Optimising the use of colistin

AIDA contributed clinical evidence and PK/PD based knowledge to the revival of colistin that is increasingly used for the treatment of critically ill patients with infections caused by extensively drug resistant Gram-negative bacteria.

Fransen F, Hermans K, Melchers MJB, Lagarde CCM, Meletiadis J, Mouton JW.: Pharmacodynamics of fosfomycin against ESBL- and/or carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2017 Oct 4.
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Zayyad H, Eliakim-Raz N, Leibovici L, Paul M.: Revival of old antibiotics: needs, the state of evidence and expectations.
Int J Antimicrob Agents. 2017 May;49(5):536-541.
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Benattar YD, Omar M, Zusman O, Yahav D, Zak-Doron Y, Altunin S, Elbaz M, Daitch V, Granot M, Leibovici L, Paul M. The Effectiveness and Safety of High-Dose Colistin: Prospective Cohort Study. Clin Infect Dis. 2016 Dec 15;63(12):1605-1612.
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Dickstein Y, Leibovici L, Yahav D, Eliakim-Raz N, Daikos GL, Skiada A, Antoniadou A, Carmeli Y, Nutman A, Levi I, Adler A, Durante-Mangoni E, Andini R, Cavezza G, Mouton JW, Wijma RA, Theuretzbacher U, Friberg LE, Kristoffersson AN, Zusman O, Koppel F, Dishon Benattar Y, Altunin S, Paul M; AIDA consortium: Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol. BMJ Open. 2016 Apr 20;6(4):e009956.
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Salim Bouchene: Physiologically Based Pharmacometric Models for Colistin and the Immune Response to Bacterial Infection. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 213. Acta Universitatis Upsaliensis, Uppsala 2016.
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Bar-Yoseph H, Hussein K, Braun E, Paul M. Natural history and decolonization strategies for ESBL/CRE carriage: Systematic review and meta-analysis.
J Antimicrob Chemother. 2016 Oct;71(10):2729-39background logo AIDA-fine line

Dickstein Y, Edelman R, Dror T, Hussein K, Bar-Lavie Y, Paul M. Carbapenem Resistant Enterobacteriaceae Colonization and Infection in Critically Ill Patients: A Retrospective Matched Cohort Comparison to Non-Carriers. J Hosp Infect. 2016 Sep;94(1):54-9.
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Benattar YD, Omar M, Zusman O, Yahav D, Zak-Doron Y, Altunin S, Elbaz M, Daitch V, Granot M, Leibovici L, Paul M.: The effectiveness and safety of high-dose colistin: prospective cohort study. Clin Infect Dis. 2016 Oct 6
In a large cohort of 529 consecutive patients, the AIDA team found no association between high colistin dosing and all-cause mortality. High dosing was associated with more nephrotoxicity.
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Zusman O, Altunin S, Koppel F, Dishon Benattar Y, Gedik H, Paul M.: Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother. 2016 Sep 13
The significant association observed in observational studies between polymyxin monotherapy and mortality cannot be taken as proof of combination therapy effects due to the low quality of the evidence. The only three RCTs to date show no effect of rifampicin/colistin or fosfomycin/colistin on mortality for Acinetobacter infections.
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Neuberger A, Shofty B, Bishop B, Naffaa ME, Binawi T, Babich T, Rappaport ZH, Zaaroor M, Sviri G, Yahav D, Paul M: Risk factors associated with death or neurological deterioration among patients with Gram-negative postneurosurgical meningitis. Clin Microbiol Infect. 2016 Jun;22(6):573.e1-4
This study explored factors associated with 30-day mortality or neurological deterioration. These included days from admission to meningitis (OR 1.05 per day, 95% CI 1.02-1.09), decreased level of consciousness (OR 2.69, 95% CI 0.99-7.31), blood glucose level >180 mg/dL (OR 3.70, 95% CI 1.27-10.77), higher creatinine level (OR 4.07 per 1 mg/dL, 95% CI 1.50-11.08), and cerebrospinal fluid glucose <50 mg/dL (OR 5.02, 95% CI 1.71-14.77) at diagnosis.background logo AIDA-fine line

Tsala M, Vourli S, Miriagou V, Tzouvelekis L, Zerva L, Daikos GL, Mouton JW, Meletiadis J: Pharmacodynamics of Colistin-Meropenem Combination Against Carbapenemase Producing 
Klebsiella pneumoniae Isolates in an In Vitro PK-PD Model. Poster ASM Microbe, Boston 2016
Combination therapy of meropenem and colistin could be used to treat infections caused by strains with low-level resistance to carbapenems with MICs ≤16mg/L.background logo AIDA-fine line

Khan DD, Friberg LE, Nielsen EI: A pharmacokinetic-pharmacodynamic (PKPD) model based on in vitro time-kill data predicts the in vivo PK/PD index of colistin. J Antimicrob Chemother. 2016 Jul;71(7):1881-4.
This study provides further support that PKPD models based on longitudinal data can be a useful tool to make drug development more efficient within the infectious diseases area.
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Dickstein Y, Leibovici L, Yahav D, Eliakim-Raz N, Daikos GL, Skiada A, Antoniadou A, Carmeli Y, Nutman A, Levi I, Adler A, Durante-Mangoni E, Andini R, Cavezza G, Mouton JW, Wijma RA, Theuretzbacher U, Friberg LE, Kristoffersson AN, Zusman O, Koppel F, Dishon Benattar Y, Altunin S, Paul M; AIDA consortium:
Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol. BMJ Open. 2016 Apr 20;6(4):e009956.
This article describes the protocol of the AIDA colistin study. It is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin–meropenem combination therapy for infections caused by carbapenem-resistant Gram-negative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel).
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Tofas P, Skiada A, Angelopoulou M, Sipsas N, Pavlopoulou I, Tsaousi S, Pagoni M, Kotsopoulou M, Perlorentzou S, Antoniadou A, Pirounaki M, Skoutelis A, Daikos GL. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological malignancies or aplastic anaemia: Analysis of 50 cases. Int J Antimicrob Agents. 2016 Apr;47(4):335-9.
In the Cox proportional hazards model, unresolved neutropenia [hazard ratio (HR)=19.28, 95% confidence interval (CI) 2.31-160.69; P=0.006], septic shock (HR=3.04, 95% CI 1.06-8.78; P=0.04) and treatment with one active drug (HR for monotherapy versus combination therapy=3.95, 95% CI 1.23-12.65; P=0.02) were independent predictors of death, whilst combination therapy was associated with lower mortality. These findings may assist physicians in making treatment decisions for neutropenic patients with CP-Kp infections.

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Dickstein Y, Geffen Y, Leibovici L, Paul M. Comparison of Antibiotic Susceptibility Patterns of Bacterial Isolates Based on Time From Hospitalization and Culture Source: Implications for Hospital Antibiograms.
Infect Control Hosp Epidemiol. 2016 Feb;37(2):212-4.
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Shofty B, Neuberger A, Naffaa ME, Binawi T, Babitch T, Rappaport ZH, Zaaroor M, Sviri G, Paul M. Intrathecal or intraventricular therapy for post-neurosurgical Gram-negative meningitis: matched cohort study. Clin Microbiol Infect. 2016 Jan;22(1):66-70
The results of this study support the early use of intrathecal antibiotic treatment for carbapenem-resistant Gram-negative bacteria when a delivery method is available.

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Kristoffersson AN, Friberg LE, Nyberg J: Inter occasion variability in individual optimal design. J Pharmacokinet Pharmacodyn. 2015 Dec;42(6):735-50

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Salim Bouchene and Lena E. Friberg: Comparison of the rate and extent of in vitro formation of colistin for different brands of colistimethate sodium (CMS). Poster, 2nd International Conference on Polymyxins, San Diego, CA, USA, September 2015

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Andria N, Henig O, Kotler O, Domchenko A, Oren I, Zuckerman T, Ofran Y, Fraser D, Paul M. Mortality burden related to infection with carbapenem-resistant Gram-negative bacteria among haematological cancer patients: a retrospective cohort study. J Antimicrob Chemother 2015, Nov;70(11):3146-53

This study demonstrated a significant adjusted association between CRGNB and mortality up to 1 year among haemato-oncological patients receiving chemotherapy.
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Durante-Mangoni E, Del Franco M, Andini R, Bernardo M, Giannouli M, Zarrilli R. Emergence of colistin resistance without loss of fitness and virulence after prolonged colistin administration in a patient with extensively drug-resistant Acinetobacter baumannii. Diagn Microbiol Infect Dis. 2015 Jul;82(3):222-6

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Adler A, Ben-Dalak M, Chmelnitsky I, Carmeli Y. The effect of resistance mechanisms on the inoculum effect of carbapenem in carbapenem-resistant Klebsiella pneumoniae with borderline carbapenem MICs. Antimicrob Agents Chemother. 2015 Aug;59(8):5014-7.

We aimed to examine the effects of resistance mechanisms on several resistance phenotypes among carbapenem-resistant Klebsiella pneumoniae isolates with borderline carbapenem MICs. We compared carbapenemase-negative K. pneumoniae with carbapenemase-producing K. pneumoniae (CPKP) isolates with similar MICs. CPKP exhibited a marked inoculum effect and were more resistant to the bactericidal effect of meropenem. This suggests that MIC measurements alone may not be sufficient in predicting therapeutic efficacy of carbapenems against CPKP.

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Nutman A, Glick R, Temkin E, Hoshen M, Edgar R, Braun T, Carmeli Y. A case-control study to identify predictors of 14-day mortality following carbapenem-resistant Acinetobacter baumannii bacteraemia. Clin Microbiol Infect. 2014 Dec;20(12):O1028-34.

Differences in virulence between CRAB clones may partly explain heterogeneous results in previous studies of mortality following CRAB infection.

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Temkin E, Adler A, Lerner A, Carmeli Y: Carbapenem-resistant Enterobacteriaceae: biology, epidemiology, and management. Ann N Y Acad Sci. 2014 Sep;1323(1):22-42

Introduced in the 1980s, carbapenem antibiotics have served as the last line of defense against multidrug-resistant Gram-negative organisms. Over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have emerged as a significant public health threat. This review summarizes the molecular genetics, natural history, and epidemiology of CRE and discusses approaches to prevention and treatment.

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Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, Mussini C, Leibovici L.: Combination therapy for carbapenem-resistant Gram-negative bacteria.
J Antimicrob Chemother. 2014 Sep;69(9):2305-9.
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Zusman O, Avni T, Leibovici L, Adler A, Friberg L, Stergiopoulou T, Carmeli Y, and Paul M. published a Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems in Antimicrob Agents Chemother. 2013 Oct;57(10):5104-11.
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A. Huttner, E. Von Dach, A. Renzoni, M. Affaticati, B. Huttner, L. Pagani, Y. Daali, J. Pugin, A. Karmime, M. Fathi, S. Harbarth presented their poster Augmented Renal Clearance, Subtherapeutic Beta-lactam Concentrations, and Clinical Outcomes in the Critically Ill at ICAAC 2013
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S. Bouchene, S. Marchand, W. Couet, L. E. Friberg, P. Gobin, I. Lamarche, S. Björkman, M. O. Karlsson presented their poster Comparison of Colistin and Colistimethate sodium (CMS) Model-Predicted Whole Body Distribution with Measured Tissue:Plasma Concentrations Ratios in rats at ICAAC 2013.

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Mical Paul. Are polymyxins effective? A meta-analysis of polymyxin use. 1st International Conference on Polymyxins, 2-3 May, 2013, Prato, Italy.

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Oren Zusman, Tomer Avni, Leonard Leibovici, Amos Adler, Lena Friberg, Yehuda Carmeli, Mical Paul. In vitro synergy of polymyxins and carbapenems: Systematic review and meta analysis. 1st International Conference on Polymyxins, 2-3 May, 2013, Prato, Italy.
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Paul M, Yahav D, Leibovici L. Efficacy, use and dosing of colistin: what have contemporary studies taught us? (Educational session). 22st European Congress of Clinical Microbiology and Infectious Diseases, 31 March-3 April 2012, London, UK.
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Yahav D, Farbman L, Leibovici L, Paul M. Colistin: new lessons on an old antibiotic.
Clin Microbiol Infect 2012;18:18-29.
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ICAAC 2012 in San Francisco (A-032, Sunday, Sep 09, 2012). Lena Friberg’s team, partner in work package 4, designed a sparse pharmacokinetic sampling strategy of colistin pharmacokinetics. This sparse sampling schedule will be used for the clinical trial in work package 1 to help characterizing PKPD relationships in the enrolled critically ill patients. Given a target concentration and a fast method for concentration quantification a similar methodology could be applied to develop a therapeutic drug monitoring sampling schedule. This PK/PD study will support the clinical study of WP1.

A. N. Kristoffersson, J. Nyberg, L. E. Friberg: Optimal Design of a Colistin Sparse Sampling Schedule for individual PK-parameter Estimation