendorf H. Issues in pharmacokinetics and

pharmacodynamics of anti-infective agents: distribution in tissue. Anti-

microb Agents Chemother 2004; 48: 1441-53

6. Drusano GL. Infection site concentrations: their therapeutic importance and

the macrolide and macrolide-like class of antibiotics. Pharmacotherapy

2005; 25 (Pt 2): 150S-158S

7. Ambrose PG, Bhavnani SM, Ellis-Grosse EJ, et al. Pharmacokinetic-

pharmacodynamic considerations in the design of hospital-acquired or

ventilator-associated bacterial pneumonia studies: look before you leap! Clin

Infect Dis 2010; 51 Suppl. 1: S103-10

8. Honeybourne D. Antibiotic penetration in the respiratory tract and im-

plications for the selection of antimicrobial therapy. Curr Opin Pulm Med

1997; 3: 170-4

9. Nix DE. Intrapulmonary concentrations of antimicrobial agents. Infect Dis

Clin North Am 1998; 12: 631-46

10. Fish DN. Bronchoscopic sampling of drug concentrations: penetration to

tissue is the issue. Am J Respir Crit Care Med 2003; 168: 1263-5

11. Baldwin DR, Honeybourne D, Wise R. Pulmonary disposition of anti-

microbial agents: in vivo observations and clinical relevance. Antimicrob

Agents Chemother 1992; 36: 1176-80

12. Dhanani J, Roberts JA, ChewM, et al. Antimicrobial chemotherapy and lung

microdialysis: a review. Int J Antimicrob Agents 2010; 36: 491-500

13. ZeitlingerM,MullerM, JoukhadarC. Lungmicrodialysis: a powerful tool for

the determination of exogenous and endogenous compounds in the lower

respiratory tract (mini-review). AAPS J 2005; 7: E600-8

14. Mouton JW, Theuretzbacher U, Craig WA, et al. Tissue concentrations: do

we ever learn? J Antimicrob Chemother 2008; 61: 235-7

15. Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios mea-

sured in epithelial lining fluid. Antimicrob Agents Chemother 2008; 52: 24-36

16. Baldwin DR, Honeybourne D, Wise R. Pulmonary disposition of anti-

microbial agents: methodological considerations. Antimicrob Agents Che-

mother 1992; 36: 1171-5

17. Rennard SI, Basset G, Lecossier D, et al. Estimation of volume of epithelial

lining fluid recovered by lavage using urea as marker of dilution. J Appl

Physiol 1986; 60: 532-8

18. Mimoz O, Dahyot-Fizelier C. Mini-broncho-alveolar lavage: a simple and

promising method for assessment of antibiotic concentration in epithelial

lining fluid. Intensive Care Med 2007; 33: 1495-7

19. Burke WMJ, Roberts CM, Bryant DH, et al. Smoking-induced changes in epi-

thelial lining fluid volume, cell density and protein. Eur Respir J 1992; 5: 780-4

20. Roberts CM, Cairns D, Bryant DH, et al. Changes in epithelial lining fluid

albumin associated with smoking and interstitial lung disease. Eur Respir J

1993; 6: 110-5

21. HasegawaN,Nishimura T,WatabnabeM, et al. Concentrations of clarithromycin

and activemetabolite in the epithelial lining fluid of patients withMycobacterium

avium complex pulmonary disease. Pulm Pharmacol Ther 2009; 22: 190-3

22. Kikuchi E, Kikuchi J, Nasuhara Y, et al. Comparison of the pharmaco-

dynamics of biapenem in bronchial epithelial lining fluid in healthy volun-

teers given half-hour and three-hour intravenous infusions. Antimicrob


23. Kikuchi E, Yamazaki K, Kikuchi J, et al. Pharmacokinetics of clarithromycin

in bronchial epithelial lining fluid. Respirology 2008; 13: 221-6

24. Kikuchi J, Yamazaki K, Kikuchi E, et al. Pharmacokinetics of telithromycin

using bronchoscopic microsampling after single and multiple oral doses.

Pulm Pharmacol Ther 2007; 20: 549-55

25. Yamazaki K, Ogura S, Ishizaka A, et al. Bronchoscopic microsampling

method for measuring drug concentration in epithelial lining fluid. Am J

Respir Crit Care Med 2003; 168: 1304-7

26. Bamberger DM, Foxworth JW, Bridwell DL, et al. Extravascular anti-

microbial distribution and the respective blood and urine concentrations in

humans. In: Lorain V, editor. Antibiotics in laboratory medicine. 5th ed.

Philadelphia (PA): Lippincott Williams & Wilkins, 2005: 719-809

27. Chu H-M, Ette EI. Analysis of quantic pharmacokinetic study: robust esti-

mation of tissue-to-plasma ratio. In: Ette EI, Williams PJ, editors. Phar-

macometrics: the science of quantitative pharmacology. Hoboken (NJ):

John Wiley & Sons, Inc., 2007: 1035-68

28. Cook PJ, Andrews JM, Woodcock J, et al. Concentration of amoxycillin and

clavulanate in lung compartments in adults without pulmonary infection.

Thorax 1994; 49: 1134-8

29. Baldwin DR, Andrews JM, Wise R, et al. Bronchoalveolar distribution of

cefuroxime axetil and in-vitro efficacy of observed concentrations against

respiratory pathogens. J Antimicrob Chemother 1992; 30: 377-85

30. Conte Jr JE, Golden J, Duncan S, et al. Single-dose intrapulmonary phar-

macokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefurox-

ime in volunteer subjects. Antimicrob Agents Chemother 1996; 40: 1617-22

31. Muller-Serieys C, Bancal C, Dombret MC, et al. Penetration of cefpodoxime

proxetil in lung parenchyma and epithelial lining fluid of noninfected

patients. Antimicrob Agents Chemother 1992; 36: 2099-103

32. Andrews JM, Wise R, Baldwin DR, et al. Concentrations of ceftibuten in

plasma and the respiratory tract following a single 400mg oral dose. Int J

Antimicrob Agents 1995; 5: 141-4

33. Cook PJ, Andrews JM, Wise R, et al. Distribution of cefdinir, a third gen-

eration cephalosporin antibiotic, in serum and pulmonary compartment.

J Antimicrob Chemother 1996; 37: 331-9

34. Mazzei T, Novelli A, Esposito S, et al. New insight into the clinical phar-

macokinetics of cefaclor: tissue penetration. J Chemother 2000; 12: 53-62

35. Lodise TP, Kinzig-Schippers M, Drusano GL, et al. Use of population

pharmacokinetic modeling and Monte Carlo simulation to describe the

pharmacodynamic profile of cefditoren in plasma and epithelial lining fluid.

Antimicrob Agents Chemother 2008; 52: 1945-51

36. Boselli E, Breilh D, Cannesson M, et al. Steady-state plasma and in-

trapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g adminis-

tered to critically ill patients with severe nosocomial pneumonia. Intensive

Care Med 2004; 30: 976-9

37. Baldwin DR, Maxwell SRJ, Honeybourne D, et al. The penetration of cef-

pirome into the potential sites of pulmonary infection. J Antimicrob Che-

mother 1991; 28: 79-86

38. Cazzola M, Matera MG, Polverino M, et al. Pulmonary penetration of cef-

tazidime. J Chemother 1995; 7: 50-4

39. Boselli E, Breilh D, Rimmele T, et al. Plasma and lung concentrations of

ceftazidime administered in continuous infusion to critically ill patients with

severe nosocomial pneumonia. Intensive Care Med 2004; 30: 989-91

40. Boselli E, Breilh D, Duflo F, et al. Steady-state plasma and intrapulmonary

concentrations of cefepime administered in continuous infusion in critically

ill patients with severe nosocomial pneumonia. Crit Care Med 2003; 31:

2102-6

41. Rodvold KA, Nicolau DP, Lodise TP, et al. Identifying exposure target for

treatment of staphylococcal pneumonia with ceftopibrole. Antimicrob


660 Rodvold et al.


42. Krumpe P, Lin C-C,Radwanski E, et al. The penetration of ceftibuten into the

respiratory tract. Chest 1999; 116: 369-74

43. Bayat S, Louchahi K, Verdiere B, et al. Comparison of 99mTc-DTPA and urea

for measuring cefepime concentrations in epithelial lining fluid. Eur Respir J

2004; 24: 150-6

44. Laohavaleeson S, Tessier PR, Nicolau DP. Pharmacodynamic characteriza-

tion of ceftobiprole in experimental pneumonia caused by phenotypically

diverse Staphylococcus aureus strains. Antimicrob Agents Chemother 2008;

52: 2389-94

45. Allegranzi B, Cazzadori A, Di Perri G, et al. Concentrations of single-dose

meropenem (1 g iv) in bronchoalveolar lavage and epithelial lining fluid.


46. Conte Jr JE, Golden JA, KelleyMG, et al. Intrapulmonary pharmacokinetics

and pharmacodynamics of meropenem. Int J Antimicrob Agents 2005; 26:

449-56

47. Burkhardt O,Majcher-Peszynska J, BornerK, et al. Penetration of ertapenem

into different pulmonary compartments of patients undergoing lung surgery.

J Clin Pharmacol 2005; 45: 659-65

48. Boselli E, Breilh D, Saux M-C, et al. Pharmacokinetics and lung concentra-

tions of ertapenem in patients with ventilator-associated pneumonia. In-

tensive Care Med 2006; 32: 2059-62

49. Drusano GL, Sorgel F, Ma L, et al. Pharmacokinetics and penetration

of meropenem into epithelial lining fluid in patients with ventilator-

associated pneumonia [abstract no. A-222]. 45th Interscience Conference

on Antimicrobial Agents and Chemotherapy (ICAAC); 2005 Dec 16-19;

Washington, DC

50. Lodise TP, Sorgel F, Melnick D, et al. Penetration of meropenem into epi-

thelial lining fluid of patients with ventilator-associated pneumonia. Anti-

microb Agents Chemother 2011; 55: 1606-10

51. Conte Jr JE, Golden JA, Duncan S, et al. Intrapulmonary pharmacokinetics

of clarithromycin and erythromycin. Antimicrob Agents Chemother 1995;

39: 334-8

52. Chastre J, Brun P, Fourtillan JB, et al. Pulmonary disposition of roxithro-

mycin (RU 28965), a new macrolide antibiotic. Antimicrob Agents Che-

mother 1987; 31: 1312-6

53. Nakamura H, Fujishima S, Inoue T, et al. Clinical and immunoregulatory

effects of roxithromycin therapy for chronic respiratory tract infection. Eur

Resp J 1999; 13: 1371-9

54. Cazzola M, Matera MG, Tufano MA, et al. Pulmonary penetration of diri-

thromycin in patients suffering from acute exacerbations of chronic bron-

chitis. Pul Pharmacol 1994; 7: 377-81

55. Furuie H, Saisho Y, Yoshikawa T, et al. Intrapulmonary pharmacokinetics of

S-013420, a novel bicyclolide antibacterial, in healthy Japanese subjects.


56. Honeybourne D, Kees F, Andrews JM, et al. The levels of clarithromycin and

its 14-hydroxy metabolite in the lung. Eur Respir J 1994; 7: 1275-80

57. Patel KB, Xuan D, Tessier PR, et al. Comparison of bronchopulmonary

pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agents

Chemother 1996; 40: 2375-9

58. Rodvold KA, GotfriedMH, Danziger LH, et al. Intrapulmonary steady-state

concentrations of clarithromycin and azithromycin in healthy adult volun-

teers. Antimicrob Agents Chemother 1997; 41: 1399-402

59. Gotfried MH, Danziger LH, Rodvold KA. Steady-state plasma and bron-

chopulmonary characteristics of clarithromycin extended-release tablets in

normal healthy adult subjects. J Antimicrob Chemother 2003; 52: 450-6

60. Baldwin DR,Wise R, Andrews JM, et al. Azithromycin concentrations at the

sites of pulmonary infection. Eur Resp J 1990; 3: 886-90

61. Olsen KM, San Pedro GS, Gann LP, et al. Intrapulmonary pharmacokinetics

of azithromycin in healthy volunteers given five oral doses. Antimicrob


62. Capitano B, Mattoes HM, Shore E, et al. Steady-state intrapulmonary con-

centrations of moxifloxacin, levofloxacin, and azithromycin in older adults.

Chest 2004; 125: 965-73

63. Rodvold KA, Danziger LH, Gotfried MH. Steady-state plasma and bron-

chopulmonary concentrations of intravenous levofloxacin and azithromycin

in healthy adults. Antimicrob Agents Chemother 2003; 47: 2450-7

64. Kadota J-I, Ishimatsu Y, Iwashita T, et al. Intrapulmonary pharmacokinetics

of telithromycin, a new ketolide, in healthy Japanese volunteers. Antimicrob


65. Khair OA, Andrews JM, Honeybourne D, et al. Lung concentrations of teli-

thromycin after oral dosing. J Antimicrob Chemother 2001; 47: 837-40

66. Ong CT, Dandekar PK, Sutherland C, et al. Intrapulmonary concentrations

of telithromycin: clinical implications for respiratory tract infections due to

Streptococcus pneumonia. Chemotherapy 2005; 51: 339-46

67. Muller-Serieys C, Soler P, Cantalloube C, et al. Bronchopulmonary disposi-

tion of the ketolide telithromycin (HMR 3647). Antimicrob Agents Che-

mother 2001; 45: 3104-8

68. Conte Jr JE, Golden JA, Kipps J, et al. Steady-state plasma and in-

trapulmonary pharmacokinetics and pharmacodynamics of cethromycin.


69. Matera MG, Tufano MA, Polverino M, et al. Pulmonary concentrations of

dirithromycin and erythromycin during acute exacerbation of mild chronic

obstructive pulmonary disease. Eur Resp J 1997; 10: 98-103

70. Bergman KL, Olsen KM, Peddicord TE, et al. Antimicrobial activities and

postantibiotic effects of clarithromycin, 14-hydroxy-clarithromycin, and

azithromycin in epithelial cell lining fluid against clinical isolates of Hae-

mophilus influenzae and Streptococcus pneumoniae. Antimicrob Agents

Chemother 1999; 43: 1291-3

71. Noreddin AM, Roberts D, Nichol K, et al. Pharmacodynamic modeling of

clarithromycin against macrolide-resistant [PCR-positive mef(A) or erm(B)]

Streptococcus pneumoniae simulating clinically achievable serum and epi-

thelial lining fluid free-drug concentrations. Antimicrob Agents Chemother

2002; 46: 4029-34

72. Maglio D, Capitano B, Banevicius MA, et al. Differential efficacy of clarithro-

mycin in lung versus thigh infection models. Chemotherapy 2004; 50: 63-6

73. Noreddin AM, El-Khatib WF, Aolie J, et al. Pharmacodynamic target at-

tainment potential of azithromycin, clarithromycin, and telithromycin in

serum and epithelial lining fluid of community-acquired pneumonia patients

with penicillin-susceptible, intermediate, and resistant Streptococcus

pneumoniae. Int J Antimicrob Agents 2009; 13: 483-7

74. Kays MB, Denys GA. In vitro activity and pharmacodynamics of azi-

thromycin and clarithromycin against Streptococcus pneumoniae based on

serum and intrapulmonary pharmacokinetics. Clin Ther 2001; 23: 413-24

75. Ambrose PG. Antimicrobial susceptibility breakpoints: PK-PD and suscep-

tibility breakpoints. Treat Respir Med 2005; 4 Suppl. 1: 5-11

76. Lucchi M, Damle B, Fang A, et al. Pharmacokinetics of azithromycin in

serum, bronchial washings, alveolar macrophages and lung tissue following

a single oral dose of extended or immediate release formulations of azi-

thromycin. J Antimicrob Chemother 2008; 61: 884-91

77. Alou L, Gimenez M-J, Sevillano D, et al. A pharmacodynamic approach to

antimicrobial activity in serum and epithelial lining fluid against in vivo-

selected Streptococcus pneumoniae mutants and association with clinical

failure in pneumonia. J Antimicrob Chemother 2006; 58: 349-58

78. Sevillano D, Alou L, Aguilar L, et al. Azithromycin IV pharmacodynamic

parameters predicting Streptococcus pneumoniae killing in epithelial lining

fluid versus serum: an in vitro pharmacodynamic simulation. J Antimicrob

Chemother 2006; 57: 1128-33

79. Cafini F, Alou L, Sevillano D, et al. Bactericidal activity of moxifloxacin

against multidrug-resistant Streptococcus pneumoniae at clinically achiev-

able serum and epithelial lining fluid concentrations compared with three

other antimicrobials. Int J Antimicrob Agents 2004; 24: 334-8



80. Zhanel GG, DeCorby M, Noreddin A, et al. Pharmacodynamic activity of

azithromycin against macrolide-susceptible and -resistant Streptococcus

pneumoniae simulating clinically achievable free serum, epithelial lining

fluid andmiddle ear fluid concentrations. J Antimicrob Chemother 2003; 52:

83-8

81. Lodise TP, Preston S, BhargavaV, et al. Pharmacodynamics of an 800-mg dose of

telithromycin in patients with community-acquired pneumonia caused by ex-

tracellular pathogens. Diagn Microbiol Infect Dis 2005; 52: 45-52

82. Zhanel GG, Johanson C, Laing N, et al. Pharmacodynamic activity of teli-

thromycin at simulated clinically achievable free-drug concentrations in

serum and epithelial lining fluid against efflux (mefE)-producing macrolide-

resistant Streptococcus pneumoniae for which telithromycin MICs vary.


83. Zhanel GG, Johanson C, Hisanaga T, et al. Pharmacodynamic activity of

telithromycin against macrolide-susceptible and macrolide-resistant Strep-

tococcus pneumoniae simulating clinically achievable free serum and epi-

thelial lining fluid concentrations. J Antimicrob Chemother 2004; 54: 1072-7

84. De Vecchi E, Nicola L, Larosa M, et al. In vitro activity of telithromycin

against Haemophilus influenzae at epithelial lining fluid concentrations.

BMC Microbiol 2008; 8: 23

85. Al-Lahham A, Reinert RR. Time-kill kinetics of Streptococcus pneumoniae

with reduced susceptibility to telithromycin. Chemotherapy 2007; 53: 190-3

86. Chierakul N, Klomsawat D, Chulavatnatol S, et al. Intrapulmonary

pharmacokinetics of ofloxacin in drug-resistant tuberculosis. Int J Tuberc

Lung Dis 2001; 5: 278-82

87. Andrews JM, Honeybourne D, Brenwald NP, et al. Concentrations of trova-

floxacin in bronchial mucosa, epithelial lining fluid, alveolar macrophages and

serumafter administration of single ormultiple oral doses to patients undergoing

fibre-optic bronchoscopy. J Antimicrob Chemother 1997; 39: 797-802

88. Peleman RA, Van De Velde V, Germonpre PR, et al. Trovafloxacin con-

centrations in airway of patients with severe community-acquired pneu-

monia. Antimicrob Agents Chemother 2000; 44: 178-80

89. Honeybourne D, Banerjee D, Andrews J, et al. Concentrations of gatifloxacin

in plasma and pulmonary compartments following a single 400mg oral dose

in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother

2001; 48: 63-6

90. Kikuchi J, Yamazaki K, Kikuchi E, et al. Pharmacokinetics of gatifloxacin

after a single oral dose in healthy young adult subjects and adult patients

with chronic bronchitis, with a comparison of drug concentrations obtained

by bronchoscopic microsampling and bronchoalveolar lavage. Clin Ther

2007; 29: 123-30

91. Andrews J, Honeybourne D, Jevons G, et al. Concentrations of garenoxacin

in plasma, bronchial mucosa, alveolar macrophages and epithelial lining

fluid following a single oral 600mg dose in healthy adult subjects. J Anti-

microb Chemother 2003; 51: 727-30

92. Panteix G, Harf R, Desnottes JR, et al. Accumulation of pefloxacin in the

lower respiratory tract demonstrated by bronchoalveolar lavage. J Anti-


93. WiseR,Andrews J, ImbimboBP, et al. The penetration of rufloxacin into sites

of potential infection in the respiratory tract. J Antimicrob Chemother 1993;

32: 861-6

94. Honeybourne D, Andrews JM, Cunningham B, et al. The concentrations of

clinafloxacin in alveolar macrophages, epithelial lining fluid, bronchial

mucosa and serum after administration of single 200mg oral doses to

patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother

1999; 43: 153-5

95. Baldwin DR, Wise R, Andrews JM, et al. The distribution of temafloxacin in

bronchial epithelial lining fluid, alveolar macrophages and bronchial mu-

cosa. Eur Respir J 1992; 5: 471-6

96. Wise R, Baldwin DR, Andrews JM, et al. Comparative pharmacokinetic

disposition of fluoroquinolones in the lung. J Antimicrob Chemother 1991;

28 Suppl. C: 65-71

97. Cazzola M, Matera MG, Tufano MA, et al. Pulmonary disposition of lo-

mefloxacin in patients with acute exacerbations of chronic obstructive pul-

monary disease: a multiple-dose study. J Chemother 2001; 13: 407-12

98. Baldwin DR, Wise R, Andrews JM, et al. Comparative bronchoalveolar

concentrations of ciprofloxacin and lomefloxacin following oral adminis-

tration. Respir Med 1993; 87: 595-601

99. Schuller P, Zemper K, Borner K, et al. Penetration of sparfloxacin and

ciprofloxacin into alveolar macrophages, epithelial lining fluid, and poly-

morphonuclear leucocytes. Eur Respir J 1997; 10: 1130-8

100. Honeybourne D, Greaves I, Baldwin DR, et al. The concentrations of spar-

floxacin in lung tissues after single and multiple oral doses. Int J Antimicrob

Agents 1994; 4: 151-5

101. Gotfried MH, Danziger LH, Rodvold KA. Steady-state plasma and in-

trapulmonary concentrations of levofloxacin and ciprofloxacin in healthy

adult subjects. Chest 2001; 119: 1114-22

102. Soman A, Honeybourne D, Andrews J, et al. Concentrations of moxifloxacin

in serum and pulmonary compartments following a single 400mg oral dose

in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother

1999; 44: 835-8

103. Brillault J, De Castro WV, Harnois T, et al. P-glycoprotein-mediated trans-

port of moxifloxacin in a Calu-3 lung epithelial cell model. Antimicrob


104. Morrissey I, George JT. Measurement of the bactericidal activity of fluoro-

quinolones against Streptococcus pneumonia using the bactericidal index

method. Int J Antimicrob Agents 2001; 17: 33-7

105. Florea NR, Tessier PR, Zhang C, et al. Pharmacodynamics of moxifloxacin and

levofloxacin at simulated epithelial lining fluid drug concentrations against

Streptococcus penumoniae. Antimicrob Agents Chemother 2004; 48: 1215-21

106. Schubert S, Dalhoff A, StassH, et al. Pharmacodynamics of moxifloxacin and

levofloxacin simulating human serum and lung concentrations. Infection

2005; 33 Suppl. 2: 15-21

107. Lee SY, Fan HW, Sutherland C, et al. Antibacterial effects of moxifloxacin

and levofloxacin simulating epithelial lining fluid concentrations against

community-acquired methicillin-resistant Staphylococcus aureus. Drugs R

D 2007; 8: 69-77

108. Deryke CA, Du X, Nicolau DP. Evaluation of bacterial kill when modeling

the bronchopulmonary pharmacokinetic profile of moxifloxacin and levo-

floxacin against parC-containing isolates of Streptococcus pneumoniae.


109. Noreddin AM, Reese AA, Ostroski M, et al. Comparative pharmaco-

dynamics of garenoxacin, gemifloxacin, and moxifloxacin in community-

acquired pneumonia caused by Streptococcus pneumoniae: a Monte Carlo

simulation analysis. Clin Ther 2007; 29: 2685-9

110. De Vecchi E, Nicola L, Ossola F, et al. In vitro selection of resistance in

Streptococcus pneumoniae at in vivo fluoroquinolone concentrations.


111. Andrews JM, Honeybourne D, Jevons G, et al. Concentrations of levo-

floxacin (HR 355) in the respiratory tract following a single oral dose in

patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother

1997; 40: 573-7

112. Zhang J, Xie X, ZhouX, et al. Permeability and concentration of levofloxacin

in epithelial lining fluid in patients with lower respiratory tract infections.

J Clin Pharmacol 2010; 50: 922-8

113. Boselli E, Breilh D, Rimmele T, et al. Pharmacokinetics and intrapulmonary

diffusion of levofloxacin in critically ill patients with severe community-

acquired pneumonia. Crit Care Med 2005; 33: 104-9

114. Conte Jr JE, Golden JA, McIver M, et al. Intrapulmonary pharmacokinetics

and pharmacodynamics of high-dose levofloxacin in healthy volunteer

subjects. Int J Antimicrob Agents 2006; 28: 114-21

115. Conte Jr JE, Golden JA, McIver M, et al. Intrapulmonary pharmaco-

dynamics of high-dose levofloxacin in subjects with chronic bronchitis or

662 Rodvold et al.


chronic obstructive pulmonary disease. Int J Antimicrob Agents 2007; 30:

422-7

116. Drusano GL, Preston SL, Gotfried MH, et al. Levofloxacin penetration into

epithelial lining fluid as determined by population pharmacokinetic mod-

eling andMonte Carlo simulation. Antimicrob Agents Chemother 2002; 46:

586-9

117. Noreddin AM, Marras TK, Sanders K, et al. Pharmacodynamic target at-

tainment analysis against Streptococcus pneumoniae using levofloxacin

500mg, 750mg, and 1000mg once daily in plasma (P) and epithelial lining

fluid (ELF) of hospitalized patients with community acquired pneumonia.

Int J Antimicrob Agents 2004; 24: 479-84

118. Louie A, Fregeau C, Liu W, et al. Pharmacodynamics of levofloxacin in a

murine pneumonia model of Pseudomonas aeruginosa infection: determi-

nation of epithelial lining fluid targets. Antimicrob Agents Chemother 2009;

53: 3325-30

119. Panidis D, Markantonis SL, Boutzouka E, et al. Penetration of gentamicin

into the alveolar lining fluid of critically ill patients with ventilator-

associated pneumonia. Chest 2005; 128: 545-52

120. Mazzei T, Novelli A, De Lalla F, et al. Tissue penetration and pulmonary

disposition of tobramycin. J Chemother 1995; 7: 363-70

121. Carcas AJ, Garcia-Satue JL, Zapater P, et al. Tobramycin penetration into

epithelial lining fluid of patients with pneumonia. Clin Pharmacol Ther 1999;

65: 245-50

122. Boselli E, Breilh D, Djabarouti S, et al. Reliability of mini-bronchoalveolar

lavage for the measurement of epithelial lining fluid concentrations of to-

bramycin in critically ill patients. Intensive Care Med 2007; 33: 1519-23

123. Rosenfeld M, Gibson R, McNamara S, et al. Serum and lower respiratory

tract drug concentrations after tobramycin inhalation in young children with

cystic fibrosis. J Pediatr 2001; 139: 572-7

124. Valcke VJ, Vogelaers DP, Colardyn FA, et al. Penetration of netilmicin in the

lower respiratory tract after once-daily dosing. Chest 1992; 101: 1028-32

125. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of

vancomycin in adult patients: a consensus review of the American Society of

Health-System Pharmacists, the Infectious Diseases Society of America, and

the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm

2009; 66: 82-98

126. Scheetz MH, Wunderink RG, Postelnick MJ, et al. Potential impact of van-

comycin pulmonary distribution on treatment outcomes in patients with

methicillin-resistant Staphylococcus aureus pneumonia. Pharmacotherapy

2006; 26: 539-50

127. Lamer C, De Beco V, Soler P, et al. Analysis of vancomycin entry into pul-

monary lining fluid by bronchoalveolar lavage in critically ill patients. An-

timicrob Agents Chemother 1993; 37: 281-6

128. Georges H, Leroy O, Alfandari S, et al. Pulmonary disposition of vancomycin

in critically ill patients. Eur J Clin Microbiol Infect Dis 1997; 16: 385-8

129. Rodvold KA, Gotfried MH, Loutit JS, et al. Plasma and intrapulmonary

concentrations of oritavancin and vancomycin in normal healthy adults

[abstract no. O-254]. Clin Microbiol Infect 2004; 10 Suppl. 3: 44

130. Mimoz O, Rolland D, Adoun M, et al. Steady-state trough serum and epi-

thelial lining fluid concentrations of teicoplanin 12mg/kg per day in patients

with ventilator-associated pneumonia. Intensive Care Med 2006; 32: 775-9

131. Gotfried MH, Shaw J-P, Benton BM, et al. Intrapulmonary distribution of

intravenous telavancin in healthy subjects and effects of pulmonary surfac-

tant on in vitro activities of telavancin and other antibiotics. Antimicrob


132. Drusano GL, Rubino CM, Ambrose PG, et al. Penetration of vancomycin

into epithelial lining fluid [abstract no. A-11]. 47th Interscience Conference

for Antimicrobial Agents and Chemotherapy (ICAAC); 2007 Sep 17-20;

Chicago (IL)

133. HarigayaY, Bulitta JB, Forrest A, et al. Pharmacodynamics of vancomycin at

simulated epithelial lining fluid concentrations against methicillin-resistant

Staphylococcus aureus (MRSA): implications for dosing in MRSA pneu-

monia. Antimicrob Agents Chemother 2009; 53: 3894-901

134. Lodise TP, Gotfried M, Barriere S, et al. Telavancin penetration into human

epithelial lining fluid determined by population pharmacokinetic model-

ing and Monte Carlo simulation. Antimicrob Agents Chemother 2008; 52:

2300-4

135. Conte Jr JE, Golden JA, Kipps J, et al. Intrapulmonary pharmacokinetics of

linezolid. Antimicrob Agents Chemother 2002; 46: 1475-80

136. Honeybourne D, Tobin C, Jevons G, et al. Intrapulmonary penetration of

linezolid. J Antimicrob Chemother 2003; 51: 1431-4

137. Boselli E, Breilh D, Rimmele T, et al. Pharmacokinetics and intrapulmonary

concentrations of linezolid administered to critically ill patients with venti-

lator-associated pneumonia. Crit Care Med 2005; 33: 1529-33

138. Conte Jr JE, Golden JA, Kelly MG, et al. Steady-state serum and in-

trapulmonary pharmacokinetics and pharmacodynamics of tigecycline. Int J

Antimicrob Agents 2005; 25: 523-9

139. Andrews J, Honeybourne D, Ashby J, et al. Concentrations in plasma, epi-

thelial lining fluid, alveolarmacrophages and bronchial mucosa after a single

intravenous dose of 1.6mg/kg of iclaprim (AR-100) in healthy men. J An-

timicrob Chemother 2007; 60: 677-80

140. Rubino CM,Ma L, Bhavnani SM, et al. Evaluation of tigecycline penetration

into the colon wall tissue and epithelial lining fluid using a population

pharmacokinetic model and Monte Carlo simulation. Antimicrob Agents

Chemother 2007; 51: 2085-9

141. Crandon JL, KimA, Nicolau DP. Comparison of tigecycline penetration into

the epithelial lining fluid of infected and uninfected murine lungs. J Anti-


142. Koomanachai P, Crandon JL, Banevicius MA, et al. Pharmacodynamic

profile of tigecycline against methicillin-resistant Staphylococcus aureus in

an experimental pneumoniamodel. AntimicrobAgents Chemother 2009; 53:

5060-3

143. Deguchi Y, Sun J, Tauchi Y, et al. Distribution characteristics of grepa-

floxacin, a fluoroquinolone antibiotic, in lung epithelial lining fluid and

alveolar macrophage. Drug Metab Pharmacokinet 2003; 18: 319-26

144. Sun J, Deguchi Y, Tauchi Y, et al. Distribution characteristics of orally ad-

ministered olamufloxacin, a newly synthesized fluoroquinolone antibacter-

ial, in lung epithelial lining fluid and alveolar macrophage in rats. Eur J

Pharm Biopharm 2006; 64: 238-45

145. AokiM, Iguchi M, Hayashi H, et al. Active uptake of ulifloxacin in plasma to

lung that controls its concentrations in epithelial lining fluid. Biol Pharm

Bull 2009; 32: 1095-100

146. Winther L, Guardabassi L, Baptiste KE, et al. Antimicrobial disposition in

pulmonary epithelial lining fluid of horses: part I. Sulfadiazine and tri-

methoprim. J Vet Pharmacol Ther 2011; 34: 277-84

147. Winther L, Honore Hansen S, Baptiste KE, et al. Antimicrobial disposition in

pulmonary epithelial lining fluid of horses: part II. Doxycycline. J Vet

Pharmacol Ther 2011; 34: 285-9

148. Winther L, Baptiste KE, Friis C. Antimicrobial disposition in pulmonary

epithelial lining fluid of horses: part III. Cefquinome. J Vet Pharmacol Ther.

Epub 2010 Nov 18

149. Winther L, Baptiste KE, Friss C. Pharmacokinetics in pulmonary epithelial

lining fluid and plasma of ampicillin and pivampicillin administered to

horses. Res Vet Sci. Epub 2010 Dec 6

150. Javsicas LH, Giguere S, Womble AY. Disposition of oral telithromycin in

foals and in vitro activity of the drug against macrolide-susceptible and

macrolide-resistant Rhodococcus equi isolates. J Vet Pharmacol Ther 2010;

33: 383-8

151. Womble A, Giguere S, Lee EA. Pharmacokinetics of oral doxycycline and

concentrations of body fluids and bronchoalveolar cells of foals. J Vet

Pharmacol Ther 2007; 30: 187-93



152. Womble AY, Giguere S, Lee EA, et al. Pharmacokinetics of clarithromycin

and concentrations in body fluids and bronchoalveolar cells of foals. Am J

Vet Res 2006; 67: 1681-6

153. Jacks S, Giguere S, Gronwall RR, et al. Pharmacokinetics of azithromycin

and concentrations in body fluids and bronchoalveolar cells of foals. Am J

Vet Res 2001; 62: 1870-5

154. Suarez-Mier G, Giguere S, Lee EA. Pulmonary disposition of erythromycin,

azithromycin, and clarithromycin in foals. J Vet Pharmacol Ther 2007; 30:

109-55

155. Hawkins EC, Boothe DM, Guinn A, et al. Concentrations of enrofloxacin

and its active metabolite in alveolar macrophages and pulmonary epithelial

lining fluid in dogs. J Vet Pharmacol Ther 1998; 21: 18-23

156. Togami K, Chono S, Seki T, et al. Aerosol-based efficient delivery of teli-

thromycin, a ketolide antimicrobial agent, to lung epithelial lining fluid and

alveolar macrophages for treatment of respiratory infections. Drug Dev Ind

Pharm 2010; 36: 861-6

157. Togami K, Chono S, Seki T, et al. Distribution characteristics of teli-

thromycin, a novel ketolide antimicrobial agent applied for treatment of

respiratory infection, in lung epithelial lining fluid and alveolar macro-

phages. Drug Metab Pharmacokinet 2009; 24: 411-7

158. Chono S, Tanino T, Seki T, et al. Efficient drug delivery to alveolar macro-

phages and lung epithelial lining fluid following pulmonary administration

of liposomal ciprofloxacin in rats with pneumonia and estimation of its

antibacterial effects. Drug Dev Ind Pharm 2008; 34: 1090-6

159. Chono S, SuzukiH,TogamiK, et al. Efficient drug delivery to lung epithelial lining

fluid by aerosolization of ciprofloxacin incorporated into PEGylated liposomes

for treatment of respiratory infections. Drug Dev Ind Pharm 2011; 37: 367-72

160. Chono S, Tanino T, Seki T, et al. Pharmacokinetic and pharmacodynamic

efficacy of intrapulmonary administration of ciprofloxacin for the treatment

of respiratory infections. Drug Metab Pharmacokinet 2007; 22: 88-95

Correspondence: Professor Keith A. Rodvold, University of Illinois at

Chicago, College of Pharmacy, m/c 886, 833 South Wood Street, Room

# 164, Chicago, IL 60612, USA.

E-mail: [email protected]

664 Rodvold et al.


penetration of anti infective agents into.3

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