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Review

10.1517/14656566.9.1.23 © 2008 Informa UK Ltd ISSN 1465-6566 23

Carbapenems: a potent classof antibioticsDavid P Nicolau

Hartford Hospital, Center for Anti-Infective Research and Development, 80 Seymour Street,Hartford, Connecticut 06102-5037, USA

The purpose of this review is to assess the relative strengths and

weaknesses of individual members of the carbapenem class of antibiotics.

Clinical trials and review articles were identified from a Medline

search (1979 – July 2006), in addition to, reference citations from identified

publications, abstracts from the Interscience Conferences on Antimicrobial

Agents and Chemotherapy and the 12th International Congress on Infectious

Disease, and package inserts. Articles in English were reviewed, with emphasis

on those containing efficacy or safety data. Carbapenems bind to critical

penicillin-binding proteins, disrupting the growth and structural integrity of

bacterial cell walls. They provide enhanced anaerobic and Gram-negative

coverage as compared with other β -lactams and their stability against

extended-spectrum β -lactamases (ESBLs) makes them an effective treatment

option. The most common adverse effects are infusion-site complications

and gastrointestinal distress. Ertapenem has limited efficacy against

non-fermenting, Gram-negative bacteria, restricting its use to community-

acquired infections. Imipenem is slightly more effective against

Gram-positive organisms and meropenem slightly more effective against

Gram-negative organisms. However, both have broad-spectrum activity,

including non-fermenting, Gram-negative bacteria. Among non-fermenting,

Gram-negatives, resistance to imipenem in particular is increasing.

Doripenem is in late-stage clinical development and combines the

broad-spectrum coverage of imipenem and meropenem, and more potent

activity against Pseudomonas aeruginosa . Due to the increasing challengesrepresented by ESBLs and multi-drug resistant organisms, the carbapenems

are assuming a greater role in the treatment of serious infections. Imipenem

and meropenem are presently available and have been shown to be

effective against nosocomial infections. Doripenem is an investigational

carbapenem that has completed Phase III clinical trials and that has

the potential to improve on this efficacy and minimize the emergence of

resistance to the carbapenem class.

Keywords: β -lactam, carbapenem, doripenem, ertapenem, imipenem, meropenem

Expert Opin. Pharmacother. (2008) 9 (1):23-37

1. Introduction

More than half of all antibiotics presently available and many antibiotics indevelopment are β -lactams. These antibiotics have a long history of extraordinaryefficacy and unsurpassed safety and remain the most commonly prescribed anti-bacterial agents [1] . This popularity, however, has led to the emergence of resistantbacteria, significantly impairing antibiotic efficacy. Rates of infection withmulti-drug resistant (MDR) pathogens have increased dramatically in hospitalizedpatients and these infections are becoming increasingly important determinants ofclinical outcome [2,3] . Moreover, resistant pathogens have begun to extend beyond

1. Introduction

2. Overview of carbapenems

3. Differentiating the

carbapenems: not all

carbapenems are the same

4. Conclusion

5. Expert opinion



Carbapenems: a potent class of antibiotics

24 Expert Opin. Pharmacother. (2008) 9(1)

the hospital setting. Clearly, MDR pathogens, includingGram-negative bacteria such as Pseudomonas aeruginosa andβ -lactamase-producing (extended-spectrum β -lactamases[ESBLs], AmpC β -lactamases) Enterobacteriaceae spp., are agrowing challenge both from a treatment and infection-controlperspective. Addressing this problem will require developing

new antibiotics, as well as the rational use of presentlyavailable agents [4] .

Carbapenems are the most potent class of β -lactams and,therefore, have typically been reserved in the hospital forthe treatment of the most severely ill patients. They have arelatively broad spectrum of activity against Gram-negativeand Gram-positive organisms, including anaerobes [1] . As aresult, their clinical use has increased over the last 20 yearsas the prevalence of resistance to penicillins, cephalosporins,fluoroquinolones and aminoglycosides has increased [5,6] .Carbapenems are recommended for empiric treatment of avariety of serious infections, including nosocomial pneumonia(in the absence of methicillin-resistant Staphylococcus aureus ),complicated urinary tract infections, complicated intra-abdominal infections, febrile neutropenia, septicemia,complicated skin and skin structure infections, meningitis,and cystic fibrosis [1,3,7-12] . This article reviews thecarbapenem class, particularly focusing on differences amongthose presently available and one that has completedPhase III clinical trials.

2. Overview of carbapenems

2.1 Chemistry

As with most other β -lactams, carbapenems contain a

four-member lactam ring fused to a five-memberthiazolidinic secondary ring through the nitrogen andadjacent tetrahedral carbon atom. In penicillins, this secondaryring is a five-member thiazolidine ring, whereas incephalosporins it is a six-member dihydrothiazine ring.Therefore, the basic structure of carbapenems differsfrom that of penicillins only by the substitution of acarbon atom for sulfur at position 1 and the presence of anunsaturated bond between carbon atoms 2 and 3 inthe secondary ring. It is the side chains attached to thisbasic two-ring structure that differentiate the carbapenemsfrom each other [1] . So far, only three carbapenems,imipenem, meropenem and ertapenem, have been approved

for use in the US and a fourth, doripenem, has recentlycompleted Phase III clinical trials. Figure 1 depicts thechemical structures of these four carbapenems. The sidechains influence antimicrobial activity and provide significantactivity against β -lactamase-producing bacteria. However,these side chains frequently contribute to chemicalinstability and, thus, have limited the clinical use of manycompounds in this class [1] . This instability, as well asthe desire to preserve the class, probably account for therelatively small number of carbapenems developed compared with other β -lactams.

2.2 Mechanisms of action

Carbapenems, like other β -lactams, bind to and inactivatecritical penicillin-binding proteins (PBPs) responsible forelongating and crosslinking the peptidoglycan of the bacterialcell wall. This inhibits growth and also results in damage tothe cell wall, which frequently leads to cell lysis and death.

This interaction occurs near the cell surface in Gram-positivebacteria. However, in Gram-negative bacteria, carbapenemsfirst must gain entry into the periplasmic space between thecell wall and surrounding membrane bypassing throughchannels in the membrane that normally function to provideaccess for essential nutrients. The ability to pass throughthese channels, along with a high affinity for critical PBPsand resistance to a broad range of β -lactamases, is thought toaccount for the broader spectrum of activity of carbapenemsversus most other antibiotics [1,13,14] . In addition, preferentialbinding affinities for various PBPs contributes to the inherentpotency of an antibiotic. Members of the carbapenem classlargely exhibit similar affinities for PBPs and subsequentlypossess similar potency of antimicrobial activity. Imipenembinds preferentially to PBP2, followed by PBP1a and 1b,and has weak affinity for PBP3. Meropenem preferentiallybinds to PBPs 2, 3 and 4. Ertapenem has the strongestbinding affinity for PBPs 2 and 3 of Escherichia coli , althoughit can also bind to PBPS 1a, 1b, 4 and 5, similar toimipenem. Preliminary studies showed that doripenempreferentially binds PBP2 of E. coli and PBPs 2 and 3of P. aeruginosa , similar to meropenem [15] .

Carbapenem activity tends to be both rapid andbactericidal [9,11,13,16,17] . Unlike most other antibiotics,most carbapenems are effective against clinically-significant,

Gram-negative, non-fermenters (e.g., P. aeruginosa ,Burkholderia cepacia and Acinetobacter spp.) [18-20] and anaerobes [12] .

Of all β -lactams, carbapenems provide the bestcoverage against Gram-negative organisms [12] . This enhancedcoverage is due to several factors. Unlike other β -lactams,carbapenems are stable against ESBLs and AmpCβ -lactamases [3,12,21,22] . Although they are susceptible tocarbapenemases and metallo-β -lactamases, so far, theseresistance mechanisms are less common; however, they areincreasing worldwide [23-25] . In addition, carbapenemsare the only β -lactams with a significant postantibiotic effectagainst Gram-negative organisms [26-28] .

In contrast to the efficacy of aminoglycosides andfluoroquinolones, which is concentration-dependent, theefficacy of carbapenems and other β -lactams is time-dependent(i.e., directly related to the percentage of the dosing intervalduring which free-drug concentration exceeds minimuminhibitory concentration [%T > MIC]) [29-32] . Moreover,carbapenems require a %T > MIC that is lower than otherβ -lactams. The %T > MIC required varies somewhat accordingto the specific drug and pathogen examined, but the%T > MIC required for bacterial stasis is ∼ 20% forcarbapenems, 30% for penicillins and 40% for cephalosporins.



Nicolau

Expert Opin. Pharmacother. (2008) 9(1) 25

Similarly, the %T > MIC required for maximum kill is∼ 40% for carbapenems, 50% for penicillins and 60 – 70%for cephalosporins [31] . The lower %T > MIC required forcarbapenems to achieve either bacterial stasis or kill may bea result of their postantibiotic effect or increased affinity forcertain PBPs as compared with other β -lactams [1,26] .

Most carbapenems are administered as an intravenousinfusion. Because efficacy is directly related to %T > MIC,prolonging infusion duration can improve efficacy withoutrequiring an increase in dose [30,33] . A minimal stability of

Figure 1 . Chemical structures of imipenem, meropenem, ertapenem and doripenem [52-54,98] .

Imipenem

Meropenem

Ertapenem

Doripenem

Carbapenem core Side chain

OH

N

O

NH

NH

O

NH

O

NH

S

O

NH

O

NH2

NH

H

NH

S

HO

H

OH

H

CH3

CH3

O

O

N

S

HO

H

OH

O

N

O

S

HO

H H

O

O

OH

N

S

HOCH3

H H

O

O

OH

N

the drug in solution is a prerequisite for prolonging infusionduration: the drug must remain stable from the time it isprepared for infusion until the end of the infusion period [34] .Both imipenem and meropenem are considered relativelyunstable (10% degradation at 25° C after 3.5 and 5.5 h,respectively) [35] . Therefore, these drugs cannot be infusedfor > 2 – 3 h, unless extraordinary measures are used [34,36] .Doripenem appears to have increased stability compared with other carbapenems, such that it is stable in solutionfor ≤ 12 h at 25° C [37] .





2.3 Safety

Carbapenems have a safety profile similar to or better thanthat of other β -lactams [14] . Although there are somedrug-specific considerations (discussed under the individualdrugs in Section 3), as a class, the most common clinicaladverse events are infusion site complications, diarrhea, nausea

and vomiting [14,38,39] . In addition, although the overall riskof seizures is low (< 2%) there is an increased risk of seizuresassociated with carbapenems when given in high doses or topatients with renal dysfunction or CNS injury. Consequentlythe FDA requires carbapenem class labeling that warns ofseizures as a possible adverse event [8,14,38,40,41] .

This safety profile compares favorably with that of othercommonly employed antibiotics. The prevalence of drugfever and/or drug rash with carbapenems is lower than thatfor penicillins and sulfa-containing drugs [42] , and theprevalence of nausea and vomiting is substantially lowerthan that reported for the broad-spectrum glycylcyclinetigecycline [43] . Cephalosporins can induce thrombocytopenia with or without leukopenia, but this does not appear to bea significant issue with carbapenems [14,44] . Fluoroquinolonescan cause hepatotoxicity and prolongation of the QTc interval,and their use in children is frequently limited by concernsregarding joint/cartilage toxicity [45-47] . Vancomycin isassociated with dose-related nephrotoxicity and neutropeniaand requires monitoring of drug levels [48,49] . Similarly,aminoglycosides are associated with both nephrotoxicity andototoxicity, and require monitoring of drug levels [44,50,51] .

2.4 Hypersensitivity

Present labeling states that, before initiating therapy with a

carbapenem, a careful inquiry should be made about previoushypersensitivity reactions to penicillins, cephalosporins andother β -lactams [52-54] . However, whether or not this historyshould preclude the use of carbapenems remains unresolved.

It is important to consider that the reliability ofhistorical information concerning a penicillin allergy isgenerally quite low, as patients tend to confuse adversedrug reactions with allergic reactions [55] . A correctdiagnosis of a penicillin allergy does not necessarily,however, preclude the safe use of a carbapenem. First of all,there is limited cross-reactivity between carbapenems andother β -lactams [55-57] . Approximately 11% of patients with a documented penicillin allergy experience an allergic

reaction to a carbapenem [56] . In addition, hypersensitivityreactions tend to be stereotyped (i.e., the reaction toan allergen on subsequent exposures is similar to that ofprevious reactions) [55] . Maculopapular rashes and/or drugfever comprise most penicillin allergic reactions, but notanaphylaxis. Therefore, patients are not likely to suddenlydevelop an anaphylactic reaction on re-exposure to aβ -lactam [55] . When a carbapenem is being considered, itusually means the patient is at risk for a serious nosocomialinfection and safe, effective treatment options other than acarbapenem are limited. These patients are also most likely

to be treated in an intensive care setting where, if ananaphylactic reaction occurs, appropriate personnel arepresent to rapidly recognize and treat it.

3. Differentiating the carbapenems: not allcarbapenems are the same

Individual members of the carbapenem class possess distinctpharmacologic properties, spectra of activity and safetyprofiles (Table 1 ), which significantly impact treatmentselection in individual patients.

3.1 Imipenem

In 1976, Kahan et al. presented their discovery of the firstmedically-important carbapenem, thienamycin, which hadan unusually broad spectrum of antibiotic activityagainst Gram-positive and -negative organisms. However,it hydrolyzed at pH > 8 and reacted with nucleophiles(including its own primary amine), thereby limiting itsclinical use [58] . N -formimidoyl thienamycin (imipenem) was more chemically stable and became the first carbapenemapproved for clinical use in the US in 1985 [1,14] . Imipenemis still widely used, despite its disadvantages compared withnewer carbapenems.

Imipenem is hydrolyzed by dehydropeptidase I (DHP-I)at renal brush border cells. This process not onlyinactivates imipenem, but can also produce a nephrotoxiccompound. Consequently, the DHP-I inhibitor cilastatin, which has no antimicrobial activity of its own, isalways coadministered with imipenem in a 1:1 ratioby weight [14] . For convenience, the term imipenem will

be used in this review to refer to either imipenem orimipenem/cilastatin.

3.1.1 Pharmacokinetics/dosing

Imipenem is administered as a 20- to 60-min intravenousinfusion. Its half-life is 1 h and 20% of it binds toplasma proteins. Urinary recovery is ∼ 70% at 10 h, withno further recovery detected thereafter. Once reconstituted,imipenem is stable for ∼ 4 h at room temperature [54] .In a comparative evaluation in aqueous solution, 10% ofimipenem was degraded after 3.5 h, 30% was degraded after24 h and degradation was not reduced by maintainingthe solution at 4° C (30% degradation at 24 h) [35] . This

degradation limits the ability of imipenem infusions to beused in an extended (3 – 4 h) infusion that could optimizethe pharmacodynamic profile of the agent [31] .

In patients weighing ≥ 70 kg with normal or onlymildly-impaired renal function, the recommended doseof imipenem varies from 250 to 1000 mg every 6 – 8 h,depending on the type and severity of infection.Resulting peak plasma concentrations range from 14 to24 µg/ml for the 250-mg dose to 41 – 83 µg/ml for the1000-mg dose; plasma concentrations decline to < 1 µg/mlafter 4 – 6 h [54] .



Nicolau


Table 1. Comparison of the characteristics of each carbapenem.

Characteristic Imipenem Meropenem Ertapenem Doripenem

FDA status Approved 1985 Approved 1996 Approved 2001 Fast-track designation

Dose 250 – 1000 mgdepending on type and

severity of infection

500 – 2000 mg‡ depending on type

of infection

1000 mg§ TBD

Administration

Intravenous infusion Yes Yes Yes Yes

Infusion duration 20 – 60 min 15 – 30 min¶ 30 min TBD

Intramuscular injection Yes No Yes No

Frequency of administration Every 6 – 8 h Every 8 h‡ Every 24 h TBD

Pharmacologic properties

Half-life ∼ 1 h ∼ 1 h ∼ 4 h ∼ 1 h

Protein binding 20% 2% 85 – 95% 9%

Renal excretion 70% 70% 80% 60 – 75%

Stability in aqueous solution

at room temperature

∼ 4 h ∼ 6 h ∼ 6 h ∼ 12 h

Spectrum of activity#

Gram-positive aerobes

Corynebacteria‡‡ Susceptible Susceptible Susceptible Susceptible

EnterococcusEnterococcus faecalis

Enterococcus faecium

Susceptible (excludingvancomycin-resistant)Resistant

Susceptible (excludingvancomycin-resistant)Resistant

Resistant

Resistant

Susceptible (excludingvancomycin-resistant)Not reported

Listeria Susceptible Susceptible Resistant Not reported

Rhodococcus equi Susceptible Resistant Not reported Not reported

Staphylococcus aureus Susceptible (excludingmethicillin-resistant)

Susceptible (excludingmethicillin-resistant)



Streptococcus pneumoniae Susceptible Susceptible Susceptible(excludingpenicillin-resistant)

Susceptible

Streptococcus pyogenes Susceptible Susceptible Susceptible Susceptible

Viridans group streptococci Susceptible Susceptible Susceptible Susceptible

Gram-negative aerobes

Acinetobacter Susceptible Susceptible Resistant Susceptible

Burkholderia cepacia Resistant (most) Susceptible Resistant Susceptible

Citrobacter Susceptible Susceptible Susceptible Susceptible

Enterobacter Susceptible Susceptible Susceptible Susceptible

Escherichia coli Susceptible Susceptible Susceptible Susceptible

Flavobacterium Resistant Resistant Not reported Not reported

Gardnerella vaginalis Susceptible Susceptible Not reported Not reported

Haemophilus Susceptible Susceptible Susceptible Susceptible

*Reduce dose in patients with body weight < 70 kg or creatinine clearance≤ 70 ml/min/1.73 m2 .

‡ Reduce frequency of administration in patients with creatinine clearance≤ 50 ml/min; reduce dose and frequency of administration in patients with creatinine

clearance ≤ 25 ml/min.§Reduce dose by 50% in patients with creatinine clearance≤ 30 ml/min/1.73 m2 .¶Doses ≤ 1000 mg may be given as an intravenous bolus over 3 – 5 min.#Includes available in vitro data with unknown clinical significance.**Based on imipenem, meropenem and ertapenem package insert [51-53]. Based on doripenem clinical trials [38,106,107]. Incidence may vary as they are not

head-to-head studies.‡‡ Except for Corynebacterium jeikeium , which is resistant.

NA: Not applicable; TBD: To be determined.





Table 1. Comparison of the characteristics of each carbapenem (continued).

Characteristic Imipenem Meropenem Ertapenem Doripenem

Klebsiella Susceptible Susceptible Susceptible Susceptible

Moraxella Susceptible Susceptible Susceptible Susceptible

Morganella morganii Susceptible Susceptible Susceptible Susceptible

Neisseria Susceptible Susceptible Susceptible Not reported

Proteus mirabilis Susceptible Susceptible Susceptible Susceptible

Proteus vulgaris Susceptible Susceptible Susceptible Susceptible

Providencia rettgeri Susceptible Susceptible Susceptible Susceptible

Pseudomonas aeruginosa Susceptible (most) Susceptible Resistant Susceptible

Serratia Susceptible Susceptible Susceptible Susceptible

Stenotrophomonasmaltophilia

Resistant Resistant Resistant Resistant

Anaerobes

Bacteroides Susceptible Susceptible Susceptible Susceptible

Clostridium difficile Susceptible Susceptible Susceptible Susceptible Eubacterium Susceptible Susceptible Susceptible Not reported

Fusobacterium Susceptible Susceptible Susceptible Susceptible

Peptococcus Susceptible Susceptible Not reported Not reported

Peptostreptococcus Susceptible Susceptible Susceptible Susceptible

Propionibacterium Susceptible Susceptible Not reported Susceptible

Adverse events (> 2%** )

Phlebitis/thrombophlebitis 3.1% < 2% < 2% 0 – 10.6%

Injection-site inflammation NA 2.4% NA NA

Infusion vein complications 3.7%

Gastrointestinal

Diarrhea < 2% 4.8% 5.5% 2.5 – 13.2%Nausea 2.0% NA 3.1% 2.9 – 14.5%

Vomiting < 2% NA < 2% NA

Nausea/vomiting NA 3.6% NA 6.6%

Headache NA 2.3% 2.2% 4.5%

Vaginitis (females) NA NA 2.1% NA

Mechanism of acquiredbacterial resistance

Carbapenemases/ metallo-β -lactamasesDecreased affinity ofpenicillin-binding proteins

Reduction in porin channels

Carbapenemases/metallo-β -lactamasesDecreased affinityof penicillin-bindingproteins Reduction in porinchannels combined

with upregulation ofefflux mechanisms

Carbapenemases/ metallo-β -lactamasesDecreased affinityof penicillin-bindingproteinsReduced intracellularaccumulation

Carbapenemases/ metallo-β -lactamasesDecreased affinityof penicillin-bindingproteins Reduction in porinchannels combined

with upregulation ofefflux mechanisms

*Reduce dose in patients with body weight < 70 kg or creatinine clearance≤ 70 ml/min/1.73 m2 .

‡ Reduce frequency of administration in patients with creatinine clearance≤ 50 ml/min; reduce dose and frequency of administration in patients with creatinine

clearance ≤ 25 ml/min.§Reduce dose by 50% in patients with creatinine clearance≤ 30 ml/min/1.73 m2 .¶Doses ≤ 1000 mg may be given as an intravenous bolus over 3 – 5 min.#Includes available in vitro data with unknown clinical significance.**Based on imipenem, meropenem and ertapenem package insert [51-53]. Based on doripenem clinical trials [38,106,107]. Incidence may vary as they are not

head-to-head studies.‡‡ Except for Corynebacterium jeikeium , which is resistant.

NA: Not applicable; TBD: To be determined.



Nicolau


3.1.2 Safety

Imipenem is generally safe and well tolerated (Table 1 compares the carbapenems) [14,54] . Although the overall riskof seizures is low, a concern about β -lactam administrationand seizures re-emerged when imipenem was introduced [59] .Several studies reported a higher rate of seizures (generally

between 5 and 10%) when a higher dose (4 g/day) ofimipenem was used [41,60,61] ; when the dose was reduced to2 g/day, seizure activity ceased [61] . Although there was aslightly higher drug-related seizure rate associated withimipenem versus meropenem in patients (excluding those with CNS disease) in clinical studies directly comparingimipenem and meropenem, there was no significant difference(0.28 versus 0.08%) between imipenem and meropenem [62,63] .Therefore, the risk of seizures with imipenem may not behigher than that observed with the other carbapenems whenthe dose is limited to 2 g/day. However, special caution isneeded when treating patients with renal impairment, asthey do not clear the drug well (resulting in potentiallyseizurogenic levels in the blood) [40,61] , and in patients withCNS injury (e.g., stroke, head injury) [64] . Moreover, dosinglimitations may contribute to treatment failure for seriousinfections caused by P. aeruginosa and other Gram-negativeorganisms, and may ultimately be a factor in the emergenceof resistance to imipenem therapy [32,65-67].

Imipenem-related gastrointestinal adverse events arealso dose-dependent [68] . Nausea and vomiting usuallyoccur during imipenem infusion and, in some, but notall individuals, can be ameliorated by decreasing theinfusion rate [14,68] .

3.1.3 EfficacyImipenem has one of the broadest spectra of activity ofany available, systemic antibiotic. Most Gram-positiveand -negative aerobic and anaerobic bacteria aresusceptible to imipenem, including those producingESBLs (Table 1 ) [5,14,17,54,69] . The primary exceptions tothis sensitivity are methicillin-resistant staphylococci,vancomycin-resistant enterococci and corynebacteria amongGram-positive aerobic bacteria; B. cepacia, Flavobacterium and Stenotrophomonas maltophilia among Gram-negativeaerobic bacteria; and Clostridium difficile among anaerobicbacteria. In general, imipenem has higher MIC valuesthan other carbapenems against Gram-negative bacteria,

although for most pathogens this probably has littleclinical impact [14,70,71] .

The recommended imipenem dose is 2 – 4 g/day [14,40,72] .The higher neurotoxicity potential of imipenem at highdoses (≥ 4 g/day) increases the complexity of usingimipenem and may preclude its use for infections requiringhigh doses of antibiotics, such as bacterial meningitis [8] . When 2 g/day of imipenem was used, relapses and super-infections with Pseudomonas spp. were more common withimipenem (6/18) than with ceftazidime (1/11) [73] . The curerate of complicated intra-abdominal infections achieved with

imipenem 500 mg every 6 h was 76%; this 24% failurerate suggests that the lower dose of imipenem may beinadequate [74] . Separately, in 18 patients who had culturesthat responded to imipenem, the 500-mg every 6 h dosefailed to result in a clinical response in 14 of the patients.Many of the persisting isolates were highly susceptible to

imipenem and a response was observed at 1 g every 6 h [75] .There is no report, however, of a double-blind clinical trialcomparing imipenem 2 g/day with 4 g/day.

The emergence of resistance in P. aeruginosa hasbeen observed during imipenem therapy [65,76,77] . In acase-controlled evaluation of hospitalized patients, priorimipenem therapy was found to be the most significantindependent risk factor for the detection of imipenem-resistantP. aeruginosa (odds ratio: 23.2; 95% CI: 4.1 – 132.7) andthese resistant bacteria were also typically resistant to otherantipseudomonal agents [77] . Similarly, in a study of patients with P. aeruginosa treated with a variety of antibiotics,the use of imipenem was associated with a significantlyincreased risk of emergent resistance to imipenem itself(hazard ratio: 44; p = 0.001), as well as to other antibiotics(hazard ratio: 2.8; p = 0.02) [65,76,77] . Lastly, periods ofextensive imipenem use have been associated with significantincreases in P. aeruginosa resistance to imipenem [78] .

3.1.4 Development of resistance

Bacterial resistance is acquired through one of threemechanisms: i) production of carbapenemases/metallo- β -lactamases; ii) alteration of critical PBPs; andiii) downregulation of porin channels (Table 1 ) [25,66,79,80] .Carbapenemases/metallo-β -lactamases are either chromo-

somally encoded or plasmid-mediated enzymes that hydro-lyze the β -lactam ring of virtually all β -lactams, includingcarbapenems. These enzymes are still relatively rarecompared with other β -lactamases, but, once acquired, areeasily transmitted between bacteria and produce multi-drugresistance [25] . Structural changes in critical PBPs, such asoccur in methicillin-resistant staphylococci, alter the affinityof these proteins for β -lactams, including carbapenems [80] .Finally, various Gram-negative bacteria (P. aeruginosa ,Enterobacter spp., Klebsiella pneumoniae ) can downregulatethe porin channels necessary for antibiotics to enter thebacterial cell [66,81,82] .

The downregulation of the OprD porin in mutants

of P. aeruginosa increases the MIC of imipenem by 8- to16-fold, usually conferring resistance, but does not in itselfproduce resistance to most other β -lactams. Resistance ofGram-negatives to imipenem also requires increasedβ -lactamase activity. For P. aeruginosa , Enterobacter spp. andother organisms that contain a chromosomal copy of an AmpC β -lactamase, this is a simple matter of increasingexpression of this gene [66,81] . Furthermore, it should benoted that imipenem induces expression of AmpCβ -lactamase in P. aeruginosa more readily than meropenemor doripenem [83] . For K. pneumoniae , an ESBL or AmpC





β -lactamase must be acquired by means of a plasmid inorder to become fully imipenem resistant, which is a lessfrequent occurrence [82] .

3.2 Meropenem

Meropenem, another thienamycin derivative, was approved

for use in the US in 1996 [14] . Meropenem has a 1-β -methylsubstitution in its side chain (Figure 1 ) and this substitutionprobably accounts for the differences in pharmacologicproperties between it and imipenem. Unlike imipenem, it isnot significantly affected by DHP-I and, thus, does notrequire coadministration of a DHP-I inhibitor duringclinical use [14,68] .


The pharmacokinetic properties of meropenem are similarto those of imipenem (Table 1 ) [14,52] . Meropenem istypically administered as a 15- to 30-min intravenousinfusion, although a dose ≤ 1000 mg can be given as abolus over 3 – 5 min. It has a half-life of ∼ 1 h and 2%is bound to plasma proteins. Urinary recovery is ∼ 70% at12 h, with no further recovery detected thereafter [52] .

At room temperature, meropenem is stable for ∼ 2 h when reconstituted in dextrose solution and 4 h when reconstituted in sodium chloride solution [52] .Meropenem was 10% degraded, however, after 5.25 hand ∼ 22% degraded after 24 h at 25° C. However, unlikeimipenem, this degradation could be eliminated almostcompletely by maintaining the reconstituted solutionat 4° C [35] . As with imipenem, this low stability inaqueous solution without resorting to cooling, limits

the practicality of extended infusions that couldmaximize %T > MIC. Therefore, infusions longer than 3 hhave not routinely been performed [34] .

In adults with normal or only mildly-impaired renalfunction, the recommended doses of meropenem are500 mg every 8 h for skin infections, 1000 mg every 8 hfor intra-abdominal infections and 2000 mg every 8 h formeningitis. When infused over 30 min, peak plasmaconcentrations range from 14 to 26 µg/ml for the 500-mgdose and from 39 to 58 µg/ml for the 1000-mg dose.Plasma concentrations decline to ∼ 1 µg/ml after 6 h.Similar to imipenem, these doses must be reduced in patients with renal insufficiency [14,52] .

3.2.2 Safety

Meropenem, also generally safe and well tolerated, isassociated with a lower overall adverse event rate thanimipenem (Figure 2 ) [68] . It has a lower risk for seizuresat high doses and its gastrointestinal effects are notdose-dependent [14,62,63] . As a result, meropenem doses canbe elevated to improve efficacy and potentially reduce theemergence of resistant organisms [4,14,66] . Its safety at higherdoses and lower CNS toxicity permit it to be used to treatbacterial meningitis [1,8,14] .

3.2.3 Efficacy

Meropenem has a broad spectrum of activity thatcovers most Gram-positive and -negative aerobic andanaerobic bacteria (Table 1 ) [1,12-14,17,24,52,70,71,84,85] . Ingeneral, it is slightly less active against Gram-positivebacteria and slightly more active against Gram-negative

bacteria than imipenem in vitro [14,86] . In a meta-analysis ofclinical trials comparing meropenem with imipenem, mero-penem was associated with slightly, but significantly greater,clinical and bacteriologic responses and a nonsignificantreduction in mortality (Figure 2 ) [68] .


The mechanisms by which P. aeruginosa resistance tomeropenem is acquired are similar to those for imipenem with one notable exception (Table 1 ): unlike imipenem, for which a single mutation that reduces porin channels(i.e., OprD mutants) confers resistance, resistance to meropenemrequires two independent mutations. These are the OprDmutation, which reduces porin channels, and a mutationto upregulate cellular efflux mechanisms mediated byMexA-MexB-OprM (nalB mutation at the mexR locus) [23,66] .One of these mutations alone only reduces sensitivity tomeropenem and does not confer resistance [23,66] . Inaddition, as with imipenem, the derepression of AmpCβ -lactamase is required to achieve frank resistance [66] .

The likelihood that a cell will simultaneously undergoboth mutations is < 10-14 compared with a 10-7 likelihoodfor a single mutation [66] . Consequently, the rate of selectionof resistance to meropenem in vitro is lower than that forimipenem [23] . However, when resistance to meropenem

occurs, the upregulated efflux seen in such isolates alsoconfers broad-spectrum resistance to most β -lactams,fluoroquinolones, tetracycline and chloramphenicol [66] .Nevertheless, the overall prevalence of resistance tomeropenem has remained lower than that of imipenem overthe last 10 years of clinical use [12,20,22] .

3.3 Ertapenem

Ertapenem was approved for use in the US in 2001and remains the least prescribed of the carbapenems asmeasured by international sales [87] . Its pharmacologicproperties and spectrum of activity are different enoughfrom those of imipenem and meropenem that it is generally

considered to belong to its own separate class within thecarbapenem group [38,87] .


The pharmacokinetics/dosing of ertapenem are summarizedin Table 1 [38,53,87] . Of note, ertapenem has a highprotein-binding percentage and a long half-life, permittingonce-daily administration. This administration can occur viaintramuscular or intravenous injection, eliminating anyconcern over drug stability in aqueous solution. Dosing appearsto be less susceptible to the effects of renal dysfunction.



Nicolau


3.3.2 Safety

Ertapenem is generally safe and well tolerated (Table 1 ).The most common adverse events are gastrointestinal andinfusion-site complications. Similar to meropenem, it haslow potential to induce seizures [38,53] .

3.3.3 EfficacyThese beneficial pharmacokinetic properties, however, are offsetby a reduced spectrum of activity (Table 1 ) [16,17,38,53,70,87-89] .Ertapenem has only limited activity against Gram-negative,non-fermenting bacteria, such a P. aeruginosa, B. cepacia and Acinetobacter spp. [16,38,87] . Although ertapenem is indicatedfor clinical use to treat infections with ESBL-producingpathogens, its activity is lower against these bacteria thanother carbapenems [90,91] . As a result, the use of ertapenemis limited to treating serious community-acquired infections;it should not be routinely used empirically to treatnosocomial infections [38] .

3.3.4 Development of resistanceResistance to ertapenem results from acquisition ofβ -lactamases, decreased affinity of PBPs and reducedintracellular accumulation [87] . Resistance to ertapenem byGram-negatives, especially those expressing β -lactamases,appears to occur more easily than for other carbapenems [92] .In a recent case report, treatment of ertapenem-susceptible K. pneumoniae led to the emergence of anESBL-producing ertapenem-resistant strain [90] . Ertapenemis also more sensitive to the action of efflux pumpsin Gram-negatives [18] .

3.4 Doripenem

Doripenem is an investigational carbapenem that hascompleted Phase III studies for the treatment ofcomplicated intra-abdominal infections, complicated urinarytract infections and nosocomial pneumonia (includingventilator-associated pneumonia). Doripenem was approved

in Japan in July 2005 and has been effective clinically andmicrobiologically for the treatment of various infections,including hospital-acquired pneumonia [93,94] . Similarly tomeropenem and ertapenem, it has a 1-β -methyl substitutionin its side chain (Figure 1 ), rendering it stable to DHP-I andeliminating the need for coadministration of a DHP-Iinhibitor [95] . Similar to other carbapenems, doripenem hasa basic group in the side chain at position two (Figure 1 ).However, the side chain of doripenem at position two is lessbasic than that of meropenem or imipenem, probablyexplaining its enhanced activity in vitro against P. aeruginosa (see below) [96] .

3.4.1 Pharmacokinetics/dosingThe pharmacokinetics/dosing of doripenem are comparableto those observed for impenem and meropenem, and aresummarized in Table 1 [17,69,97-100] . The one notableexception is a threefold greater duration of stability inaqueous solution at room temperature. This increased stabilityallows for preparation in advance of its use and extendedinfusion durations to improve efficacy and minimize theemergence of resistant organisms without having to resortto external cooling [31] . The use of extended infusiontimes becomes more valuable for infections with bacteria

Figure 2 . Comparative clinical response, bacteriologic response, mortality and adverse events for meropenem versusimipenem plus cilastatin, based on a meta-analysis of clinical trial data. Dots represent the point estimate of the relative risk for

meropenem versus imipenem plus cilastatin and lines represent the 95% confidence intervals around these point estimates [68] .

0.70 0.75 0.80 0.85 0.90 0.95 1.00 1.05 1.10 1.15 1.20 1.25 1.30 1.35

Relative risk (95% confidence interval)

Clinical response

Bacteriologic response

Mortality

Adverse event rate

1.04 (1.01 – 1.06)

1.05 (1.01 – 1.08)

0.98 (0.71 – 1.35)

0.87 (0.77 – 0.97)





that have relatively high MIC values. Figure 3 depictssimulated concentration–time profiles based on populationpharmacokinetic parameters for a single 500-mg dose ofdoripenem infused over 1 – 6 h. This figure illustrates thatextending the infusion time of doripenem increases the%T > MIC for relatively difficult-to-treat pathogens, butstill using the same total dose [97] .

3.4.2 Safety

In initial Phase I and II studies, doripenem appeared to begenerally safe and well tolerated. In animal studies, thepropensity of doripenem to induce seizure activity was lessthan that of other carbapenems. Intravenous injection ofdoripenem in rats (100 – 400 mg/kg) had no effect onelectroencephalograph (EEG) patterns or behavior, incontrast to imipenem, which caused spikes in EEG patternsand various behavioral signs of neurotoxicity, and meropenem, which caused wet dog shakes [41] . Intracerebroventricularinjection of doripenem in dogs (100 – 1000 µg) had noeffects on either EEG patterns or behavior, whereas similardoses of meropenem and, especially, imipenem causedvarious EEG spikes, spasms and even convulsions. Seizure

activity of β -lactams is thought to be a function of theirability to block binding of GABA to its receptor. Consistent with this, doripenem had lower affinity to GABA receptorsthan meropenem, as measured by 3H-muscimol binding incerebral cortical membranes from mice [41] .

In Phase III clinical trials, doripenem 500 mg every 8 h was well tolerated in patients with complicated intra-abdominalinfections. No seizures were reported and the most commondrug-related adverse events were nausea (3.7%) and diarrhea(2.5%) [39,83] . Additional surveillance will be critical tofurther characterizing the safety profile of this drug.

3.4.3 Efficacy

Doripenem has an activity profile that combines thebest features of imipenem and meropenem(Table 1 ) [1,17,19,23,69-71,101,102] . It has better activity againstGram-positive organisms than meropenem and better activityagainst Gram-negative organisms than imipenem [17,70] . Inaddition, its MIC values against P. aeruginosa are lower thanother antipseudomonal agents, including the availablecarbapenems [19,103] , but it still maintains its potency against

ESBL-containing pathogens [23,71] .Based on in vitro studies, doripenem can be combinedsafely with a wide variety of antimicrobial agents, includingamikacin, cotrimoxazole, levofloxacin, daptomycin, vanco-mycin and linezolid, allowing for an even greater spectrumof activity. There is synergistic activity with doripenem plusdaptomycin against enterococci, and doripenem plusvancomycin against 92% of methicillin-resistant strainsof S. aureus [102,104] . Additional clinical studies of combinationtherapy with doripenem are needed.

Doripenem 500 mg every 8 h i.v. was clinically effectivein the treatment of patients with complicated intra-abdominalinfections, with clinical cure rates similar (non-inferior)

to meropenem 1 g every 8 h i.v. (83.3 versus 83.0%clinical cure, respectively, in the microbiologically-evaluablepopulation) [39,105] . Doripenem was microbiologicallyeffective against the major of causative pathogens ofcomplicated intra-abdominal infections, includingE. coli , K. pneumoniae , P. aeruginosa , Streptococcus intermedius ,Bacteroides caccae, Bacteroides thetaiotaomicron , Bacteroides fragilis and Bacteroides uniformis , with similar microbiologiceradication rates as meropenem [39,105] . Doripenem 500 mgevery 8 h i.v. was also microbiologically and clinicallyeffective in the treatment of patients with complicated

Figure 3 . Simulated effect of infusion duration on the concentration–time profile of a 500-mg dose of doripenem based on

population pharmacokinetic parameters [97] .LLQ: Lower limit of quantification.

6 h5 h4 h3 h2 h1 h

Duration of infusion

Time (h)

0.25

C o n c e n t r a t i o n ( µ g / m l )

0.5

1

2

4

8

16

0 2 4 6 8 10 12

0.2 LLQ



Nicolau


urinary tract infection and pyelonephritis, with clinicalcure rates similar (non-inferior) to levofloxacin 250 mgevery 24 h i.v. Doripenem was microbiologically effectiveagainst the major causative pathogens of complicatedurinary tract infections, including E. coli , Proteus spp.,Klebsiella spp., Enterobacter spp. and P. aeruginosa [106] .


Doripenem has the lowest in vitro rate of emergence ofresistant P. aeruginosa [23,107] of all presently availablecarbapenems and this rate can be further reduced by addingan aminoglycoside [108] . However, resistance to doripenemis believed to occur through similar mechanisms as formeropenem (Table 1 ) [23,70,102] . Decreased resistanceselection with doripenem may help to preserve and prolongthe overall use of the entire carbapenem class.

4. Conclusion

Carbapenems are the most potent β -lactams available. Theygenerally have low resistance rates for most Gram-negativepathogens and favorable safety profiles. Carbapenems playan increasingly important role in treating serious nosocomialinfections, but they are not all the same. Ertapenem use isgenerally restricted to community-acquired infections due toits limited efficacy against non-fermenting, Gram-negativebacteria. In contrast, imipenem and meropenem are generallyeffective against these bacteria (although resistance isincreasingly common among strains of P. aeruginosa ) and areindicated for the treatment of nosocomial infections.Doripenem, an investigational carbapenem that completedPhase III clinical trials, combines the antibacterial activity

profile of imipenem and meropenem and is associated witha lower in vitro rate of the emergence of resistance.Consequently, doripenem has the promising potentialto improve on the efficacy of carbapenems and minimizeresistance to the carbapenem class.

5. Expert opinion

The use of carbapenems for the treatment of complicatednosocomial infections began > 20 years ago with theavailability of imipenem combined with cilastatin.

Meropenem became available 10 years later and it had animproved profile against Gram-negative pathogens, notablyP. aeruginosa , compared with imipenem. Ertapenem was thenext addition to the class, but its susceptibility profilemade it less useful for complicated nosocomial infections,but useful for complicated community-acquired infections

where P. aeruginosa was not considered a pathogen ofconcern. It has a long half-life and can be given by infusionor intramuscularly once a day.

The rise in MDR, Gram-negative pathogens, such asP. aeruginosa , and a dearth of new, highly effective antibioticshas necessitated finding ways to use existing antibiotics moreeffectively. The use of pharmacodynamic approaches tomaximize antibiotic efficacy has emerged and the extendedor prolonged intravenous infusion technique has been shownto be an effective way to optimize efficacy and minimize(at least theoretically) emergent resistance. Into this milieu,doripenem is likely to emerge. Surveillance data have shownit to be more potent than the other carbapenems and ithas a stability (12 h) in 0.9% saline that is triple that ofimipenem and meropenem. Therefore, doripenem is expectedto be clinically useful against MDR pathogens when used asboth a standard 1-h intravenous infusion and the extended-infusion methodologies because of its stability and potency.Positive efficacy and safety data for doripenem at higherdoses would additionally improve its suitability for moreresistant infections.

Although there is no doubt that the use of thecarbapenem class will increase in an attempt to keep pace with the rising prevalence of MDR pathogens in the globalhealthcare setting, attention must be given to the optimal

use of these agents (i.e., antimicrobial stewardship activities[antimicrobial discontinuation, shorten duration andde-escalation when appropriate]) if their long-term clinical

viability is to be maintained.

Declaration of interest

D Nicolau has received no financial support for this review.However, he has received research grants, is a consultantfor and is on the speaker’s bureau for AstraZeneca, Johnson & Johnson, Merck and Ortho-McNeil.





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Nicolau


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Affiliation David P Nicolau PharmD FCCP

Hartford Hospital,

Center for Anti-Infective Research

and Development,

80 Seymour Street, Hartford,Connecticut 06102-5037, USA

Tel: +1 860 545 3941; Fax: +1 860 545 3992;

E-mail: [email protected]

expert opinion on pharmacotherapy volume 9 issue 1 2008 [doi 10.1517%2f14656566.9.1.23] nicolau,...

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