United Kingdom
The Netherlands, Switzerland, Austria, Italy, Sweden, Denmark, France, Poland
Israel, Greece

Publications

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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Wijma RA, Bahmany S, Wilms EB, van Gelder T, Mouton JW, Koch BCP.: A fast and sensitive LC-MS/MS method for the quantification of fosfomycin in human urine and plasma using one sample preparation method and HILIC chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Sep 1;1061-1062:263-269

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Fransen F, Melchers MJB, Lagarde CMC, Meletiadis J, Mouton JW.: Pharmacodynamics of nitrofurantoin at different pH levels against pathogens involved in urinary tract infections. J Antimicrob Chemother. 2017 Sep 11.
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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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Huttner A, Brossier C, Von Dach E, Kowalczyk A, Godycki-Cwirko M, Babitch T, Turjeman A, Leibovici L, Theuretzbacher U, Mouton J, Harbarth S: Increasing nitrofurantoin resistance in Escherichia coli urinary isolates in a country with over-the-counter antibiotic sales. Abstract EV0557, ECCMID Vienna 2017
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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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Kowalczykl A, Harbarth S, Huttner A, Leibovici L, Mouton J, Godycki-Cwirko M: Protocol for clinical trial: "Randomized clinical trial comparing fosfomycin vs. nitrofurantoin for treatment of uncomplicated lower urinary tract infection in female adults at increased risk of antibiotic-resistant bacterial infection, AIDA". Annual Meeting of General Practice Research on Infections Network (GRIN), Oxford 2016.
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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):2729-39
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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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Theuretzbacher U: Optimizing the Use of Old Antibiotics—A Global Health Agenda. APUA Newsletter 2016, 34(2)
In the context of a global resistance threat and insufficient pipelines of new antibiotics, optimizing the use of old antibiot-ics—based on cutting-edge science and clinical evidence—is imperative to ensure good clinical outcome in patients and extend the life span of our older antibiotics.
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Muller AE, Verhaegh EM, Harbarth S, Mouton JW, Huttner A.: Nitrofurantoin's efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trials. Clin Microbiol Infect. 2016 Aug 17
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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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Fransen F, Melchers MJ, Meletiadis J, Mouton JW: Pharmacodynamics and differential activity of nitrofurantoin against ESBL-positive pathogens involved in urinary tract infections. J Antimicrob Chemother. 2016 Jun 7.
Nitrofurantoin was bactericidal against all species, demonstrating an unusual differential pattern of activity with concentration-dependent-type killing behaviour against E. cloacae and time-dependent killing behaviour against E. coli, which may have significant consequences on species-dependent dosing regimens. The results also demonstrate that the pharmacodynamic properties of some drugs cannot be generalized within a family, here the Enterobacteriaceae.
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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

Inter occasion variability (IOV) is of importance to consider in the development of a design where individual pharmacokinetic or pharmacodynamic parameters are of interest. IOV may adversely affect the precision of maximum a posteriori (MAP) estimated individual parameters, yet the influence of inclusion of IOV in optimal design for estimation of individual parameters has not been investigated. In this work two methods of including IOV in the maximum a posteriori Fisher information matrix (FIMMAP) are evaluated: (i) MAPocc-the IOV is included as a fixed effect deviation per occasion and individual, and (ii) POPocc-the IOV is included as an occasion random effect. Sparse sampling schedules were designed for two test models and compared to a scenario where IOV is ignored, either by omitting known IOV (Omit) or by mimicking a situation where unknown IOV has inflated the IIV (Inflate). Accounting for IOV in the FIMMAP markedly affected the designs compared to ignoring IOV and, as evaluated by stochastic simulation and estimation, resulted in superior precision in the individual parameters. In addition MAPocc and POPocc accurately predicted precision and shrinkage. For the investigated designs, the MAPocc method was on average slightly superior to POPocc and was less computationally intensive.background logo AIDA-fine line

Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA.Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA: Therapeutic drug monitoring of the b-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother. 2015 Dec;70(12):3178-83.

Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing β-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient ('mug') in equal measure.
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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

Conclusions:
- The model could well describe the time‐course of in vitro conversion of CMS to colistin in human plasma for all investigated CMS batches
- Only one of the investigated batches had a significantly higher rate of formation than the others (Colimicina). The older batch from Sigma formed a lower fraction of colistin A+B (87% of the other batches)
- This study does not support that the reported study differences in the rate of formation of CMS to colistin in vivo is due to the use of different CMS brands
- Since the analyzed colistin A+B concentration at time=0 was low, the amount of colistin in all investigated products is deemed to be negligible and have minor influence on the PK
- The information on conversion rates can also be valuable as prior information for characterization of CMS and colistin in vivobackground logo AIDA-fine line

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

OBJECTIVES: Carbapenem-resistant Gram-negative bacteria (CRGNB) pose a clinical challenge. We attempted to estimate the mortality burden of CRGNB among haematological cancer patients. METHODS: This was a retrospective cohort study. We included adult patients hospitalized in the haemato-oncological/bone marrow transplantation departments for chemotherapy, between 2008 and 2014, with Gram-negative aerobic bacteraemia. We compared patients with CRGNB and carbapenem-susceptible Gram-negative bacteraemia (CSGNB). The primary outcome was 14 day all-cause mortality. In addition, we assessed 1 year survival. Multivariable logistics regression analysis and adjusted Cox regression analysis were conducted. Analyses were adjusted to the propensity for CRGNB bacteraemia. RESULTS: The cohort included mostly young patients (mean age 50.1 years) with acute leukaemia (264/423, 62.4%) and the median absolute neutrophil count at bacteraemia onset was 0 × 109/L. The unadjusted 14 day mortality rate was higher for patients with CRGNB compared with CSGNB [45.6% (47/103) versus 15% (48/320), respectively (P < 0.001)]. Adjusting to baseline prognostic factors, infection characteristics and the propensity score retained a significant association between CRGNB and 14 day mortality (OR 5.14, 95% CI 2.32-11.38). Including only the first bacteraemic episode per patient, 1 year mortality was 74.7% (68/91) for patients with CRGNB versus 49.8% (119/239) for patients with CSGNB (P < 0.001). Adjusting for risk factors associated with 1 year mortality, the HR for mortality with CRGNB was 1.48 (95% CI 1-2.2). CRGNB bacteraemia was associated with several risk factors for mortality, including inappropriate empirical antibiotic treatment and less effective definitive antibiotics. CONCLUSIONS: 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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Theuretzbacher U, Paul M: Editorial. Revival of old antibiotics: Structuring the re-development process to optimise usage. CMI 2015, Oct;21(10):878-80

In an era of increasing antibiotic resistance and few treatment options for infections caused by multidrug-resistant (MDR) bacteria, the use of old drugs that retain activity against MDR organisms becomes attractive. Old drugs that have been recently revived include colistin, temocillin, fosfomycin, mecillinam, nitrofurantoin and chloramphenicol for MDR Gram-negative bacteria and trimethoprim-sulfamethoxazole for methicillin-resistant Staphylococcus aureus. These old antibiotics have never been characterized in a structured process for drug assessment and lack regulatory approval according to current standards.
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Theuretzbacher U, Van Bambeke F, Cantón R, Giske CG, Mouton JW, Nation RL, Paul M, Turnidge JD, Kahlmeter G. Reviving old antibiotics. J Antimicrob Chemother. 2015; 70(8):2177-81

In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to 're-develop' these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today's standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance. This paper describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.
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Muller AE, Theuretzbacher U, Mouton JW. Usage of old antibiotics now and in the future from a PK/PD perspective. Clin Microbiol Infect. 2015, Oct;21(10):881-5.

Due to the increase in bacterial resistance to commonly used antibacterial drugs, old antibiotics are 'revived' and, once again, are attracting interest. Many of these old antibiotics were approved long ago, in an era when there was no clear process for development and requirements that efficacy be demonstrated in rigorous clinical trials did not exist. At the time of these approvals, pharmacokinetic and pharmacodynamic principles were largely unknown and did not inform the dose finding process or recommendations for optimal usage. Indeed, the task of generating basic vital information for these old antibiotics remains to be done. In this review, we provide a brief overview of the most essential data needed for dose justification and optimisation. An overview of the shortage of data for selected old antibiotics illustrates the scope of the problem. In order to prevent harming patients with clinical decisions based on inadequate evidence, a re-development procedure for old antibiotics is urgently needed, including a regulatory framework.
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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

The spread of extensively drug-resistant (XDR) gram-negative bacteria has boosted colistin use, with a resultant selection of colistin-resistant, often pandrug-resistant strains. Whether acquisition of further resistance mechanisms translates into a reduced virulence is the subject of active research. In this report, we describe clinical features of an immunocompromised patient who developed infection due to colistin-resistant Acinetobacter baumannii while on long-term colistin therapy. We analyzed phenotypic and genotypic characteristics, molecular mechanisms of colistin resistance, and in vitro and in vivo fitness of sequential colistin-sensitive and colistin-resistant strains isolated from the patient. Both colistin-sensitive and colistin-resistant strains were XDR and showed identical ST78 genotype. At variance with prior reports on colistin-resistant strains of A. baumannii, resistance to colistin due to P233S mutation in PmrB sensor kinase did not associate with any measurable reduction in strain fitness, growth characteristics, and virulence.
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Huttner A, Verhaegh EM, Harbarth S, Muller AE, Theuretzbacher U, Mouton JW. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015 Sep;70(9):2456-64

OBJECTIVES: Nitrofurantoin's use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review and meta-analysis to assess nitrofurantoin's efficacy and toxicity in the treatment of lower UTI. METHODS: We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials. RESULTS: Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin's clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare. CONCLUSIONS: When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.

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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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U. Theuretzbacher presented a poster at ECCMID 2015: AIDA – Preserving old antibiotics for the future. Poster at the European Conference of Clinical Microbiology and Infectious Diseases (ECCMID) April 2015 in Copenhagen

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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.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an increasingly common nosocomial pathogen. We sought to identify clinical and microbiological predictors of 14-day mortality among patients with CRAB bacteraemia. This case-control study included all adult patients in one Israeli hospital with CRAB on blood culture between July 2008 and June 2011. Cases were defined as patients who died within 14 days of bacteraemia onset and controls as patients who survived over 14 days. Sequence-typing of the blaOXA-51-like gene and REP-PCR identified CRAB clone groups. Logistic regression was performed to analyze predictors of 14-day all-cause mortality. To correct for differences in treatment onset, Cox regression was used to examine the effect of receiving an active antibiotic. Eighty-three cases and 89 controls were included. Six major CRAB clone groups were identified, with 14-day mortality ranging from 17 to 66%. Independent predictors of 14-day mortality were severity of illness (OR = 1.38 for each 1-point increase in Sequential Organ Failure Assessment (SOFA) score; 95% CI, 1.21, 1.56), independence in activities of daily living (ADL) on admission (OR = 3.40; 95% CI, 1.20, 9.67, for fully dependent vs. independent), surgery before bacteraemia (OR = 0.25; 95% CI, 0.11, 0.59) and clone group (OR = 7.76; 95% CI, 2.52, 23.85, for the most virulent group vs. the reference group). In the multivariate Cox model using a propensity score to adjust for SOFA, clone, ADL and surgery, active antibiotic treatment was protective (HR = 0.30; 95% CI, 0.15, 0.60). Differences in virulence between CRAB clones may partly explain heterogeneous results in previous studies of mortality following CRAB infection.

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L. Jakobsen, N. Frimodt-Møller Fosfomycin PK/PD in Experimental Urinary Tract Infection ICAAC 2014, Poster A-046

Background: Fosfomycin (FOS) has become an attractive drug of choice for treatment of urinary tract infections (UTI) due to the rise of antimicrobial resistant uropathogens, especially the difficult-to-treat extended-spectrum β-lactamase producers. Although an old antimicrobial agent, the predictive PK/PD indices of FOS have not been elucidated for UTI. Methods: In OF-1 mice, PK of FOS after single sc. doses of 0.75, 7.5, and 30 mg/mouse (~ 25-1000 mg/kg) were determined in blood and urine (sampling times after dosing: 15 min - 4 hours). FOS concentrations were measured by bioassay. Dose-dependent PK (T>MIC, Cmax/MIC, AUC24/MIC) were analyzed using the Hill equation (GraphPad Prism). Efficacy of 6 FOS dosage regimens (total dose of 0.05 - 1.6 mg/mouse; dosing frequency of 6-72 hours) was investigated using the murine model of ascending UTI to estimate the most predictive PK/PD indices. Infection was induced by inoculating 50 μl (5x106 CFU) E. coli (NU14; FOS MIC 0.75 mg/L) via a catheter (retracted after inoculation) transurethrally and treatment was initiated sc. 1 day post infection for 3 days with FOS or saline. Urine, bladder, and kidneys were collected 4 days post infection for CFU determination. Results: Peak FOS serum concentrations of 30 to 800 mg/l were seen at the 3 doses used, with a serum elimination T½ of 30 min, and urine peak FOS concentrations from 2000- 90000 mg/l sustained above MIC for 6 - 18h. Six dose regimens were chosen which resulted in varying the serum PKPD indices: Time>MIC % from 5 - 80%, and the AUC/MIC ratios from 25 - 400 h, respectively. All doses significantly reduced CFUs as related to control, untreated mice (% reduction, lowest to highest doses; median control counts); urine: 80 - 100% (control mice: Log 6,8 CFU/ml; bladder: ca. 50% (control mice: Log 5,7 CFU/bladder); kidneys: 50-100% (control mice: log 2,9 CFU/kidney). The optimal PKPD indices for urine CFU/ml were (R2): AUC/MIC, 0,82; and Time>MIC of 1.dose: 0,82. Low correlations were found for Time>MIC % in all tissues, and for all indices for kidney counts. Conclusions: FOS was very effective in reducing urine counts even at a dose of 0,47 mg/mouse BID. Bladder counts remained at Log 3 CFU/bladder in all mice even after a dose of 30 mg/mouse, while this dose eradicated all bacteria in the kidneys in 5/6 mice. The optimal PKPD indices included AUC/MIC ratio (> 200), or Time>MIC of 1. Dose (>2 h).

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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.

Carbapenem-resistant Gram-negative bacteria (CR-GNB) represent an increasing hazard in healthcare settings. A central question concerning the treatment of invasive infections caused by CR-GNB involves the use of combination therapy. Potential advantages of combination therapy include improved efficacy due to synergy, while the disadvantages include adverse events and increased antibiotic use with a potential drive towards resistance. Several observational studies have examined whether combination therapy offers an advantage over colistin/polymyxin monotherapy. We highlight the inherent limitations of these studies related to their observational design and sample size to show why they do not at present provide an answer to the question of combination versus monotherapy. This distinction is important to guide clinical practice until solid evidence has been obtained and to enable the recruitment of patients into randomized controlled trials. A few randomized controlled trials examining specific combinations have recently been completed or are ongoing. Currently, however, there is no evidence-based support for most combination therapies against CR-GNB, including colistin/carbapenem combination therapy.Sep;69(9):2305-9

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U. Theuretzbacher presented a poster at ECCMID 2014: AIDA – Preserving old antibiotics for the future. Poster at the European Conference of Clinical Microbiology and Infectious Diseases (ECCMID) May 2014 in Barcelon

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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.

Our objective was to examine the evidence of in vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB). A systematic review and meta-analysis were performed. All studies examining in vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concentration index of ≤0.5 or a >2-log reduction in CFU, were pooled separately for time-kill, checkerboard, and Etest methods in a mixed-effect meta-analysis of rates. We examined whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for Acinetobacter baumannii, 44% (95% CI, 30 to 59%) for Klebsiella pneumoniae, and 50% (95% CI, 30 to 69%) for Pseudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. 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 studies. The use of combination therapy led to less resistance development in vitro. The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.

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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

Background Augmented renal clearance (ARC) is well described in the critically ill. Our objective was to evaluate its impact on beta-lactam (BL) plasma concentrations ([c]) and clinical outcome in intensive care unit (ICU) patients with severe bacterial infections. Methods In this prospective, single-center observational pilot study conducted from 2010 to early 2013, peak, intermediate and trough [c] of 4 BL were drawn on days (d) 1-3 and 5 from non-pregnant ICU patients aged 18 - 60 years (y) with severe infection and creatinine clearance (CrCl) ≥ 60 ml/min. ARC was evaluated as defined both by (1) CrCl ≥ 120 and (2) ≥ 140 ml/min; CrCl was estimated by the Cockcroft-Gault formula. BL [c] were deemed subtherapeutic if they did not meet EUCAST-defined non-species-related breakpoints (< 2 mg/l for imipenem [IPM] and meropenem [MEM], < 4 mg/l for piperacillin/tazobactam [TZP] and cefepime [FEP]). Clinical resolution was defined as disappearance of signs and symptoms related to the infection, failure as insufficient lessening of those signs and symptoms, including death. Patients were followed for 28 d. Analyses were performed within Stata 12 (College St., TX). Results 100 patients were enrolled; mean follow-up was 19 d. Three quarters were male; mean age was 42 y. Mean Apache II score was 21.2 with 87 patients intubated at inclusion. Pneumonia (63%) and bloodstream infections (16%) predominated. Mean CrCl at inclusion was 149.5 ml/min (range 62 - 307.1). When defined as CrCl ≥ 120 ml/min, ARC was present in 69%. Fifty-four patients were on IPM, 33 on TZP, 11 on MEM, and 2 on FEP. Of 91 patients with trough [c], 90% had at least one subtherapeutic [c]. Among IPM and TZP trough [c], 77% and 61% were subtherapeutic, respectively. ARC strongly predicted subtherapeutic trough [c] (odds ratio 5.89, p= 0.016, 95% CI 1.4 - 24.7 when CrCl ≥ 120 ml/min). There were 18 failures (9 non-response; 9 death); however, a link between ARC and failure was not observed (p = .77). Conclusions ARC and subtherapeutic BL [c] are common among the critically ill. We did not observe an association with clinical failure but the study may have been underpowered to detect a small but clinically important effect.
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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.

Background:Characterizing colistin tissue distribution is important in order to optimize bacteria killing and reduce toxicity. The aim of this study is to compare tissue:plasma concentration ratio (kp) predictions from a whole body physiologically-based pharmacokinetic (WBPBPK) model to kp measured ex vivo. Methods:Twelve rats were used to measure kp values: 6 received a 3-h constant IV-infusion of 8.5 mg/h/kg CMS and 6 received a 4-h constant IV-infusion of 350 µg/h/kg colistin. Plasma, CSF, kidneys, heart, lungs, liver, fat, muscle and duodenum were collected at 3h for CMS and at 4h for colistin. All samples were assayed by LC-MS/MS [1]; kp values of lung, heart, liver and kidney were corrected for blood contamination [2]. A single IV-bolus of 15 mg/kg CMS was administered to 6 rats. Arterial blood was collected from 5-180 min post-dose; CMS and colistin were assayed at each time point. A WBPBPK model was developed describing each tissue as a perfusion limited and well-stirred compartment. CMS and colistin kp values were estimated using prior information from literature [3]. Results: kp values estimated from the WBPBPK model and measured from infusion experiments are summarized in Table 1.
Conclusions: The WBPBPK model well described CMS and colistin plasma concentration-time profiles. The measured kp values in kidney were high compared to the model predictions. This may be due to substance undergoing renal transport [4] and help to explain colistin nephrotoxicity. References: [1] Gobin et al., Antimicrob Agents Chemother. 2010 [2] de Boer et al., Nutrient Metabolism. 2005 [3] Björkman et al., J Pharm Sci. 2001 [4] Ma et al., Antimicrob Agents Chemother. 2009

WBPBPK and measured kp values for CMS and colistin
  kp CMS
WBPBPK model
kp CMS measured kp colistin WBPBPK model kp colistin
measured
Lungs 0.160 0.0659 0.459 0.694
Brain 0.0549 0.0143 0.0932 0.0586
Heart 0.108 0.0863 0.244 0.398
Muscle 0.0637 0.0125 0.109 0.0817
Fat 0.0511 0.0440 0.0860 0.140
Duodenum 0.0598 0.0304 0.108 0.205
Liver 0.166 0.0690 0.291 0.743
Kidneys 0.132 4.42 0.227 20.9
CSF   0.0173    

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The study Pharmacodynamics of minocycline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection by AR Noel, KE Bowker, S Tomaselli, AP MacGowan, WW Hope has been presented at ICAAC 2013. This PK/PD study will support the clinical study of WP3.

Background: Minocycline (MIN) is a widely used oral therapy for mild to moderate MRSA infection which can be safely treated with non-parenteral antibiotics. Despite a long tradition of use to treat Staphylococcal infection, there is little data to support present dosing regimens and no data on the risks of emergence of resistance. Clinical breakpoints, both in Europe and USA, are based on historic data. Our objective was to provide modern information on the pharmacodynamic index size for minocycline and S.aureus with a view to re-assessing established clinical breakpoints and potential dose regimens. Methods: An in vitro dilutional pharmacokinetic model was used to perform a series of dose ranging studies against 4 strains of S.aureus (MIN MIC 0.19-0.5mg/L, all susceptible by EUCAST breakpoints S≥0.5mg/L). Antibacterial effect was measured by changes in viable count over 72h and changes in population profile by recovery on MICx4 or MICx8 plates after 24, 48 and 72h MIN exposure. Results: The fAUC/MIC at 24h for static and -1 log reductions in viable count were 11.5±6.1 and 18.1±8.1 respectively. For -2 log reduction in viable count, the fAUC/MIC was >200 for two strains, and 33.1 and 42.8 for the two others. fAUC/MIC targets were modestly increased after 72h being 12.9±2.9, static effect; 17.7±5.2, -1 log drop; 2 log drop values were >75, and 32.1 and 18.2 for the other two strains. There were no changes in population profiles indicated by growth on MICx4 or MICx8 plates at 24, 48 or 72h. Conclusions: A suitable fAUC/MIC target related to static -1 log drop for MIN is 10-15. This target was not associated with any change in population profiles and would suggest a clinical breakpoint of S≤0.25-0.5mg/L for a dose of 100mg 12 hrly.
Poster
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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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The first study of the AIDA project was presented at ICAAC 2012 in San Francisco (A-032, Sunday, Sep 09, 2012, 11:30 AM - 1:30 PM). 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

Background: For development of optimized dosing regimen of colistin the concentration-effect relationship needs to be characterized. Sparse PK sampling combined with a population PK model can be used to determine individual concentration-time profiles by maximum a posteriori (MAP) estimations, allowing a more precise concentration-effect description. The objective of this work was to design a sparse sampling schedule of colistin PK for a clinical trial aiming at characterizing PKPD relationships in 300 critically ill patients. Methods: The design was based on a dosing regimen of 9MU (720 mg) CMS as load (15-min infusion), followed by a maintenance dose of 4.5MU q12. The PK model used for the OD features interindividual (IIV) and inter occasion (IOV) variability (Friberg et al, ICAAC 2010, A1-665), but the optimization focused on individual precision in clearance of colistin and CMS (CLi), intercompartmental CL of CMS (Qi) and colistin residual error (REi). Schedules of 1, 2 or 3 sampling times (concurrent CMS and colistin measure) over the initial 72h were optimized in the PopED software using an individual Bayesian D-optimality criterion with IIV as prior and inflated to include IOV. The schedules were evaluated by 100 stochastic simulations and MAP re-estimations. Results: The optimal sampling times were at 37h after treatment initiation for the 1-sample schedule, at 0.5 and 64h for the 2-sample schedule and at 2 x 0.5 and 72h for the 3-sample schedule. Simulation and estimation for the 1-sample design yielded CLi estimates with moderate shrinkage towards the population CL, while the 2-sample design generated precise and unbiased CLi estimates with minimal shrinkage. The 3-sample design had similar precision and shrinkage in CLi as the 2-sample design while the Qi and REi estimates were slightly improved. Conclusion: A 2-sample schedule at 0.5 and 64h was produced by OD and shown to result in unbiased estimates of CLi for colistin. Given a target concentration and a fast method for concentration quantification a similar methodology could be applied to develop a TDM sampling schedule. Acknowledgement: This work was funded by grants from Swedish Foundation of Strategic Research and the EU-funded AIDA project (Health-F3-2011-278348) to LEF.

Presentations

Yael Dishon, Mical Paul, on behalf of AIDA Consortium. Colistin alone vs. colistin plus meropenem against carbapenem-resistant Gram-negative bacteria. Poster. The D. Dan and and Betty Kahn 6th Annual Scientific Symposium for the Michigan-Israel Partnership for Research and Education, Haifa, 2016.

Paul M. Colistin monotherapy is still a viable option for treatment of MDR-GNB. ASM Microbe 2016. 16-20 June, 2016. Boston, US.

Paul M. Combination therapy for MDR bugs: when and for whom? ASM Microbe 2016. 16-20 June, 2016. Boston, US.