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WP 1

D1.1

Multicenter open-label RCT to compare colistin alone vs.

colistin plus meropenem

1


BACKGROUND

Colistin has resurged in the last decade for the treatment of multidrug-resistant Gram-negative

bacteria due to lack of other antibiotics. This antibiotic, firstly discovered in 1947, belongs to the

polymyxin family and is a mixture of polymyxin E1 and polymyxin E2. The polymyxins act by

disrupting the cell membrane. They have a strong positive charge and a hydrophobic acyl chain

that confer them a high binding affinity to lipopolysaccharide (LPS) molecules. They interact

electrostatically with these molecules and competitively displace divalent cations from them,

causing disruption of the membrane. [1, 2] Electron microscopy studies show protrusions and

bleb formation of the cell membrane with leakage of cell contents. [3-5] Colisitn is bacteriocidal;

whether interaction with membranes is the cause of bacterial cell death is unknown. [1]

Polymyxins also bind to the lipid A portion of the LPS and, in animal studies, block many of the

biologic effects of endotoxin. [6] Colistin has broad in-vitro activity against Gram-negative

bacteria, with the exception of Proteus spp., Providencia spp., Serratia spp., and rarer bacteria

(Brucella spp., Edwardsiella spp., Pseudomonas mallei and Burkholderia cepacia). Breakpoints

for susceptibility are defined for enterobacteriaceae, Acinetobacter spp. and Pseudmonas spp.

The CLSI define 2 mg/L for all and EUCAST defines 2 mg/L for Acinetobacter sp. and

enterobacteriaceae and 4 mg/L for Pseudomonas sp. [7]

Colistimethate sodium (CMS) is the preparation currently used for systemic treatment. CMS is a

prodrug that undergoes spontaneous hydrolysis in-vivo or in aqueous solutions to the active drug,

colistin. The existence of these two forms has complicated PK/PD studies, since old bioessays

did not differentiate between the two forms, which have different half lives and modes of

excretion. [8] To further complicate matters, colistin is measured using different units. One mg

of CMS is equivalent to 12,500 international units (IU, where 1 IU is defined as the minimal

concentration which inhibits the growth of E. coli 95 I.S.M in 1 ml broth at pH 7.2 [9]). One mg

of colistin base activity (CBA, the unit of measurement used in the US formulation) is equivalent

to 33,250 IU. Considering a 70kg adult, the classically maximal recommended daily dose of

colistin in the US, 5 mg/kg CBA would translate to 11.5 mill IU, while in Europe 9 mill IU per

day would translate to 3.9 mg/kg CBA.

2


Since its resurgence, observational studies have tried to examine the effectiveness of colistin.

Although individual studies reported favourable results regarding both effectiveness and safety, a

compilation of these studies shows higher mortality among patients treated with colistin or

polymyxin B compared to patients given other antibiotics, mostly beta-lactams (Figure 1). [2] In

most studies colistin was used in combination with other antibiotics, mainly carbapenems, and

colistin was probably underdosed. In the largest study, conducted in Israel, colistin was given

almost always as monotherapy at a mean dose of 6.1 ±2.3 MU/day and mortality was

significantly higher with colistin when compared to carbapenems or ampicillin-sulbactam. [10]

Pooling of adjusted results from multivariable analyses or matched studies shows similar results

(Figure 2).

In the same comparative studies rates of nephrotoxicity were higher with colistin compared to

other antibiotics (Figure 3). Rates of nephrotoxicity in recent studies designed to assess this

outcome have ranged from 6-14% in some [11-15] to 32-55% in others[16-20]. The wide range

of nephrotoxicity rates is explained at least partially by different definitions of renal failure. Both

the daily dose [17, 20] and the total cumulative dose [15, 16, 21] have been associated with

increased risk of nephrotoxicity. Among patients with colistin-induced nephrotoxicity between

0-1.5% [16, 20] to ~20% [14, 18, 19] required short-term renal replacement therapy. Studies

monitoring patients up to 1-3 months after colistin last dose demonstrated reversibility of renal

failure in at least 88% of patients [12, 16, 18]. The other feared toxicity of colistin is

neurological. Manifestation range from dizziness, muscle weakness, paresthesias, hearing loss,

visual disturbances and vertigo to confusion, hallucinations, seizures, ataxia, and neuromuscular

blockade with apnea[22]. The latter manifestations are rare in clinical practice.

Studies currently focus on improving the efficacy and safety profile of colistin. A first step is the

optimization of dosing and schedule of administration. Recent PK studies demonstrate that it

takes about 36-48 hours for colistin (rather than CMS) to reach therapeutic concentrations in

plasma (≥2 mg/L) using classical dosing in patients with normal renal function [23, 24]. Thus, a

loading dose, equaling to about the total daily dose is currently recommended. Furthermore,

these studies demonstrate that once or twice daily dosing is probably sufficient[8]. For example,

targeting a colistin steady state level of 2.5 mg/liter for a patient with a creatinine clearance of 70

3


ml/min/1.73, requires 337.5 mg CBA per day (11.2 mill IU). [23] With higher creatinine

clearance rates the dose increases further. A recent study reported on the clinical experience of

treating critically ill patients with colistin using a 9 mill IU loading dose followed by 4.5 mill IU

q12h for normal renal function. [25] A response rate of 82.1% (23/28) and nephrotoxicity of

17.8% (5/28) was reported.

The suboptimal efficacy of colistin and the nephrotoxicity associated with high dosing regimens

has led to the search for combination therapies that might improve clinical success via better

killing or inhibition of the pathogen, more rapid killing, killing or inhibition at lower drug

concentrations, thus avoiding toxicity, and prevention of resistance selection or emergence.

Combinations suggested with colistin include various beta-lactams, azithromycin, co-

trimoxazole, rifampin, doxycycline, minocycline, tigecyclin, vancomycin, aminoglycosides,

quinolones, fosfomycin and sulbactam[26]. Most of the clinical experience exists with

carbapenems that are sometimes used alone or in addition to colistin for carbapenem-resistant

infections when MICs are relatively above the susceptibility breakpoint, mainly for

Acinetobacter baumannii, in the assumption that high dosing might overcome resistance, but few

data support this practice. In a mouse model, intratracheal meropenem was significantly more

effective than colistin for carbapenem-resistant Acinetobacter baumannii pneumonia with an

MIC for meropenem of 32 μg/ml[27]. The main rationale for combination therapy lies in the

existence of in-vitro synergy. Synergistic interaction between antibiotics is usually defined as a

>2-log10-lower number of CFU/ml for the combination than for its most active component in

time-kill studies. Antagonism is defined as >2-log10 increase in CFU/ml between the

combination and the most active single agent and additivity is defined as a 1 to <2-log10-lower

number of CFU per milliliter for the combination. Other interactions are considered indifferent.

[28-30] In the checkerboard and Etest methods, synergy is defined using the fractional inhibitory

concentrations index (FICI), where FICI is the sum of the FICs of individual antibiotics in a

combination and the FIC of an antibiotic is defined as the combination’s MIC divided by the

MIC of the antibiotic alone. The common convention is that FICIs of <0.5, >0.5–4, and >4

represent synergy, no interaction and antagonism, respectively, [31-33] although variations exist

and older studies considered FICIs>1 as antagonistic. [34]

4


For in-vitro data, a systematic review and meta-analysis of the literature was performed as part of

the background for the clinical trial. The following search string was used to locate all studies

published in PubMed:

(colistin OR colisti* OR colistimethate OR polymyxin) AND (imipenem OR meropenem OR

doripenem OR ertapenem OR carbapenem) AND (pharmacokinetic OR pharmacodynamic OR

synergy OR synerg* OR antagonis* OR additive) AND (in-vitro OR checkerboard OR time-kill

OR Etest OR E-test OR microdilution OR agar dilution OR susceptibility). A search was run also

in Google scholar and the ICAAC, IDSA and ECCMID conference proceedings for the years

2007-2012. References of all included studies were reviewed for more eligible studies.

(colistin OR polymyxin) AND (imipenem OR meropenem OR doripenem OR carbapenem)

AND (combination[ti] OR synergy[ti] OR synerg*[ti] OR combin*[ti]). In addition, the

references of all included studies were searched for additional studies.

For each study, we sought to extract the method of in-vitro synergy testing, bacterial species, the

type of carbapenem and polymyxin used, and number of isolates tested. Reported MICs of study

isolates for the carbapenem and polymyxin tested were also extracted and susceptibility was

assessed according to the European Committee on Antimicrobial Susceptibility Testing

(EUCAST) published breakpoints. [35] We calculated synergy rates, where synergy was counted

as an event and the sample size was the number of isolates tested. We used mixed-effects

analysis in order to provide a pooled rate. The I2 statistic was used to test heterogeneity.

Comprehensive Meta-Analysis V2.2 (Biostat, Englewood NJ, 2005) was used for analysis.

Thirty-eight published studies and 15 conference proceeding were included, reporting on 244

different tests on 1050 bacterial isolates. A summary of selected studies are presented in Table 1.

In time-kill studies, combination therapy showed synergy rates of 77% (95% CI 64-87) for A.

baumannii, 44% (95% CI 23-51%) for Klebsiella pneumoniae and 50% (95% CI 30-69%) for

Pseudomonas aeruginosa with low antagonism rates for all. For A. baumannii, meropenem was

more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard

and Etest studies generally reported lower synergy rates than time-kill. Comparisons of

resistance development between monotherapy and combination therapy were found in one study

5


on 3 A. baumannii isolates and four studies on 14 P. aeruginosa isolates, all recent studies. Use

of combination therapy led to less resistance development in-vitro.

Thus, in-vitro studies show variable results, but overall synergy is substantial. Carbapenem-

polymyxin synergy is probably more likely when isolates are more susceptible to one or both of

the drugs in the combination. It was observed more frequently with A. baumannii than with K.

pneumonia or P. aeruginosa strains and this could be related to lower MICs for A. baumannii to

carbapenems in general. Difference between carbapenems is less clear and depended on bacteria

type, with doripenem having some advantage.

Learning from in-vitro studies on clinical effects is difficult because the bacterial inocula differ,

drug levels may be affected by practical constraints of antibiotic administration and clinical

effects are confounded by underlying conditions and adverse effects. Furthermore, poor

correlation has been shown between different in-vitro methods for synergy testing. [34] Indeed,

despite strong in-vitro proof of synergy and prevention of resistance induction for beta-lactam-

aminoglycoside combinations for various Gram-negative and Gram-positive bacteria,

randomized controlled trials do not show a clinical benefit for the same combinations compared

with beta-lactams alone in the treatment of sepsis by the same bacteria[36]. Detriments of

combination therapy may comprise of further resistance induction, increased toxicity and

antagonistic interactions between antibiotics. Thus, the effects of combination therapy must be

tested in clinical studies

Data from in-vivo and human studies on combination therapy is weak. Three in-vivo studies

examined the role of carbapenem-polymyxin combination (Table 2), all examining the effect of

combining imipenem and colistin. While two studies P. aeruginosa studies found improved

outcome with combination, the third tested on A. baumannii showed no benefit with this

combination. Three studies were found reporting on the clinical effects of combination therapy

(Table 3) [37-39]. Two were retrospective comparative studies, comparing carbapenem-colistin

combination therapy to colistin monotherapy. One showed worst survival with combination

therapy [37], but there was an inherent difference between patient groups in that patients with P.

aeruginosa were treated with colistin monotherapy while combination therapy was given mostly

6


to patients infected by A. baumannii. The second very small study showed improved survival in

five patients receiving combination therapy compared to seven patients treated with polymyxin

monotherapy among patients with K. pneumoniae bacteremia[38]. The last study compared any

combination therapy (the most common combination was tigecycline and colistin) to any

monotherapy (the most common was tygecycline) and found an overall advantage to

combination therapy[39]. Colistin monotherapy was given to 22 patients and colistin-meropenem

combination therapy to 6 patients in this study.

The objective of the current trial is to examine the clinical effects of colistin-carbapenem

combination therapy in the optimal trial design. Basing on the review of PK studies we will

select the currently optimal dosing regimen for colistin, including a loading dose. Given no

difference in the expected interactions, we will select meropenem as the carbapenem tested since

high doses can be given to critically-ill patients and is the carbapenem of choice in the trial

centers. To avoid bias we will conduct a randomized controlled trial, but given the expected

difficulties in obtaining informed consent we will prospectively collect data from all eligible

patients, documenting their treatment regimen if not recruited into the randomized controlled

trial.

7


Table 1: Studies examining colistin-carbapenem combination therapy

First author Year published

Polymyxin tested

Carbapenem tested

Bacteria type no. of isolates

Carbapenem

resistance

Polymyxin Resistance

Synergy methods

Outcome reported

Chan[34] 1987 colistin imipenem P. aeruginosa, S. maltophilia

33 R,S R checkerboard, time-kill

FICI

Rynn[40] 1999 colistin meropenem P. aeruginosa 2 S S time-kill AUKBC

Yoon[41] 2003 polymyxin B imipenem A.baumannii 8 R R checkerboard, time-kill

FICI, time-kill synergy, bactericidality

Landman[42] 2005 polymyxin B imipenem P. aeruginosa 10 R S time-kill bactericidality

Bratu[43] 2005 polymyxin B imipenem K. pneumoniae 16 R R,S time-kill bactericidality, time-kill synergy

Timurkaynak[44] 2006 colistin meropenemA. baumannii, P.

aeruginosa 10 R,S S checkerboard FICIWareham[45] 2006 polymyxin B imipenem A. baumannii 5 R S Etest FICI

Tateda[46] 2006 polymyxin B imipenem P. aeruginosa 12 R Rcheckerboard

breakpoint FICI

Biancofiore[47] 2007 colistin meropenem A. baumannii 1 R S checkerboard FICI

Cirioni[48] 2007 colistin imipenem P. aeruginosa 2 R,S Rcheckerboard, time-kill FICI, time-kill synergy

Tripodi[49] 2007 colistin imipenem A. baumannii 9 R S time-kill bactericidality, time-kill synergy

Pankuch[50] 2008 colistin meropenemP. aeruginosa, A.

baumannii 102 R,S R,S time-kill time-kill synergyTascini[51] 2008 colistin imipenem E. cloaca 1 S S checkerboard FICIGuzel[52] 2008 colistin meropenem P. aeruginosa 50 S S checkerboard FICI

Guelfi[53] 2008 polymyxin B meropenemP. aeruginosa, A.

baumannii 20 R,S S checkerboard FICI

Burgess[54]2008

ICAAC colistin meropenem A. baumannii 5 R S time-kill bactericidality, time-kill synergy

Ullman[55]2008

ICAAC colistin meropenem A. baumannii 3 R,S S PK/PD time-kill bactericidality

Pankey[56] 2009 polymyxin B meropenem A. baumannii 8 R S Etest, time-killFICI, bactericidality, time-kill

synergySouli[57] 2009 colistin imipenem K. pneumonia 42 R,S R,S time-kill time-kill synergy

Burgess[58]2009

ICAAC colistin imipenem A. baumannii 5 R S time-kill bactericidality, time-kill synergy

Hilliard[59]2009

ICAAC colistin doripenem P. aeruginosa 2 S S checkerboard FICIMilne[60] 2010 colistin meropenem, P. aeruginosa 144 R,S R,S Etest, SBPI FICI, SBPI

8


imipenem

Pongpech[61] 2010 colistinmeropenem,

imipenem A. baumannii 30 R Scheckerboard,

time-kill FICIRodriguez[62] 2010 colistin imipenem A. baumannii 14 R,S R,S time-kill bactericidality, synergy

Elemam[63] 2010 polymyxin B imipenem K. pneumoniae 12 R R checkerboard FICILin [64] 2010 colistin imipenem E. cloaca 1 S S time-kill bactericidality, synergy

Shields[65] 2010 colistinimipenem, doripenem A. baumannii 17 R S Etest, time-kill FICI, bactericidality, synergy

Sopirala[66] 2010 colistin imipenem A. baumannii 8 R Scheckerboard, Etest, time-kill FICI, time-kill synergy

Urban[67] 2010 polymyxin B doripenem

K. pneumoniae, A. baumannii, P.

aeruginosa, E. coli 20 R,S R,S time-kill bactericidality

Pankuch[68] 2010 colistin doripenemA. baumannii, P.

aeruginosa 50 R,S R,S time-kill time-kill synergy

Steed[69]2010

ECCMID colistin imipenem A. baumannii 8 R S time-kill bactericidality, time-kill synergy

Souli[70]2010

ECCMID colistinmeropenem, ertapenem K. pneumoniae 55 R,S R,S time-kill time-kill synergy

Khuntayaporn[71]2010

ICAAC colistin

imipenem, meropenem, doripenem P. aeruginosa 57 R - checkerboard FICI

Dorobisz[72]2010

ICAAC colistin doripenem Acinetobacter 6 R Rcheckerboard,

time-kill FICI, bactericidality

Srispha-Olarn[73]2010

ICAAC colistin meropenem A. baumannii 3 R S PK/PD time-kill bactericidality, time-kill synergy

Ly[74]2011

ICAAC colistin doripenem P. aeruginosa 3 S R,S PK/PD time-kill bactericidalityLiang[75] 2011 colistin meropenem A. baumannii 4 R S time-kill bactericidality, synergy

Pankey[76] 2011 polymyxin B meropenem K. pneumoniae 14 R,S R,S Etest, time-killFICI, bactericidality, time-kill

synergy

Sheng[77] 2011 colistin imipenem A. baumannii 18 R Scheckerboard,

time-killFICI, bactericidality, time-kill

synergyBergen[78] 2011 colistin imipenem P. aeruginosa 6 R,S R,S time-kill bactericidality, time-kill synergyBergen[79] 2011 colistin doripenem P. aeruginosa 2 R,S R,S PK/PD time-kill bactericidality, time-kill synergy

Santimaleeworagun[80] 2011 colistin imipenem A. baumannii 8 R S checkerboard FICI

Lim[81] 2011 polymyxin B meropenem P. aeruginosa 22 R S,R time-kill bactericidality

Morosini[82]2011

ECCMID colistin meropenem K. pneumoniae 1 S S time-kill bactericidality, FICI

9


Poudyal[83]2011

ECCMID colistin doripenem A. baumannii 3 R,S S PK/PD time-kill bactericidality, time-kill synergy

Teo[84]2011

ICAAC polymyxin B doripenem P. aeruginosa 16 R - time-kill bactericidality, time-kill synergy

Principe[85]2011

ICAAC colistin doripenem A. baumannii 24 R,S - checkerboard synergy

Mohamed[86]2011

ICAAC colistin meropenem P. aeruginosa 2 R,S S PK/PD time-kill bactericidality, time-kill synergy

Peck[87] 2012 colistin imipenem A. baumannii 6 R R,S time-kill bactericidality, synergy

Jernigan[88] 2012 colistin doripenem K. pneumoniae 12 R S,R time-killbactericidality, time-kill synergy,

AUBKCDeris[89] 2012 colistin doripenem K. pneumoniae 4 R,S R,S PK/PD time-kill bactericidality, time-kill synergy

Ozseven[90] 2012 polymyxin Bimipenem,

meropenem A. baumannii 34 R S checkerboard FICIHe[91] 2012 colistin doripenem P. aeruginosa 100 R S Etest, time-kill FICI

R - resistant, S - sensitive, MDR – multidrug resistant, XDR – extremely drug resistant, AUBKC – area under the bacterial killing curve

10


Table 2 – in-vivo studies

Study Methods Type of

carbapenem 1

Bacteria (MIC

in mg/L)

Outcome Effect on defined

outcome

Effect summary

Cirioni

2007 [31]

In-vivo randomized

(BALB/c male mice

with bacteremia

following IV injection of

P. aeruginosa)

Imipenem P. aeruginosa, 1

quality control

strain: imipenem

MIC 0.5, colistin

MIC 4)

One CR MDR

clinical isolate:

imipenem MIC

32 colistin MIC

8

Deaths

(colistin vs.

combi)

Positive

blood culture

at 24h

Control strain: 8/20

vs. 2/20

Clinical strain: 6/20

vs. 3/20

Control strain: 8/20

vs. 2/20

Clinical strain: 13/20

vs. 3/20 (p<0.05 for

all)

significant

effects in-vivo on

survival and

bacteremia

clearance

Aoki

2008[92]

In-vivo - BALB/c

female mice pneumonia

model (intranasal and

subcutaneous)

imipenem P. aeruginosa, 1

PAO1 strain and

6 clinical strains

Survival,

lung bacterial

burden

90% survival in

combination vs 10%

in monotherapy,

reduced bacterial

burden

Significant

effects on

survival and

bacterial burden

with colistin

Song

2009 [93]

In-vivo randomized

(neutropenic mice with

pneumonia following

Imipenem A. baumannii, 1

clinical CR

isolate OXA-51

Lung

bacterial

loads at 48h

Combi 7.15 ± 3.56

vs.

Colistin alone 6.35 ±

In-vivo bacterial

load, bacteremia

and mortality

11


tracheal A. baumannii

inoculation)

positive.

Imipenem MIC

64, colistin ≤0.5 Bacteremia

eradication at

48h

Mortality at

48h

0.98

Combi 0/3 vs.

Colistin alone 0/3

Combi 1/3 vs.

Colistin alone 1/3

12


Table 3- observational studies

Study Methods Type of

carbapenem 1

Bacteria (MIC

in mg/L)

Outcome Effect on

defined

outcome

Effect summary

Falagas

2006 [37]

Clinical,

retrospective

(most pneumonia,

24% bacteremia)

Meropenem Colistin alone

(14 patients)

mostly P.

aeruginosa

Combi (57

patients (mostly

A. baumannii)

In-hospital death

(colistin vs. combi)

Response

Nephrotoxicity

0/14 vs.

21⁄57

(36.8%),

p=0.007

12/14

(85.7%) vs.

39⁄57

(68.4%),

NS

0/14 vs.

4⁄57 (7%),

NS

_

More deaths with

combi

Qureshi

2012 [38]

Clinical,

retrospective (all

bacteremia)

NS (probably

mostly

imipenem)

CR K.

Pneumoniae

MIC50 colistin

MIC ≤0.25,

imipenem MIC 4

Death (colistin vs.

combi)

4/7 (57.1%)

vs. 1/5

(20%)

+

Less deaths with

combi

Tumbarello Clinical, Meropenem CR K. Death (colistin alone vs. 11/22 vs. Overall advantage to

13


2012 [39] retrospective (all

bacteremia)

(definitive

therapy)

Pneumoniae 2 or 3-drug

combinations including

colistin-meropenem

combination)

12/37

(32%)

combination.

Colistin-carbapenem

not specifically

examined.

1 Unless otherwise stated, data the carbapenem was combined with colistin

2 Data obtained from Landman 2008 [94]

CI – continuous infusion

14


Figure 1: Synergy rates for polymyxin and carbapenem combination by type of bacteria

Study names are comprised of first author and either publication year or convention name and

year accordingly. Subgroups within studies (according to resistance profile, antibiotic used, etc –

see Methods section) were listed separately and denoted by continuous numbering in parenthesis

15


Figure 2: All-cause mortality in observational studies comparing colistin or polymyxin B vs.

comparator antibiotics for sepsis 1

Study or SubgroupQureshi 2012 AACDurakovic 2011 Intern MedBetrosian 2008 J InfectGarnacho-Montero 2003 CIDGounden 2009 BMC InfectKvirko 2011 (polyB) JACRios 2007 Eur RespHachem 2007 AACKallel 2007 Int CMOliveira 2008 (polyB) JACReina 2005 Int CMPaul 2011 JAC

Total (95% CI)Total eventsHeterogeneity: Chi² = 13.29, df = 11 (P = 0.27); I² = 17%Test for overall effect: Z = 4.67 (P < 0.00001)

Events535

131630161921631678

285

Total1426152132453131608266

200

623

Events43499

25143015543485

286

Total14261314328840646085

130295

861

Weight2.2%2.3%2.4%3.5%3.8%4.8%5.1%6.5%8.3%

10.5%14.8%35.8%

100.0%

M-H, Fixed, 95% CI1.39 [0.28, 6.84]1.00 [0.18, 5.48]1.13 [0.23, 5.54]0.90 [0.22, 3.68]2.56 [0.91, 7.20]

5.04 [2.32, 10.93]1.98 [0.76, 5.16]1.79 [0.75, 4.30]1.62 [0.73, 3.56]1.90 [0.97, 3.75]0.90 [0.46, 1.79]1.58 [1.08, 2.31]

1.70 [1.36, 2.13]

Colistin Comparator Odds Ratio Odds RatioM-H, Fixed, 95% CI

0.01 0.1 1 10 100Favours colistin Favours comparator

1 Betrosian 2008 was a quasi-randomized study, using alternation for patient allocation

16


Figure 3: Adjusted all-cause mortality in observational studies comparing colistin or polymyxin

B vs. comparator antibiotics for sepsis

Study or SubgroupBetrosian 2008 J InfectDurakovic 2011 Intern MedKallel 2007 Int CMKvirko 2011 (polyB) JACOliveira 2008 (polyB) JACPaul 2011 JAC

Total (95% CI)Heterogeneity: Chi² = 1.54, df = 5 (P = 0.91); I² = 0%Test for overall effect: Z = 3.34 (P = 0.0008)

log[Odds Ratio]0.1178

00.47960.64710.72750.3646

SE0.81310.86810.40270.30170.3561

0.23

Weight3.2%2.8%

13.2%23.5%16.9%40.4%

100.0%

IV, Fixed, 95% CI1.13 [0.23, 5.54]1.00 [0.18, 5.48]1.62 [0.73, 3.56]1.91 [1.06, 3.45]2.07 [1.03, 4.16]1.44 [0.92, 2.26]

1.63 [1.22, 2.17]

Odds Ratio Odds RatioIV, Fixed, 95% CI

0.05 0.2 1 5 20Favours experimental Favours control

17


Figure 4: Nephrotoxicity for patients treated with colistin vs. comparator antibiotics in

observational studies

Study or SubgroupBetrosian 2008 J InfectDurakovic 2011 Intern MedGarnacho-Montero 2003 CIDHachem 2007 AACKallel 2007 Int CMKvirko 2011 (polyB) JACLim 2011 J Korean medOliveira 2008 (polyB) JACPaul 2011 JACReina 2005 Int CMRios 2007 Eur Resp

Total (95% CI)Total eventsHeterogeneity: Chi² = 9.11, df = 7 (P = 0.25); I² = 23%Test for overall effect: Z = 2.51 (P = 0.01)

Events535705

10182600

79

Total1526213160452069

1685531

541

Events206

1406

10211700

76

Total1326146460883581

24413020

775

Weight3.0%0.9%

11.5%14.8%

7.6%7.6%

30.0%24.6%

100.0%

M-H, Fixed, 95% CI2.75 [0.43, 17.49]

7.89 [0.39, 160.91]0.42 [0.10, 1.79]1.04 [0.37, 2.92]Not estimable1.71 [0.49, 5.94]2.50 [0.80, 7.84]1.01 [0.49, 2.10]2.44 [1.28, 4.67]Not estimableNot estimable

1.58 [1.11, 2.26]

Colistin Comparator Odds Ratio Odds RatioM-H, Fixed, 95% CI

0.002 0.1 1 10 500Favours colistin Favours comparator

18


METHODS

Trial design: Randomized, open-label, controlled clinical trial (RCT).

Setting: Multicenter study including the following sites/ departments:

1. Italy, Rome: Universita Cattolica del Sacro Cuore, Agostino Gemelli Hospital. Four

departments: ICU, Infectious Diseases, Internal Medicine and Pneumology

2. Greece, Athens: Laikon Hospital, all departments

3. Greece, Athens: Attikon Hospital, all departments

4. Israel, Tel-Aviv: Tel Aviv Sourasky Medical Center, all departments

5. Israel, Petah-Tikva: Rabin Medical Center, Beilinson hospital and Hasharon Hospital. All

departments.

6. Israel, Haifa: Rambam Medical Center, all departments

Inclusion/ exclusion criteria

We will include adult inpatients ≥18 years with clinically-significant infections as defined below

caused by carbapenem- non-susceptible and colistin-susceptible Gram-negative bacteria:

Acinetobacter sp., P. aeruginosa or any Enterobacteriaceae (including but not limited to K.

pneumoniae, E. coli and Enterobacter sp.). Patient recruitment will occur only after

microbiological documentation and susceptibility testing.

Types of infections and definitions:

Bloodstream infection (BSI): growth of the relevant bacteria in one or more blood culture

bottles accompanied by the systemic inflammatory response syndrome (SIRS) within 48h of

blood culture taken time. BSIs can be either primary or secondary to any other source of

infection.

Ventilator-associated pneumonia (VAP) or healthcare-associated pneumonia (HAP):

pneumonia fulfilling CDC/NHSN surveillance definition of health care-associated infection

for pneumonia with specific laboratory findings (PNU2) with modifications to the laboratory

criteria. [95] Ventilator-associated pneumonia will be defined in persons who had a device to

assist or control respiration continuously through a tracheostomy or by endotracheal

intubation within the 48-hour period before the onset of infection. BAL will not be

performed routinely for the purposes of the trial. The specific criteria required for diagnosis

of pneumonia will be all of the following:

19


1. Chest radiograph with new or progressive and persistent infiltrate, consolidation or

cavitation.

2. At least 1 of the following signs of sepsis: Fever >38ºC with no other recognized cause;

Leukopenia <4000 WBC/mm3 or leukocytosis >12,000 WBC/mm3; For adults >70 years

old, altered mental status with no other recognized cause

3. At least 1 of the following respiratory signs/symptoms: New onset of purulent sputum or

change in character of sputum or increased respiratory secretions or increased suctioning

requirements; New onset or worsening cough or dyspnea or tachypnea >25 breaths per

minute; Rales or bronchial breath sounds; Worsening gas exchange, including O2

desaturations, PaO2/FiO2 <240, or increased oxygen requirements

4. Laboratory criterion: Growth of the relevant bacteria in culture of sputum, tracheal

aspirate, bronchoalveolar lavage or protected specimen brushing. For any lower

respiratory secretion other than bronchoalveolar lavage (BAL) or protected specimen

brush (PSB), the respiratory sample has to contain >25 neutrophils and <10 squamous

epithelial cells per low power field, identified by Gram stain

Probable ventilator-associated pneumonia (VAP): pneumonia fulfilling CDC/NHSN 2013

revised surveillance definition, omitting the criterion of antimicrobial treatment before

randomization and modifying the microbiological criteria: [96]

1. Mechanical ventilation for ≥3 calendar days

2. Worsening oxygenation, following ≥ 2 calendar days of stable or decreasing FiO2 or

PEEP, presenting as:

o Minimum daily FiO2 values increase ≥ 0.20 (20 points) over baseline and remain

at or above that increased level for ≥ 2 calendar days OR

o Minimum daily PEEP values increase ≥ 3 cmH2O over baseline and remain at or

above that increased level for ≥ 2 calendar days.

3. Temperature > 38 °C or < 36°C, OR white blood cell count ≥ 12,000 cells/mm3 or ≤

4,000 cells/mm3

4. Purulent respiratory secretions AND positive respiratory culture; OR positive culture of

pleural fluid. For any lower respiratory secretion other than bronchoalveolar lavage

(BAL) or protected specimen brush (PSB), the respiratory sample has to contain >25

20


neutrophils and <10 squamous epithelial cells per low power field, identified by Gram

stain.

Urinary tract infection: positive urine culture with relevant bactera ≥105 CFU/ml with pyuria,

accompanied by the systemic inflammatory response syndrome (SIRS) with 48h of taken

time and no other explanation for SIRS

Microbiological criteria:

We will include patients with infections caused by carbapenem non-susceptible bacteria (using

EUCAST breakpoints for disc testing or MIC >2) that are sensitive to colistin (by disc testing or

MIC≤ 2 mg/L for Acinetobacter sp. and enterobacteriaceae and ≤4 mg/L for Pseudomonas sp.)

We will exclude infections when the carbapenem-resistant isolate is sensitive to quinolones or

any beta-lactam, but include those sensitive to tetracyclines, tigecycline cotrimoxazole or

aminoglycosides since these are not established treatments for such infections. We will exclude

patients with polymicrobial infections where one or more of the clinically-significant gram-

negative bacteria are susceptible to any beta-lactam. We will permit the inclusion of patients

with polymicrobial infections where the non-trial isolate/s are carbepenem-resistant Gram-

negative bacteria, Gram-positive bacteria or anaerobes (see permitted additional antibiotics

below).

Inclusion will be based on the testing performed in individual study hospitals (disc diffusion

essays, E-test, Vitek or other automated systems) with the breakpoints defined above. Isolate

identification and carbapenem MICs will be confirmed in a central laboratory.

Exclusion criteria

Previous inclusion in the trial. Patients will be included in the RCT only once for the first

identified episode of infection

Colistin administered >96 hours prior to randomization. Although prior treatment is allowed

by protocol for 4 days, all efforts should be made to recruit patients as soon as possible after

isolate identification.

Pregnant women

Epilepsy or prior seizures

Known allergy to colistin or a carbapenem

Interventions

21


Colistin arm: Patients will be given a loading dose of 9 mill IU, regardless of renal function. For

patients with normal renal function (CrCl ≥50 ml/min), the loading dose will be followed by 4.5

mill IU q12hr. [24, 97] Colistin will be administered as a 30 min intravenous infusion. Patients

treated with colistin before randomization will be given a loading dose if treated for <48 hours

and not given a loading dose at start of treatment. Patients already given a loading dose or who

have been treated for 48 hour or more will continue colistin without a loading dose, using the

trial schedule.

Dose adjustment for patients with renal failure will be based on the study by Garoznik et al.

aiming to achieve a colistin steady state average level of 2-2.5 mg/L [23]

Patients with CrCl <50 ml/min, without renal replacement therapy: Total daily dose in mill

IU = [2*(1.5*CrCl + 30)]/30. CrCl should be expressed in ml/min/1.73 m2, using the MDRD

formula, Cockcroft and Gault equation or other means.

Continuous renal replacement therapy: fixed dose of 6 mill IU q12h

Intermittent hemodialysis: 1 mill IU q12h, with a 1 mill IU supplement dose after dialysis.

Combination arm: Colistin will be administered as above and combined with IV meropenem 2gr

q8hr for patients with normal renal function (CrCl>50 ml/min). Meropenem will be administered

as prolonged infusion over 3 hr. For patients with renal function the following algorithm will be

used: [98]

CrCl 26-50 ml/min 2gr q12hr

CrCl 10-25 ml/min and continuous renal replacement therapy 1gr q12hr

CrCl <10 ml/min. Supplemental dose given after intermittent

hemodialysis

1gr q24hr

No dosage adjustments will be performed for hepatic insufficiency for both antibiotics. Duration

of antibiotic treatment will be 10 days for all listed indications. If infectious complications

mandate longer treatment, duration will be prolonged as appropriate. The day of randomization

will be defined as day 1. Modifications of antibiotic treatment will be determined by the patients’

physicians, although we will request physicians to refrain from antibiotic changes in the first 72

hrs. unless a severe adverse event is observed. We will permit the concomitant administration of

the following antibiotics for polymicrobial infections in both study arms: vancomycin, oxacillin

22


derivatives, cefazolin, ampicillin, penicillin or metronidazole. We will not permit the routine

addition of: rifampin, tigecycline, minocycline, aminoglycosides or colistin inhalations. In case

of clinical deterioration, any treatment modification will be permitted and this will be counted as

treatment failure (see secondary outcomes).

Outcomes

Primary outcome: Clinical success, defined as a composite of all of the following, all measured

at 14 days:

Patient alive

Systolic blood pressure >90 mmHg without need for vasopressor support

Stable or improved SOFA score, define as:

o for baseline SOFA ≥ 3: a decrease of at least 30%;

o for baseline SOFA <3: stable or decreased SOFA score

For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved

For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day

14 if patient still febrile

Secondary outcomes:

14 and 28-day all-cause mortality

Clinical success, as defined above, but any modification to the antibiotic treatment not

permitted by protocol will also be considered as failure. This will include any change or

addition of antibiotics not permitted by study protocol during the first 10 days after

randomization. Early discontinuation of antibiotic treatment will not be considered as failure.

Time to defervescence, defined as time to reach a temperature of <38°C with no recurrence

for 3 days

Time to weaning from mechanical ventilation in VAP for patients weaned alive

Time to hospital discharge for patient discharged alive

Change in functional capacity from baseline before infection onset to discharge from

hospital. Function capacity will be classified into 3 grades: I. Independent II. Need for

assistance for activities of daily living III. Bedridden

23


Microbiological failure, defined as isolation of the initial isolate (phenotypically identical) in

a clinical sample (blood or other) 7 days or more after start of treatment or its identification

in respiratory samples.

o For all patients with VAP/ HAP sputum or tracheal aspirates will be obtained on day

7, regardless of clinical response

o For all patients with UTI, a repeat urine culture will be obtained on day 7, regardless

of clinical response

o For patients with bacteremia, blood cultures will be repeated on day 7 and 14, only if

the patient is febrile at that time

Superinfections, defined as a new clinically or microbiologically-documented infections by

CDC criteria within 28 days

Colonization or infection by newly-acquired (other species than the initial infection)

carbapenem-resistant or colistin-resistant Gram-negative bacteria. Colonization will be

assessed by rectal surveillance (see surveillance protocol below)

Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin

test

Adverse events

Renal failure using the RIFLE GFR criteria [99] at day 14 and day 28

RIFLE category GFR criteria

Risk Serum creatinine increased 1.5 times

Injury Serum creatinine increased 2.0 times

Failure Serum creatinine increased 3.0 times or creatinine = 4 mg//dl (355

μmol/L) when there was an acute rise of >0.5 mg/dl (44 μmol/L)

Loss Persistent acute renal failure; complete loss of kidney function

requiring renal replacement therapy for longer than 4 weeks

End-stage renal disease End-stage renal disease requiring renal replacement therapy for

longer than 3 months

Seizures or other neurological adverse events including critical illness neuropathy

24


Other adverse event requiring treatment discontinuation

If patients are discharged or death occurs before end of follow-up (day 28), we will end data

collection at that date. We will attempt to determine survival status at day 28 for all patients

(central registry in Israel; re-admissions, rehabilitation centers, hospital transfers in Greece and

Italy).

Randomization

Blocked randomization will be performed in each participating center with random block sizes.

[100]. A computer generated random code, stratified by site using blocked randomization with

random block size between 4-8 patients will be accessed through a central web-based

randomization page only after patients’ recruitment to ensure adequate allocation concealment.

No blinding will be used after randomization.

Sample size

To show an improvement in clinical success (primary outcome) from 55% with colistin alone to

70% with combination therapy with a 1:1 randomization ratio, a sample of 324 patients (162 per

group) is needed (uncorrected chi-squared test, alpha=0.05, power=0.8, PS Power and Sample

Size Calculations). Assuming a non-evaluability rate of about 10%, we plan to recruit 360

patients. The graph below plots the change in number of patients in one arm (y axis) if the failure

rate in the combination arm is lower that 30% (x axis).

0

40

80

120

160

200

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Probability of the event in experimental group

25


For a 3-year trial duration we will have to recruit 120 patients/ year. Basing on the current

prevalence of carbapenem-resistant colistin-susceptible isolates in the trial sites, the plan should

be to recruit 60 patients in 3 Israeli hospitals, 50 in 2 Greek hospitals and 10-20 in Italy.

Colistin level monitoring

Blood samples for CMS and colistin concentration determination will be drawn from all patients

to evaluate PKPD-relationships and potential covariate relationships. A sparse sampling schedule

with two samples drawn at 45 minutes after start of the first infusion (i.e. 15 minutes after the

end of the loading dose infusion), and at 22 hours (i.e. 22 hours after the start of the first infusion

= 10 hours after the start of the second infusion = 2 hours before the start of the third infusion)

was determined to be suitable based on optimal design theory. Sampling at 23-24 h may risk that

CMS concentrations are not quantifiable in the assay; therefore it is important to take the sample

no later than 22-23 h after the start of the first infusion. For patients treated with colistin prior to

randomization, the first sample will be taken 15 minutes after the end of the first infusion post-

randomization and the second 2 hours before the start of the third infusion. To enable

interpretation of the measured colistin levels, we will record colistin start and end administration,

the dose and timing of colistin administration prior to randomization and the exact time of blood

sampling. Both CMS and colistin will be measured in the two samples. 70 Developed population

PK models will be used to obtain each individual’s PK parameters in the NONMEM 7 software. Handling of PK samples

Draw 5 ml venous blood in EDTA (or heparin) tubes. The sampling site has to be

different from the vein used for CMS infusion.

VERY IMPORTANT: Place on ice bath immediately after sampling.

Note the exact time of the sampling (clock time and time in relation to start and stop of

infusion(s).

Within 20 min after sampling: Centrifuge in chilled centrifuge for 10 minutes at 2000-

2500 g.

Transfer the supernatant (1.5-2 ml plasma) to polypropylene Eppendorf tubes. The tube

should be marked. Please include the following information on the labels:

26


AIDA STUDY

Study center

Patient randomization number:

Sample #: (1st or 2nd)

Date:

Time of sampling: HH:MM

Please also add Randomization number and sample number on the cap with a waterproof

marking pen.

Freeze at -70 degrees (or cooler). It is acceptable to store the sample at -20 degrees for a

few days.

Ship batch of samples to Uppsala University (approximately every 3-6 months) on dried

ice by USPS, DHL or similar service. Before shipping, it is important to confirm with

Uppsala that there will be personnel to take care of the samples upon arrival

([email protected]; [email protected])

Microbiological methods

Index culture

The index culture is defined as the pathogen/s causing the infection for which the patient was

included in the trial. The index culture will be documented in the electronic CRF and must be

kept and frozen at -70ºC.

Clinical samples

Blood cultures will be repeated every 48 hours as long as fever >38 or signs of SIRS are present.

Other cultures will be taken as deemed appropriate by attending physicians. Document in

electronic CRF all positive samples associated with clinically-significant new infections ("New

infection" day 28, only pathogen name). Enter detailed pathogen information into new culture

page for all repeat (index pathogen) or new carbapenem-resistant Gram-negative bacteria. Freeze

and store all repeat samples of index pathogen (same bacterium, carbapenem-resistant, similar

susceptibility pattern).

Surveillance samples

Sputum cultures for patients with HAP/ VAP and urine samples for patients with UTI will be

repeated at day 7 routinely, regardless of clinical signs/ symptoms. Document and store isolates

27

mailto:[email protected]

mailto:[email protected]


according to the criteira mentioned under clinical samples. Growth of bacteria different from the

index culture will be disregarded unless associated with a clinically significant infection.

Rectal surveillance cultures will be obtained using rectal swabbing at randomization and once

weekly thereafter until day 28 (or death/ discharge from hospital). Rectal swabs content will be

frozen (after extraction into glycerol containing media) using a validated protocol and shipped to

the study central laboratory (TASMC) every 4-6 months. Exact MIC of the clinical isolates to the

study drug will be determined using agar based methods. All rectal swabs will be evaluated to

determine carriage of carbapenem and/or colistin resistant organisms. Using methodology

developed in FP7 SATURN project, quantitative analysis will be performed to examine the

effect of treatment regimen on density of resistant strains, and the co-carriage of various

carbapenem-resistant strains. Co-carried resistant strains belonging to different species and

newly acquired-resistant strains will be studied for the mechanisms of resistance. When co-

carriage or a new acquisition event of a carbapenem resistant strain will be detected, strains will

be analyzed to examine between-species transfer of genetic elements encoding for resistance

(plasmids, transposomes and genes) and to determine the relationship of transfer events to the

treatment protocol. Clonality of clinical and surveillance resistant isolates will be determined

using a combination of PFGE, PCR and sequencing based (MLST) genotyping methods, as

appropriate. Mechanisms of resistance in selected clinical isolates, and in surveillance isolates in

which resistance has emerged, will be determined. These will include carbapenemase activity

assays, beta-lactamase identification, porin loss determination, and efflux pump expression.

Population analysis and modified population analysis profile (PAP) to detect colistin

heteroresistant subpopulations, analysis for stable vs. unstable colistin resistance among resistant

subpopulations and molecular analysis of the mechanism of resistance will be performed to

detect and quantify carbapenamases and OMP changes.

Synergy tests for the combination of meropenem and colistin will be conducted using time-kill

studies. For synergy testing, we will select 10 isolates each of A. baumannii, K. pneumoniae, P.

aeruginosa and E. coli. All will be carbapenem-resistant and we will try to select from each

species 5 isolates with MIC<32 to meropenem and 5 isolates with higher MICs. Correlation

between carbapenem MICs, colistin MICs, molecular typing, PAP, mechanisms of resistance and

synergy studies will be determined and correlated with the following treatment outcomes: a.

clinical success b. microbiological failure, c. emergence of resistance.

28


Data collection

We will collect data using the electronic interface/ database platform EPI-INFO

(http://wwwn.cdc.gov/epiinfo/). The data collected will include:

Patient demographics

Background conditions, including the revised Charlson comorbidity index [92] and McCabe

score

Source of infection and diagnostic criteria for VAP and HAP including type of respiratory

specimen used for patient classification

Devices present at infection onset and risk factors for MDR colonization and infection

Antibiotic treatment prior to onset of the infectious episode, empirical antibiotic treatment

and all antibiotics used from randomization until day 28. We will document colistin

administration times.

Concomitant nephrotoxic agents: aminoglycosides, IV contrast material, cyclosporine

Therapeutic procedures throughout the infectious episode (surgery, catheter extraction, etc.)

Use of colistin inhalation therapy

All outcomes as defined above

Study visits/ trial flow (grey actions not mandating a study visit):

Notification from laboratory for isolation of CR-GNB.

Application of inclusion criteria: relevant pathogen (as defined above) and relevant clinical

syndrome (BSI, VAP, HAP, probable VAP or UTI) define a potentially eligible patient

For all potentially eligible patients, enter patient into Epi-Info (first and second page). Follow

trial flow according to inclusion/ exclusion criteria – patient not fit for study, observational

study or RCT. Complete EpiInfo for all patients classified for the observational study or

RCT.

For RCT only:

Document last 5 digits of Epi-info unique identifier above.

Perform randomization at: http://ozeuss.pythonanywhere.com

(username:[email protected], password: projectaida)

Document randomization number given above and enter to EpiInfo.

29

https://outlook.rambam.health.gov.il/owa/redir.aspx?C=nFOXurK8xkCsTbivnqvDLyBMw_LWHtAI236VofjrsTHZ6qjGxKdZfdI-nEOB-MwDl601pk8FsDo.&URL=http%3A%2F%2Fozeuss.pythonanywhere.com

http://wwwn.cdc.gov/epiinfo/


Take clinical cultures as appropriate + rectal surveillance sample. Ensure storing of index

culture in the lab.

Time 0 – colistin loading dose 9MIU in 30min, followed by meropenem 2gr in 3hrs.

Document start/ stop timing

45min – colistin level testing, take on ice to centrifugation with 15 min of sampling,

centrifuge using cold centrifuge and freeze (-70˚C). Document timing of sample and

centrifugation.

Make sure that the 8, 12 and 16 hr. doses are documented and implemented

8hr – IV meropenem 2gr in 3 hrs

12hr – colistin 4.5 MIU in 30 min

16hr – IV meropenem 2gr in 3 hrs

22hr – document start/ stop timing of the 2nd dose of colistin and 2nd/ 3rd doses of meropenem.

Colistin level testing, carry on ice and centrifuge within 15 min and freeze immediately

(-70˚C). Instruct on continued treatment and repeat cultures as clinically appropriate.

24hr - colistin 4.5 MIU (30min) followed by meropenem 2gr (3hr)

48hr– clinical follow-up, adherence monitoring (avoid treatment modifications until 72 hrs),

blood cultures if febrile

Day 5 - clinical follow-up, clinical cultures as appropriate, blood cultures if febrile

Day 7 – rectal surveillance sample, sputum culture for HAP/VAP, urine culture for UTI,

blood cultures if febrile, outcome data collection

Day 9 - clinical follow-up, clinical cultures as appropriate, blood cultures if febrile

Day 10 – clinical follow-up, clinical cultures as appropriate, blood cultures if febrile

Day 14 –rectal surveillance sample, clinical cultures as appropriate, blood cultures if febrile,

outcome data collection

21 days – rectal surveillance sample

28 days –rectal surveillance sample, outcome data collection

If patient discharged at any time before day 28, complete case report form at the time of

discharge, except for death. If death before day 28, complete case report form at the time of

death. Complete as many fields as possible given known information.

Store/ freeze

30


Index culture

All repeat isolates of index culture following randomization until day 28

4 X rectal surveillance incubated in BHI

2 X colistin/ meropenem level sampling

Ethical considerations

The study will be approved by the ethics committees at each participating center. We will request

to defer informed consent among critically-ill patients. The study is planned to include

mechanically ventilated patients, other severely ill patients in ICU and patients during the acute

stage of sepsis who will not be able to provide informed consent at the time of randomization.

The interventions examined are both accepted and used in clinical practice; and there is no better

treatment known for the targeted infections. Patients who are able to provide informed consent at

the time of randomization, will be included only if providing informed consent. A data and

safety monitoring committee will be appointed and will review the study data quarterly.

Statistical analysis

An intention to treat analysis will be performed. Baseline characteristics and outcome of study

groups will be compared. Significance will be set at p=0.05 and all tests will be 2-sided. Time to

event outcomes will be assessed using survival analysis.

Predefined subgroup analyses

Patients who did not receiving covering antibiotic treatment for more than 48 hours prior to

randomization

Study patients, excluding those recruited for the indication of UTI or probable VAP

Patients in whom the infecting bacteria has an MIC to meropenem <32 mg/dl

We will conduct a multivariable analysis of the randomized cohort and the randomized +

observational cohorts (see below), to examine the independent effect of the study regimen on

28-day mortality.

Concomitant observational study

We will collect all clinical data and treatment regimens from patients not included in the RCT for

the reason detailed below, but otherwise fulfilling clinical and microbiological inclusion criteria.

31


Unable to provide informed consent or otherwise no informed consent

Identified later than 96h after start of treatment

Second and subsequent episodes of infection for patients included in the RCT. A separate

episode of infection will be defined as an infection occurring at least 28 days after the index

episode of infection and separated by at least 7 days off antibiotics.

Treatment in this arm will be based on attending physicians’ decisions. Clinical and

microbiological samples for these patients will be collected only for routine purposes and will

not be kept or analysed as for the main trial. Data will be kept anonymously. Informed consent

for data collection will not be required, as no intervention isplanned. This arm will serve for

comparison of randomized and non-randomized patients to examine the external validity of the

trial and for an observational comparison between the trial treatment regimens in the overall

cohort.

Pooled analysis with the NIH trial

A concurrent NIH-funded randomized controlled trial will be conducted in the US, assessing

similar interventions and using comparable microbiological methods. An agreement has been

reached between the current and the NIH trial PIs to examine possible collaboration. We will try

to ensure comparability between the current and the NIH trial, in particular with respect to the

outcomes assessed to allow for comparison and compilation of results after analysis of the

current trial. Heterogeneity, if existent, will be explained by differences in patient and infection

characteristics. If non-heterogeneous, we will pool results using methods of individual patient

level meta-analysis. The combined sample size will allow for subgroup analyses by types of

infections and microbiological characteristics (MICs and synergy).

The differences that currently exist between the trial protocols are the following:

NIH AIDA

Inclusion criteria, types of

infection

BSI and/or pneumonia (VAP) BSI, VAP, HAP, UTI

Inclusion criteria,

microbiological

Include preliminary result of

gram-negative non-lactose

Only documented

carbapenem-resistant GNs

32


fermenter that is oxidase

negative

included

Include prior history (within

last 6 months) of XDR-GNB

and is susceptible to colistin

Only current isolate

considered

Permit polymicrobial

infections with susceptible

GNs, but do not allow

treatment with carabepenems

in the mono arm

Exclude susceptible GNs

Exclusion criteria, prior

treatment

Colistin for more than 96

hours and imipenem,

doripenem or meropenem in

the 36 hours prior to

enrollment

Exclude patients if more than

96 hours elapsed since culture

with the study pathogen taken.

Patients may received up to 96

hours of colistin or other

antibiotics before

randomization

Exclusion criteria, other Neutropenics and those

recently treated with GCSF

excluded

Neutropenics included

Complicated infections

excluded: endocarditis,

osteomyelitis, prosthetic joint

infections, meningitis and/or

other central nervous system

infections.

Complicated infections

included (treatment

prolongation and intrathecal

treatment allowed)

Hemodialysis Any type of renal replacement

therapy included

Interventions Colistin vs. colistin +

imipenem

Colistin vs. colistin +

meropenem

Colistin dose? Colistin dose: 9 MIU loding

33


dose followed by 4.5 MIU

q12h

Duration: 14 days Duration: 10 days

Primary outcome Mortality Composite treatment success

Outcome time: 14 and 28 days Outcome time: 14 and 28 days

Other None Concomitant observational

study

34


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