Combination Of Polymyxin Research Articles

Combined nephrotoxicity of Polymyxins and Vancomycin: a study on adverse event reporting for monotherapy versus combinations using the FDA adverse event reporting system (FAERS)

ABSTRACT Background Multidrug-resistant (MDR) infections pose a global public health crisis with significant mortality and economic burdens. Combination of polymyxins and vancomycin has shown effectiveness against MDR infections. However, their combined nephrotoxicity complicates clinical use. Given these concerns, we conducted a pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) to assess the nephrotoxicity of combinations of polymyxins and vancomycin compared to monotherapy. Research design and methods In this retrospective study, data from FAERS reports (2012 Q4 to 2023 Q2) were deduplicated and analyzed for adverse events (AEs) related to vancomycin, polymyxin B, and colistin. Disproportionality analyses were performed to evaluate the association between drugs and nephrotoxicity. Results A total of 9,796,784 adverse event reports, including 73,009 reports associated with nephrotoxicity, were included. All three drugs showed significant associations with nephrotoxicity. In combination therapy, polymyxin B-vancomycin exhibited a stronger association with nephrotoxicity compared to monotherapy, whereas colistin-vancomycin demonstrated a lower association with nephrotoxicity than colistin monotherapy. Conclusions This study found that combining vancomycin with colistin alleviated colistin-induced nephrotoxicity, while combining vancomycin with polymyxin B worsened polymyxin B-induced nephrotoxicity.

Synergistic combinations of novel polymyxins and rifampicin with improved eradication of colistin-resistant Pseudomonas aeruginosa biofilms

BackgroundIncreased prevalence of antimicrobial resistance coupled with a lack of new antibiotics against Gram-negative bacteria emphasize the imperative for novel therapeutic strategies. Colistin-resistant Pseudomonas aeruginosa constitutes a challenge, where conventional treatment options lack efficacy, in particular for biofilm-associated infections. Previously, synergy of colistin with other antibiotics was explored as an avenue for the treatment of colistin-resistant infections, and recently we reported our efforts towards colistin analogs capable of combating planktonic colistin-resistant strains. AimsThe aim of the present study was to investigate whether analogs of polymyxin B with improved potency in wild-type and moderate resistant Gram-negative pathogens would retain similarly increased activity in highly colistin-resistant clinical P. aeruginosa isolates (in planktonic and biofilm growth) when applied alone and in combination with rifampicin. Materials and methodsIn this in vitro study, we tested three analogs of polymyxin B prepared by solid-phase peptide synthesis. Antimicrobial susceptibility testing was performed by measurement of minimum inhibitory concentrations via the broth microdilution method. Interactions between two antimicrobials was quantified in a checkerboard broth microdilution assay by calculating the fractional inhibitory concentration index for each combination. For testing of antibiofilm activity a previously described model with alginate beads encapsulating a biofilm culture was applied. The minimum biofilm eradication concentrations (MBECs) were evaluated, and the fractional biofilm eradication concentration indices were calculated. Three recently identified colistin analogs (CEP932, CEP936 and CEP938) were tested against three isogenic pairs of colistin-susceptible and colistin-resistant P. aeruginosa clinical isolates as well as the reference strain PAO1. ResultsFor bacteria in planktonic growth CEP938 retained almost full potency in all three resistant isolates, while exhibiting similar activity as colistin in susceptible isolates. Against biofilms CEP938 was slightly more potent against PAO1 as compared to colistin, while also retaining activity against a biofilm of the colistin-resistant strain 41,782/98. Next, synergy between CEP938 and the antibiotic rifampicin was explored. Interestingly, CEP938 did not exhibit synergy with rifampicin in planktonic cultures. Importantly, for colistin-resistant biofilms the CEP938-rifampicin combination demonstrated activity superior to that found for the colistin-rifampicin combination. ConclusionsThe present study showed in vitro efficacy of CEP938 against both colistin-susceptible and colistin-resistant P. aeruginosa biofilms as well as an ability of CEP938 to synergize with rifampicin in biofilm eradication.

Synergistic antimicrobial combination of third-generation cephalosporins and polymyxin B against carbapenem-polymyxin-resistant Klebsiella pneumoniae: an in vitro and in vivo analysis.

Antibiotic combination therapy is a promising approach to address the urgent need for novel treatment options for infections caused by carbapenem-polymyxin-resistant Klebsiella pneumoniae (CPR-Kp). The present study aimed to investigate the synergistic potential of four cephalosporins in combination with polymyxin B (PMB). A checkerboard assay was performed to evaluate the synergistic effects of cephalexin (CLX), cefixime, cefotaxime (CTX), and cefmenoxime (CMX) in combination with PMB. Subsequently, experiments evaluating the use of CTX or CMX in combination with PMB (CTX-PMB or CMX-PMB, respectively), including growth curve and SynergyFinder analysis, antibiofilm activity assays, cell membrane integrity assays, and scanning electron microscopy, were performed. Safety assessments were also conducted, including hemolysis and toxicity evaluations, using Caenorhabditis elegans. Furthermore, an in vivo model in C. elegans was adopted to assess the treatment efficacy against CPR-Kp infections. CTX-PMB and CMX-PMB exhibited low fractional inhibitory concentration indexes ranging from 0.19 to 0.50 and from 0.25 to 1.5, respectively, and zero interaction potency scores of 37.484 and 15.076, respectively. The two combinations significantly reduced growth and biofilm formation in CPR-Kp. Neither CTX-PMB nor CMX-PMB compromised bacterial cell integrity. Safety assessments revealed a low hemolysis percentage and high survival rates in the C. elegans toxicity evaluations. The in vivo model revealed that the CTX-PMB and CMX-PMB treatments improved the survival rates of C. elegans. The synergistic effects of the CTX-PMB and CMX-PMB combinations, both in vitro and in vivo, indicate that these antibiotic pairings could represent effective therapeutic options for infections caused by CPR-Kp.

Combination therapy with IV fosfomycin for adult patients with serious Gram-negative infections: a review of the literature.

Treatment of patients with serious infections due to resistant Gram-negative bacteria remains highly problematic and has prompted clinicians to use existing antimicrobial agents in innovative ways. One approach gaining increased therapeutic use is combination therapy with IV fosfomycin. This article reviews the preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection model and clinical data surrounding the use of combination therapy with IV fosfomycin for the treatment of serious infections caused by resistant Gram-negative bacteria. Data from dynamic in vitro and animal infection model studies of highly resistant Enterobacterales and non-lactose fermenters are positive and suggest IV fosfomycin in combination with a β-lactam, polymyxin or aminoglycoside produces a synergistic effect that rivals or surpasses that of other aminoglycoside- or polymyxin-containing regimens. Clinical studies performed to date primarily have involved patients with pneumonia and/or bacteraemia due to Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii. Overall, the observed success rates with fosfomycin combination regimens were consistent with those reported for other combination regimens commonly used to treat these patients. In studies in which direct treatment comparisons can be derived, the results suggest that patients who received fosfomycin combination therapy had similar or improved outcomes compared with other therapies and combinations, especially when it was used in combination with a β-lactam that (1) targets PBP-3 and (2) has exceptional stability in the presence of β-lactamases. Collectively, the data indicate that combination therapy with IV fosfomycin should be considered as a potential alternative to aminoglycoside or polymyxin combinations for patients with antibiotic-resistant Gram-negative infections when benefits outweigh risks.

Nitazoxanide synergizes polymyxin B against Escherichia coli by depleting cellular energy.

The rapid expansion of antibiotic-resistant bacterial diseases is a global burden on public health. It makes sense to repurpose and reposition already-approved medications for use as supplementary agents in synergistic combinations with existing antibiotics. Here, we demonstrate that the anthelmintic drug nitazoxanide (NTZ) synergistically enhances the effectiveness of the lipopeptide antibiotic polymyxin B in inhibiting gram-negative bacteria, including those resistant to polymyxin B. Mechanistic investigations revealed that nitazoxanide inhibited calcium influx and cell membrane depolarization, enhanced the affinity between polymyxin B and the extracellular membrane, and promoted intracellular ATP depletion and an increase in reactive oxygen species (ROS), thus enhancing the penetration and disruption of the Escherichia coli cell membrane by polymyxin B. The transcriptomic analysis revealed that the combination resulted in energy depletion by inhibiting both aerobic and anaerobic respiration patterns in bacterial cells. The increased bactericidal effect of polymyxin B on the E. coli ∆nuoC strain further indicates that NuoC could be a promising target for nitazoxanide. Furthermore, the combination of nitazoxanide and polymyxin B showed promising therapeutic effects in a mouse infection model infected with E. coli. Taken together, these results demonstrate the potential of nitazoxanide as a novel adjuvant to polymyxin B, to overcome antibiotic resistance and improve therapeutic outcomes in refractory infections.IMPORTANCEThe rapid spread of antibiotic-resistant bacteria poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Here, the synergistic activity of the FDA-approved agent nitazoxanide (NTZ) combined with polymyxin B was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of the combination of nitazoxanide and polymyxin B were explored by fluorescent dye, transmission electron microscopy (TEM), and transcriptomic analysis. The synergistic efficacy was evaluated in vivo by the Escherichia coli and mouse sepsis models. These results suggested that nitazoxanide, as a promising antibiotic adjuvant, can effectively enhance polymyxin B activity, providing a potential strategy for treating multidrug-resistant bacteria.

Synergistic interaction of polymyxin B with carvacrol: antimicrobial strategy against polymyxin-resistant Klebsiella pneumoniae.

Objective: The antimicrobial activities of the synergistic combination of carvacrol and polymyxin B against polymyxin-resistant Klebsiella pneumoniae were evaluated. Methods: The methods employed checkerboard assays to investigate synergism, biofilm inhibition assessmentand membrane integrity assay. Inaddition, the study included in vivo evaluation using a mouse infection model. Results: The checkerboard method evaluated 48 combinations, with 23 indicating synergistic action. Among these, carvacrol 10mg/kg plus polymyxin B 2mg/kg exhibited in vivo antimicrobial activity in a mouse model of infection, resulting in increased survival and a significant decrease in bacterial load in the blood. Conclusion: Polymyxin in synergy with carvacrol represents a promising alternative to be explored in thedevelopment of newantimicrobials.

OTITIS EXTERNA UNILATERAL IN CROSS BREED SHIH TZU DOG

Otitis externa is an inflammatory disease of the outer ear canal. Otitis externa can be caused by several factors such as bacteria, fungi, foreign bodies, parasitic infestations, immune diseases and atopic dermatitis. The purpose of writing this case report is to review Otitis Externa in dogs and the appropriate handling and treatment measures. A Shih Tzu crossbreed dog with cream colored hair aged 5 years and weighing 10.8 kg was examined with complaints of a runny and smelly right ear accompanied by itching and the dog stroked its head. On clinical examination, it was shown that the right ear of the case dog secreted cerumen fluid and had a pungent odor. The ear mucosa also looks reddish and slightly swollen. The results of ear swab examination on the case dog showed Otodectes cynotis mite infestation and the results of cytology examination found rod-shaped bacteria. The diagnosis in animal cases was unilateral otitis externa with a fausta prognosis. Treatment of otitis externa in case dogs is given drops of a combination of Polymyxin B Sulphate, Neomycin Sulphate, Fludrocortisone Acetate, and Lidocaine HCl (Otilon®) by administering 3 drops, 2 times a day in the right ear for 14 day. Evaluation of case dogs after being given treatment for 14 days showed a good response, where the dog had stopped scratching its ears, there was no redness and no Otodectes cynotis mites were found. Case animal owners are advised to diligently clean their dog's ears and try to keep them dry. And also cut the animal's hair that is on the inside of the ear. Pet owners are also advised to diligently clean their dog's ears and try to keep them dry. And also cut the hair of animal cases that are on the inside of the ear to reduce the possibility of otitis not recurring.

Unveiling synergism of polymyxin B with chloramphenicol derivatives against multidrug-resistant (MDR) Klebsiella pneumoniae.

Polymyxins are last-line antibiotics against multidrug-resistant Klebsiella pneumoniae but using polymyxins alone may not be effective due to emerging resistance. A previous study found that combining polymyxin B with chloramphenicol effectively kills MDR K. pneumoniae, although the bone marrow toxicity of chloramphenicol is concerning. The aim of this study is to assess the antibacterial efficacy and cytotoxicity of polymyxin B when combined with chloramphenicol and its derivatives, namely thiamphenicol and florfenicol (reported to have lesser toxicity compared to chloramphenicol). The antibacterial activity was evaluated with antimicrobial susceptibility testing using broth microdilution and time-kill assays, while the cytotoxic effect on normal bone marrow cell line, HS-5 was evaluated using the MTT assay. All bacterial isolates tested were found to be susceptible to polymyxin B, but resistant to chloramphenicol, thiamphenicol, and florfenicol when used alone. The use of polymyxin B alone showed bacterial regrowth for all isolates at 24 h. The combination of polymyxin B and florfenicol demonstrated additive and synergistic effects against all isolates (≥ 2 log10 cfu ml-1 reduction) at 4 and 24 h, respectively, while the combination of polymyxin B and thiamphenicol resulted in synergistic killing at 24 h against ATCC BAA-2146. Furthermore, the combination of polymyxin B with florfenicol had the lowest cytotoxic effect on the HS-5 cells compared to polymyxin B combination with chloramphenicol and thiamphenicol. Overall, the combination of polymyxin B with florfenicol enhanced bacterial killing against MDR K. pneumoniae and exerted minimal cytotoxic effect on HS-5 cell line.

Polymyxin B and fusidic acid, a novel potent synergistic combination against Klebsiella pneumoniae and Escherichia coli isolates with polymyxin B resistance.

The increasing prevalence of multidrug-resistant (MDR) Gram-negative bacteria and comparatively limited options of antibiotics pose a major threat to public health worldwide. Polymyxin B is the last resort against extensively resistant Gram-negative bacterial infections. However, a large number of Gram-negative bacteria exhibited high-level resistance to Polymyxin B, bringing challenges for antimicrobial chemotherapy. Combination therapies using polymyxins and other antibiotics are recommended to treat multidrug-resistant pathogens. In this study, we selected Gram-negative bacterial strains, including Klebsiella pneumoniae and Escherichia coli, to explore whether fusidic acid and polymyxin B have a synergistic killing effect. Through broth microdilution, we observed that minimum inhibitory concentrations (MICs) against polymyxin B in the isolates tested were significantly reduced by the addition of fusidic acid. Notably, chequerboard analysis indicated a synergistic effect between polymyxin B and fusidic acid. In addition, subsequent time-kill experiments showed that the combination of polymyxin B and fusidic acid was more effective than a single drug in killing bacteria. Finally, our investigation utilizing the murine model revealed a higher survival rate in the combination therapy group compared to the monotherapy group. Our research findings provide evidence of the synergistic effect between polymyxin B and fusidic acid. Fusidic acid was shown to increase the sensitivity of multi-drug resistant E. coli and K. pneumoniae to polymyxin B, thereby enhancing its bactericidal activity. This study provides new insights into a potential strategy for overcoming polymyxin B resistance, however, further investigations are required to evaluate their feasibility in real clinical settings.

Activity of polymyxin B combinations against genetically well-characterised Klebsiella pneumoniae producing NDM-1 and OXA-48-like carbapenemases

Combination therapy can enhance the activity of available antibiotics against multidrug-resistant Gram-negative bacteria. This study assessed the effects of polymyxin B combinations against carbapenemase-producing Klebsiella pneumoniae (K. pneumoniae). Twenty clinical K. pneumoniae strains producing NDM-1 (n=8), OXA-48-like (n=10), or both NDM-1 and OXA-48-like (n=2) carbapenemases were used. Whole-genome sequencing was applied to detect resistance genes (e.g. encoding antibiotic-degrading enzymes) and sequence alterations influencing permeability or efflux. The activity of polymyxin B in combination with aztreonam, fosfomycin, meropenem, minocycline, or rifampicin was investigated in 24-hour time-lapse microscopy experiments. Endpoint samples were spotted on plates with and without polymyxin B at 4 x MIC to assess resistance development. Finally, associations between synergy and bacterial genetic traits were explored. Synergistic and bactericidal effects were observed with polymyxin B in combination with all other antibiotics: aztreonam (11 of 20 strains), fosfomycin (16 of 20), meropenem (10 of 20), minocycline (18 of 20), and rifampicin (15 of 20). Synergy was found with polymyxin B in combination with fosfomycin, minocycline, or rifampicin against all nine polymyxin-resistant strains. Wildtype mgrB was associated with polymyxin B and aztreonam synergy (P=0.0499). An absence of arr-2 and arr-3 was associated with synergy of polymyxin B and rifampicin (P=0.0260). Emergence of populations with reduced polymyxin B susceptibility was most frequently observed with aztreonam and meropenem. Combinations of polymyxin B and minocycline or rifampicin were most active against the tested NDM-1 and OXA-48-like-producing K. pneumoniae. Biologically plausible genotype-phenotype associations were found. Such information might accelerate the search for promising combinations and guide individualised treatment.

Enzyme Patterns and Factors Associated with Mortality among Patients with Carbapenem Resistant AcinetobacterBaumannii (CRAB) Bacteremia: Real World Evidence from a Tertiary Center in India.

In the Indian setting, antimicrobial resistance in A. baumannii is a considerable problem, especially in intensive care units (ICUs). Due to the limited data, clinicians are left with very few choices except polymyxins for treating serious infections caused by A. baumannii. There is sparse data regarding the local mechanisms of resistance. Given the current therapeutic challenges, it is critical to know the local enzymatic patterns and antibiograms. A retrospective analysis of 50 episodes of bacteremia caused by CRAB. We analyzed the enzyme patterns and the susceptibility rates to various antibiotics. The resistance rates for amikacin, tigecycline, minocycline, and fluoroquinolones were 88, 82, 50, and 88% respectively. OXA-23 was the most commonly isolated enzyme (86% of the isolates produced OXA-23) followed by OXA-51 and NDM. The overall mortality was high (58%). On univariate analysis, pneumonia, and higher Pitt's bacteremia score were significantly associated with mortality (p = 0.04 and p = 0.001 respectively). Of the total patients who received combination therapy, a majority (58%) received polymyxin plus meropenem. Combination therapy using polymyxins as a backbone was not associated with reduced mortality (p = 0.1). A. baumannii is associated with significant morbidity and mortality, as shown in our study. The rates of resistance for aminoglycosides were very high, and minocycline showed better susceptibility rates in comparison with tigecycline. In our study, OXA-23 and NDM remained the most important enzymes. The routine use of the combination of polymyxin and meropenem may not offer a significant advantage over monotherapy. Prayag PS, Patwardhan SA, Joshi RS, Panchakshari SP, Rane T, Prayag AP. Enzyme Patterns and Factors Associated with Mortality among Patients with Carbapenem Resistant Acinetobacter Baumannii (CRAB) Bacteremia: Real World Evidence from a Tertiary Center in India. Indian J Crit Care Med 2023;27(9):663-668.

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii.

The emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination. Metabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L). The triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics. The metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii.

Eravacycline -Synergistic activity with other antimicrobials in carbapenem resistant isolates of Escherichia coli and Acinetobacter baumannii.

Carbapenem resistant Enterobacteriaceae are unaffected by most used antibiotics. Carbapenem resistance in Gram-negative bacterial isolates poses a concern. Eravacycline is a potent new therapy option to treat organisms that exhibit extended-spectrum -lactamases and carbapenem-resistant Enterobacteriaceae. The chequerboard microdilution panel method was used to evaluate the effectiveness of eravacycline when combined with other antibiotics. Most effective against Escherichia coli isolates was the combination of eravacycline and polymyxin B, with 60% synergism and eravacycline-Ceftazidime combination was the most potent combination against Acinetobacter baumannii with 80% synergism. Eravacycline is having synergistic benefits against carbapenem-resistant isolates when combined with cephalosporins or polymyxin B.

Clinical and Epidemiological Characteristics of Carbapenem-Resistant Klebsiella pneumoniae Infections in a Tertiary Hospital in China.

Purpose: Infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-KP) are an important public health problem. This study aimed to evaluate the clinical characteristics of patients with CR-KP. Methods: A retrospective cohort study was conducted of all patients with CR-KP infection. A total of 615 patients with CR-KP infection were identified and 135 patients who did not meet the eligibility criteria were excluded. Clinical characteristics, antimicrobial regimens, and patient outcomes were analyzed. Results: The overall mortality rate of CR-KP infections was 37.3% and the mortality rate in patients with bloodstream infections was 66.2%. Survival analysis revealed that there were statistically significant differences between patients with bloodstream infections and those with pulmonary and drainage fluid infections. Logistics regression analysis showed that hemopathy, age >60 years, solid tumors, diabetes, septic shock, acute kidney injury, and stroke were independent predictors of 30-day mortality rate. The chi-square test showed that treatment with a combination of carbapenems, tigecycline, and polymyxin B was superior to treatment with carbapenems with polymyxin B, without tigecycline. Conclusions: CR-KP infections, especially bloodstream infections, have a high mortality rate. The outcome is strongly dependent on patients' clinical conditions. Antimicrobial regimens combining carbapenems, tigecycline, and polymyxin B might be a better choice.

EVALUATION OF POLYMYXCIN B IN COMBINATION WITH CIPROFLOXACIN ANTIBIOTICS AGAINST PSEUDOMONAS AEURUGINOSA

The fact that bacteria may resist various antimicrobials because they have various antimicrobial-associated genes makes them the primary cause of human infection.Therefore, this study aimed to determine the bacteria resistance to antibiotics.By using the disc diffusion method,antibiotics were tested for their susceptibility to microbes.Pseudomonas aeruginosa isolates are completely sensitive to Ciprofloxacin and Polymyxin B sulfate.This study investigated the in vitro activity of the combination of Ciprofloxacin with Polymyxin B sulphate (PMB) at different concentrations against multidrug-resistant (MDR) Pseudomonas aeruginosa.The combination effect of Ciprofloxacin and Polymyxin B sulphate antibiotics was evaluated by measuring the zone of inhibition using disc diffusion method. The minimum inhibitory concentration (MIC) of antibiotics was determined using broth microdilution.Our findings suggest that the combination of Ciprofloxacin and Polymyxin B sulphate has a synergistic effect on Pseudomonas aeruginosa. As a result, the synergistic combination reported in this study needs to be tested further in vivo before being used in clinical trials

Drug Combination of Ciprofloxacin and Polymyxin B for the Treatment of Multidrug-Resistant Acinetobacter baumannii Infections: A Drug Pair Limiting the Development of Resistance.

Polymyxins are considered as last-resort antibiotics to treat infections caused by Acinetobacter baumannii. However, there are increasing reports of resistance in A. baumannii to polymyxins. In this study, inhalable combinational dry powders consisting of ciprofloxacin (CIP) and polymyxin B (PMB) were prepared by spray-drying. The obtained powders were characterized with respect to the particle properties, solid state, in vitro dissolution and in vitro aerosol performance. The antibacterial effect of the combination dry powders against multidrug-resistant A. baumannii was assessed in a time-kill study. Mutants from the time-kill study were further investigated by population analysis profiling, minimum inhibitory concentration testing, and genomic comparisons. Inhalable dry powders consisting of CIP, PMB and their combination showed a fine particle fraction above 30%, an index of robust aerosol performance of inhaled dry powder formulations in the literature. The combination of CIP and PMB exhibited a synergistic antibacterial effect against A. baumannii and suppressed the development of CIP and PMB resistance. Genome analyses revealed only a few genetic differences of 3-6 SNPs between mutants and the progenitor isolate. This study suggests that inhalable spray-dried powders composed of the combination of CIP and PMB is promising for the treatment of respiratory infections caused by A. baumannii, and this combination can enhance the killing efficiency and suppress the development of drug resistance.

Intravenous Polymyxin B as Adjunctive Therapy to High-Dose Tigecycline for the Treatment of Nosocomial Pneumonia Due to Carbapenem-Resistant Acinetobacter baumannii and Klebsiella pneumoniae: A Propensity Score-Matched Cohort Study.

Although the combination of polymyxin and tigecycline is widely used in treating carbapenem-resistant bacterial infections, the benefit of this combination is still uncertain. To assess whether adding polymyxin B to the high-dose tigecycline regimen would result in better clinical outcomes than the high-dose tigecycline therapy in patients with pneumonia caused by carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, we conducted a propensity score-matched cohort study in a single center between July 2019 and December 2021. Of the 162 eligible patients, 102 were included in the 1:1 matched cohort. The overall 14-day mortality in the matched cohort was 24.5%. Compared with high-dose tigecycline, the combination therapy was not associated with better clinical outcomes, and showed similar 14-day mortality (OR, 0.72, 95% CI 0.27-1.83, p = 0.486), clinical cure (OR, 1.09, 95% CI 0.48-2.54, p = 0.823), microbiological cure (OR, 0.96, 95% CI 0.39-2.53, p = 0.928) and rate of nephrotoxicity (OR 0.85, 95% CI 0.36-1.99, p = 0.712). Subgroup analyses also did not demonstrate any statistical differences. Based on these results, it is reasonable to recommend against adding polymyxin B to the high-dose tigecycline regimen in treating pneumonia caused by carbapenem-resistant K. pneumoniae and A. baumannii.

In vitro analysis of synergistic combination of polymyxin B with 12 other antibiotics against MDR Acinetobacter baumannii isolated from a Chinese tertiary hospital.

In clinical practice, polymyxins are suggested to be used in combination with other antibiotics for improving their antibacterial efficacy and preventing the emergency of antibiotic-resistant strains. However, even though synergistic combination of polymyxin B with many antibiotics have been confirmed in various studies with different bacterial species and analyzing methods, which antibiotic is the best option for combination therapy of polymyxin B against MDR A. baumannii remains uncertain. In this study, we systematically analyzed the synergistic combination of polymyxin B with 12 other antibiotics against MDR A. baumannii isolated from a Chinese tertiary hospital using the checkerboard assay. The results suggest that, for polymyxin B-based combination therapy against MDR A. baumannii as characterized in this hospital, cefperazone-sulbactam may be the best partner, since it has the highest synergistic rate and the best synergistic effect with polymyxin B. Minocycline, imipenem, meropenem, ceftazidime, cefepime, amikacin and sulfamethoxazole also have some synergistic effects with polymyxin B, but piperacillin-tazobactam, ciprofloxacin, levofloxacin and tobramycin show no synergism. None of these 12 antibiotics has an antagonistic effect when combined with polymyxin B.

A novel antibiotic combination of linezolid and polymyxin B octapeptide PBOP against clinical Pseudomonas aeruginosa strains

BackgroundAntibiotic-resistant Gram-negative bacteria are becoming a major public health threat such as the important opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study investigated enhancement of the linezolid spectrum, which is normally used to treat Gram-positive bacteria, at inhibiting P. aeruginosa growth.MethodsThe checkerboard test or time-kill assay were carried out to determine the antibacterial effects of linezolid in cooperation with polymyxin B octapeptide PBOP (LP) against P. aeruginosa based on in vitro model. The protective effect of LP against P. aeruginosa infection was assessed based on a Caenorhabditis elegans (C. elegans) model.ResultsThe synergistic activity and antibacterial effects were significantly increased against P. aeruginosa by LP treatment, while linezolid and PBOP as monotherapies exhibited no remarkably bactericidal activity against the clinical strains. Additionally, LP treatment modified biofilm production, morphology, swimming motility of P. aeruginosa, and protected C. elegans from P. aeruginosa infection.ConclusionsThis research demonstrates that LP combination has significant synergistic activity against P. aeruginosa, and PBOP is potential to be an activity enhancer. Notably, this strategy improved the antibacterial activity spectrum of linezolid and other anti-Gram-positive agents and represents an effective choice to surmount the antibiotic resistance of bacteria in the long term.

Acute otitis externa. Diagnosis and treatment according to modern clinical guidelines

Acute external otitis – is an infectious and inflammatory disease of the skin of the external auditory canal, which is more common in adults, less often in children. The most frequent causative agents of acute external otitis are Pseudomonas aeruginosa (20-60%) and Staphylococcus aureus (10-70%), the frequency of fungal flora does not exceed 10% and is not significant from the point of view of empirical prescription of antifungal drugs. Propensity to the disease is caused by a hot and humid climate, swimming, traumatization of the skin of the auditory canal, comorbid diseases. Patients with acute otitis externa are mainly outpatients and do not require inpatient treatment. Empiric therapy of uncomplicated acute external otitis determines the appointment of local ototopic drugs in the form of drops, which include a combination of polymyxin B, neomycin, which provides a bactericidal effect on typical pathogens, and glucocorticoid dexamethasone. Effective local treatment is facilitated by thorough cleaning of the external auditory canal. The criterion for the effectiveness of the treatment is the reduction of pain, itching and congestion within 48-76 hours and recovery within seven days.