Is it time to move away from polymyxins?: evidence and alternatives

Soman, Rajeev; Bakthavatchalam, Yamuna Devi; Nadarajan, Abinaya; Dwarakanathan, Hariharan Triplicane; Ramasubramanian, V; Veeraraghavan, Balaji

doi:10.1007/s10096-020-04053-w

Cited by 29 publications

(23 citation statements)

References 147 publications

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“…There is clinical and experimental evidence that nebulization of high-dose CMS may be an efficient treatment of MDR GNB VAP and VAT. It is unclear whether nebulized high-dose CMS is equivalent or superior to the treatment by intravenous CMS or new cephalosporin/ß-lactamase inhibitors [52,53].…”

Section: Figurementioning

confidence: 99%

“…Following intravenous administration, 70% of a CMS dose is rapidly cleared by the kidney, whereas 20-25% is slowly hydrolyzed to colistin through a process that takes more than 36 h. Penetration into all organs except the kidneys and biliary tract is also quite limited. PKPD studies indicate that it is difficult to reach bactericidal colistin concentrations at the site of infection in patients with normal renal function without exceeding the recommended plasma concentrations of 2 mg/L, above which the risk of nephrotoxicity markedly increases [52]. Microdialysis studies performed in anaesthetized healthy female pigs have shown that physico-chemical properties play a pivotal role for antibiotic penetration across the vascular endothelium, basement membrane and the respiratory epithelium.…”

Section: Future Research 71 Concerns On the Use Of Intravenous Colistimethate Sodiummentioning

confidence: 99%

“…As CMS and colistin have one of the highest molecular masses and polarities, are significantly charged (Figure 3a) and highly hydrophilic, their ability to cross the alveolo-capillary membrane is among the lowest [86]. Owing to rapid renal clearance and limited pulmonary diffusion and despite optimized CMS dosing, intravenous colistin does not appear optimal to treat lower respiratory tract infections [52,97].…”

Section: Future Research 71 Concerns On the Use Of Intravenous Colistimethate Sodiummentioning

confidence: 99%

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Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

et al. 2021

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Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20–25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis.

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Section: Figurementioning

confidence: 99%

Section: Future Research 71 Concerns On the Use Of Intravenous Colistimethate Sodiummentioning

confidence: 99%

Section: Future Research 71 Concerns On the Use Of Intravenous Colistimethate Sodiummentioning

confidence: 99%

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Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

et al. 2021

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“…In vitro activity of PLZ in comparison with that of other aminoglycosides was found to be excellent with 92.3% to 98.0% overall susceptibility in Enterobacterales including CRE ( 6 – 9 ). Recently, PLZ was also shown to be active against certain multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram negative pathogens for which limited treatment options are left ( 10 , 11 ). In the Combating Antibiotic-Resistant Enterobacteriaceae (CARE) trial, serious adverse events (including death) occurred less frequently in the PLZ group than in the colistin group of patients with CRE infections ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Multicenter Clinical Evaluation of ETEST Plazomicin (PLZ) for Susceptibility Testing of Enterobacterales

et al. 2022

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Plazomicin (PLZ), brand name ZEMDRI (Cipla Therapeutics), is a novel aminoglycoside antibiotic approved by the US Food and Drug Administration (FDA) for treatment of complicated urinary tract infections including pyelonephritis. ETEST® is a gradient diffusion method that represents an alternative to the more laborious broth micro-dilution (BMD) method for performing antimicrobial susceptibility testing (AST). A multi-center evaluation of the performance of the new ETEST® PLZ (bioMérieux) was conducted in comparison with BMD following FDA and International Standards Organization (ISO) recommendations using FDA-defined breakpoints. Clinical isolates of Enterobacterales (n=598) were included. Fifty-three isolates were resistant to PLZ according to BMD. Overall, the ETEST® PLZ demonstrated 99.0% Essential Agreement (EA), 92.8% Category Agreement (CA), 1.9% Very Major Errors (VME), 0% Major Errors (ME) and 7.0% minor Errors (mE) with both clinical and challenge isolates of Enterobacterales. The VME was found for a single Serratia marcescens strain. Individual species demonstrated EA rates ≥ 90%. In conclusion, we report that ETEST® PLZ represents an accurate tool for performing PLZ AST of Enterobacterales.

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“…Limitations in their clinical use are imposed by the outstanding incidence of renal toxicity, their poor lung, bone and central nervous system penetration and the lack of an accurate and practical susceptibility testing. Nowadays, the rising trend of resistance requires new molecules with the potential to act as colistin-supplanting agents [ 8 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

et al. 2021

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The worldwide propagation of antimicrobial resistance represents one of the biggest threats to global health and development. Multi-drug-resistant organisms (MDROs), including carbapenem-resistant non-fermenting Gram-negatives and Enterobacterales, present a heterogeneous and mutating spread. Infections by MDRO are often associated with an unfavorable outcome, especially among critically ill populations. The polymyxins represented the backbone of antibiotic regimens for Gram-negative MDROs in recent decades, but their use presents multiple pitfalls. Luckily, new agents with potent activity against MDROs have become available in recent times and more are yet to come. Now, we have the duty to make the best use of these new therapeutic tools in order not to prematurely compromise their effectiveness and at the same time improve patients’ outcomes. We reviewed the current literature on ceftazidime/avibactam, meropenem/vaborbactam and cefiderocol, focusing on antimicrobial spectrum, on the prevalence and mechanisms of resistance development and on the main in vitro and clinical experiences available so far. Subsequently, we performed a step-by-step construction of a speculative algorithm for a reasoned prescription of these new antibiotics, contemplating both empirical and targeted use. Attention was specifically posed on patients with life-risk conditions and in settings with elevated prevalence of MDRO.

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Is it time to move away from polymyxins?: evidence and alternatives

Cited by 29 publications

References 147 publications

Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

Multicenter Clinical Evaluation of ETEST Plazomicin (PLZ) for Susceptibility Testing of Enterobacterales

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

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