Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial

Paul, Mical; Daikos, George L.; Durante‐Mangoni, Emanuele; Yahav, Dafna; Carmeli, Yehuda; Benattar, Yael Dishon; Skiada, Anna; Andini, Roberto; Eliakim‐Raz, Noa; Nutman, Amir; Zusman, Oren; Antoniadou, Anastasia; Pafundi, Pia Clara; Adler, Amos; Dickstein, Yaakov; Pavleas, Ioannis; Zampino, Rosa; Daitch, Vered; Bitterman, Roni; Zayyad, Hiba; Koppel, Fidi; Levi, Itzhak; Babich, Tanya; Friberg, Lena E.; Mouton, Johan W.; Theuretzbacher, Ursula; Leibovici, Leonard

doi:10.1016/s1473-3099(18)30099-9

Cited by 426 publications

(345 citation statements)

References 29 publications

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“…A population pharmacokinetic study of polymyxin B in Thai patients is currently being conducted to determine the most appropriate dosing regimen for Thai patients. The rate of good response to polymyxin B observed in this study should not related to the prior use of carbapenems or a combination of polymyxin B and carbapenems because all isolated bacteria from the patients were resistant to carbapenems and the results from the recent randomized controlled trial (RCT) revealed that the outcomes of the patients infected with XDR Gram-negative bacteria who received a combination of colistin and meropenem was not significantly better than those who received colistin alone 14. Regarding the nephrotoxicity of polymyxin B, the findings from our study were in accordance with the recent reviews reporting that polymyxin B was associated with less risk of nephrotoxicity than colistin 15,16…”

Section: Discussionmentioning

confidence: 65%

Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand

Ngamprasertchai¹,

Boonyasiri²,

Charoenpong³

et al. 2018

IDR

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BackgroundColistimethate sodium (colistin) has been used in the treatment of infections caused by extensively drug-resistant (XDR) Gram-negative bacteria in Thailand over the past decade, with a mortality rate of 50% and a nephrotoxicity rate of 40%. Polymyxin B has not been available in Thailand. We conducted a Phase II clinical study to determine the effectiveness and safety of polymyxin B, compared with colistin, for the treatment of XDR Gram-negative bacterial infections in Thai patients.MethodsA total of 73 adult patients hospitalized at four participating tertiary care hospitals from January 2015 to December 2015 who had infections caused by XDR Gram-negative bacteria and had to receive colistin were enrolled in the study. Polymyxin B (100 mg/day) was administered intravenously every 12 hours for 7–14 days.ResultsMost of the patients were older males with comorbidities who had received antibiotics, particularly carbapenems, prior to receiving polymyxin B. More than half of the patients had pneumonia, and 51.5% of the infections were caused by XDR Acinetobacter baumannii, which was susceptible to colistin. Good clinical responses at the end of treatment were observed in 78.1% of cases, the overall 28-day mortality rate from all causes was 28.7%, the microbiological clearance of the targeted bacteria after therapy was 56.2% and nephrotoxicity occurred in 24.7% of cases. Neurotoxicity relating to reversible numbness was observed in two cases.ConclusionPolymyxin B seems to be effective and safe for the treatment of XDR Gram-negative bacterial infections. Polymyxin B should be considered as an alternative to colistin for treatment of infections caused by XDR Gram-negative bacteria in Thai adult patients, especially those at risk of nephrotoxicity.

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Section: Discussionmentioning

confidence: 65%

Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand

Ngamprasertchai¹,

Boonyasiri²,

Charoenpong³

et al. 2018

IDR

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“…There are few studies which have assessed the impact of polymyxin combination therapy with a second nonsusceptible agent on outcomes in patients with invasive CRE infections. Perhaps the best evidence suggesting a potential advantage of this strategy comes from a recently published RCT comparing colistin monotherapy versus colistin + meropenem combination therapy for the management of carbapenem‐resistant gram‐negative bacilli . In this study, only nine patients (2%) had isolates susceptible (MICs of 8 mg/L or lower) to meropenem.…”

Section: Clinical Questions and Recommendationsmentioning

confidence: 99%

“…In this study, only nine patients (2%) had isolates susceptible (MICs of 8 mg/L or lower) to meropenem. Both clinical failure and 28‐day mortality occurred in a lower proportion of patients with CRE receiving the colistin + meropenem combination than colistin monotherapy (failure rates 18/39 [46%] vs 23/34 [68%]; p=0.19, and 28‐day mortality of 21% vs 35%; p=0.24), although statistical significance was not demonstrated . Based on the lack of evidence clearly addressing this issue in CRE and the previously mentioned concerns/limitations with monotherapy, we recommend that if no second agents to which the infecting pathogen displays a susceptible MIC are available for combination therapy, a second and/or third “nonsusceptible” agent should be administered in combination with the polymyxin.…”

Section: Clinical Questions and Recommendationsmentioning

confidence: 99%

International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP)

et al. 2019

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The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram‐negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti‐Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin‐based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.

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“…For example, intent‐to‐treat does not take into account concomitant or subsequent exposures after randomization. As such, in clinical trials that allow for adjunctive therapy and changes in therapy, postrandomization antibiotics are treated as ignorable . Additionally, antibiotic therapy prior to randomization may also be treated as ignorable, and despite randomization, exposures may differ significantly between study populations .…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in the treatment of bloodstream infections identified from antibiotic exposure mapping

Caffrey

Babcock

Lopes

et al. 2019

Pharmacoepidemiology and Drug

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Purpose As changes in antibiotic therapy are common, intent‐to‐treat and definitive therapy exposure definitions in infectious disease clinical trials and observational studies may not accurately reflect all antibiotics received over the course of the infection. Therefore, we sought to describe changes in antibiotic therapy and unique treatment patterns among patients with bacteremia. Methods We conducted a retrospective cohort study of hospitalizations from Veterans Affairs (VA) Medical Centers (January 2002‐September 2015) and community hospitals (de‐identified Optum Clinformatics DataMart with matched Premier Hospital data; October 2009‐March 2013). In the VA population, antibiotic exposures were mapped from the culture collection date among those with positive Staphylococcus aureus cultures. In the Optum‐Premier population, exposures were mapped from the admission date among those with a primary diagnosis of bacteremia. Results Our study included 50 467 bacteremia admissions, with only 14% of admissions having the same treatment pattern as another admission. For every 100 bacteremia admissions, 89 had changes in antibiotic therapy. For every 100 bacteremia admissions with changes in therapy, 95 had unique antibiotic treatment patterns. These findings were consistent in both populations, over time, and among different facilities within study populations. The median time to first therapy change was 2 days after initial therapy, with a median of three changes. Conclusions Changes in antibiotic therapy for bloodstream infections were nearly universal regardless of hospital setting. Based on our findings, common antibiotic exposure definitions of intent‐to‐treat and definitive therapy would misclassify exposure in 86% of admissions, which highlights the need for better operational definitions of exposure in infectious diseases research.

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Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial

Cited by 426 publications

References 29 publications

Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand

Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand

Heterogeneity in the treatment of bloodstream infections identified from antibiotic exposure mapping

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