Polymyxin-based Combination Therapy Research Articles

Ceftazidime-avibactam with or without Aztreonam vs Polymyxin-based Combination Therapy for Carbapenem-resistant Enterobacteriaceae: A Retrospective Analysis.

Gram-negative sepsis remains one of the most difficult to treat infections in intensive care units (ICUs). Carbapenems are often considered to be robust and reliable options for treating infections due to Gram-negative bacteria. The dominance of carbapenem-resistant enterobacteriaceae (CRE) has emerged as one of the greatest challenges faced by the medical community today. Carbapenem-resistant enterobacteriaceae may be resistant to all beta lactam antimicrobials including carbapenems and often, are even resistant to other classes of drugs. There are limited studies comparing polymyxin-based therapies with ceftazidime-avibactam (CAZ-AVI)-based therapies for treating infections caused by CRE. A retrospective study comparing outcomes between patients with bacteremia caused by CRE treated with polymyxin-based combination therapy and CAZ-AVI-based therapy (with or without aztreonam). Of total 104 patients, 78 (75%) were in the CAZ-AVI group. There was no significant difference in the underlying comorbidities between the two groups. The incidence of nephrotoxicity was significantly higher in the polymyxin group (p = 0.017). Ceftazidime-avibactam-based therapy was 66% less likely to be associated with day 14 mortality (p = 0.048) and 67% less likely to be associated with day 28 mortality (p = 0.039) as compared with polymyxin-based therapy. Ceftazidime-avibactam-based therapy may be a superior option to polymyxin-based therapy for infections caused by CRE. This can have significant practical applications, in terms of optimizing therapy for the individual patient as well as sparing polymyxins and reducing the use of polymyxins in our hospitals. Prayag PS, Patwardhan SA, Panchakshari S, Sambasivam R, Dhupad S, Soman RN, et al. Ceftazidime-avibactam with or without Aztreonam vs Polymyxin-based Combination Therapy for Carbapenem-resistant Enterobacteriaceae: A Retrospective Analysis. Indian J Crit Care Med 2023;27(6):444-450.

Polymyxin B Combined with Minocycline: A Potentially Effective Combination against blaOXA-23-harboring CRAB in In Vitro PK/PD Model.

Polymyxin-based combination therapy is commonly used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. In the present study, the bactericidal effect of polymyxin B and minocycline combination was tested in three CRAB strains containing blaOXA-23 by the checkerboard assay and in vitro dynamic pharmacokinetics/pharmacodynamics (PK/PD) model. The combination showed synergistic or partial synergistic effect (fractional inhibitory concentration index ≤0.56) on the tested strains in checkboard assays. The antibacterial activity was enhanced in the combination group compared with either monotherapy in in vitro PK/PD model. The combination regimen (simultaneous infusion of 0.75 mg/kg polymyxin B and 100 mg minocycline via 2 h infusion) reduced bacterial colony counts by 0.9–3.5 log10 colony forming units per milliliter (CFU/mL) compared with either drug alone at 24 h. In conclusion, 0.75 mg/kg polymyxin B combined with 100 mg minocycline via 2 h infusion could be a promising treatment option for CRAB bloodstream infections.

Enhanced bacterial killing with colistin/sulbactam combination against carbapenem-resistant Acinetobacter baumannii

Aims: Polymyxin-based combination therapy is often used to treat carbapenem-resistant Acinetobacter baumannii (A. baumannii) infections. Although sulbactam is intrinsically active against A. baumannii, few studies have investigated colistin/sulbactam combinations against carbapenem-resistant A. baumannii.Methods: Whole genome sequencing was undertaken on eight carbapenem-resistant (colistin-susceptible) isolates of A. baumannii from Chinese patients. Bacterial killing of colistin and sulbactam, alone and in combination, was examined with checkerboard (all isolates) and static and dynamic time-kill studies (three isolates). In the dynamic studies, antibiotics were administered in various clinically-relevant dosing regimens that mimicked patient pharmacokinetics.Results: The eight isolates consisted of ST195, ST191 and ST208 belonging to clonal complex 208, which is the most epidemic clonal type of A. baumannii globally. All isolates possessed Acinetobacter-derived cephalosporinase (ADC-61 or ADC-78) and seven of eight isolates contained the carbapenem-resistance gene blaOXA-23. The colistin/sulbactam combination was synergistic against two of eight isolates in checkerboard studies. In time-kill studies, rapid bacterial killing of ca. 3–6 log10 CFU/mL was observed with colistin monotherapy, followed by steady regrowth. Sulbactam monotherapy was generally ineffective. Substantially enhanced bacterial killing was observed with colistin/sulbactam combinations in both static and dynamic models, especially with the higher sulbactam concentration (2 g) and/or longer sulbactam infusion time (2 hours) in the dynamic model.Conclusions: This study was the first to use a pharmacokinetics/pharmacodynamics model to investigate synergistic activity of colistin/sulbactam combinations against A. baumannii. It showed that clinically-relevant dosing regimens of colistin combined with sulbactam may substantially improve bacterial killing of multidrug-resistant and carbapenem-resistant A. baumannii.

Polymyxin monotherapy versus polymyxin-based combination therapy against carbapenem-resistant Klebsiella pneumoniae: A systematic review and meta-analysis

ObjectivesThis meta-analysis was performed to compare polymyxin monotherapy and polymyxin-based combination therapy for carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections. MethodsWe conducted searches on MEDLINE, Embase and Cochrane Collaborative database for both observational studies and randomised controlled trials (RCTs) comparing polymyxin monotherapy with polymyxin-based combination therapy in patients with CR-KP infection. The primary outcome was mortality. We divided all included studies into several groups according to different combination-combination and different infection types. The odds ratio (OR) and 95% confidence intervals (CI) were calculated for outcome analysis. ResultsTen studies with 481 patients were included. Polymyxin monotherapy was associated with higher mortality than polymyxin-based combination therapy in treatment of CR-KP bloodstream infections (BSI) (OR 1.93, 95% CI 1.14–3.27, P = 0.01) and ventilator-associated pneumonia (VAP)/hospital-acquired pneumonia (HAP) (OR 3.82, 95% CI 1.15–12.71, P = 0.03). In subgroup analysis of different combinations, mortality was significantly higher with polymyxin monotherapy compared with combination therapy with tigecycline (OR 1.88, 95% CI 1.05–3.37, P = 0.03), or with cabapenem (OR 3.11, 95% CI 1.25–7.74, P = 0.01), but no differences were found in combinations with aminoglycosides (OR 1.29, 95% CI 0.72–2.29, P = 0.38). Three-drug combination therapy including polymyxin was also associated with significant survival benefit (OR 3.86, 95% CI 1.60–9.32, P = 0.003). ConclusionsPolymyxin-based combination therapy provides significant survival benefit in treatment of CR-KP, which appears to be more pronounced when a carbapenem or tigecycline is included in the regimen.

Review of Ceftazidime-Avibactam, Meropenem-Vaborbactam, and Imipenem/Cilastatin-Relebactam to Target Klebsiella pneumoniae Carbapenemase-Producing Enterobacterales.

Objective: To provide a review of 3 novel antimicrobial agents-ceftazidime-avibactam, meropenem-vaborbactam, and imipenem/cilastatin-relebactam-regarding treatment of Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC). Data Sources: A literature search of PubMed and OVID (MEDLINE) was performed up to March 2020 using the following search terms: Vabomere, meropenem-vaborbactam, vaborbactam, RPX7009, Klebsiella pneumoniae carbapenemase, KPC, carbapenem-resistant Enterobacteriaceae, CRE, relebactam, imipenem-relebactam, MK-7655, ceftazidime-avibactam. Abstracts from conferences, article bibliographies, and product information were also reviewed. Study Selection and Data Extraction: Articles were first screened by English language, then title, then abstract, and finally by review of the full article. Fifty-five clinical and preclinical studies were included. Data Synthesis: These 3 novel β-lactam/β-lactamase inhibitor combinations have shown considerable improvement in safety and efficacy as compared with traditional polymyxin-based combination therapy for the treatment of KPC infections. While meropenem-vaborbactam has not shown improved activity against Pseudomonas aeruginosa, it has shown decreased rates of resistance to KPC versus ceftazidime-avibactam. Conclusions: With increasing incidence of KPC infections on a global scale, pharmacists should be aware of the notable similarities and differences between these 3 agents, and the current data supporting their use. Pharmacists may want to consider meropenem-vaborbactam over ceftazidime-avibactam for KPC infections due to decreased likelihood of resistance.

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).

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.

Treatment of Klebsiella Pneumoniae Carbapenemase (KPC) infections: a review of published case series and case reports

The emergence of Klebsiella pneumoniae carbapenemases (KPCs) producing bacteria has become a significant global public health challenge while the optimal treatment remains undefined. We performed a systematic review of published studies and reports of treatment outcomes of KPC infections using MEDLINE (2001–2011). Articles or cases were excluded if one of the following was fulfilled: no individual patient data provided, no treatment regimen specified, no treatment outcome specified, report of colonization, or greater than three antibiotics were used to treat the KPC infection. Data extracted included patient demographics, site of infection, organism, KPC subtype, antimicrobial therapy directed at KPC-infection, and treatment outcome. Statistical analysis was performed in an exploratory manner. A total of 38 articles comprising 105 cases were included in the analysis. The majority of infections were due to K. pneumoniae (89%). The most common site of infection was blood (52%), followed by respiratory (30%), and urine (10%). Forty-nine (47%) cases received monotherapy and 56 (53%) cases received combination therapy directed at the KPC-infection. Significantly more treatment failures were seen in cases that received monotherapy compared to cases who received combination therapy (49% vs 25%; p= 0.01). Respiratory infections were associated with higher rates of treatment failure with monotherapy compared to combination therapy (67% vs 29% p= 0.03). Polymyxin monotherapy was associated with higher treatment failure rates compared to polymyxin-based combination therapy (73% vs 29%; p= 0.02); similarly, higher treatment failure rates were seen with carbapenem monotherapy compared to carbapenem-based combination therapy (60% vs 26%; p= 0.03). Overall treatment failure rates were not significantly different in the three most common antibiotic-class combinations: polymyxin plus carbapenem, polymyxin plus tigecycline, polymyxin plus aminoglycoside (30%, 29%, and 25% respectively; p=0.6). In conclusion, combination therapy is recommended for the treatment of KPC infections; however, which combination of antimicrobial agents needs to be established in future prospective clinical trials.