Polymyxin B 10,000units/g / Trimethoprim 5mg/g eye ointment

The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia , but data on strains resistant to current first-line agents are limited, and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the in vitro activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, or trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical S. maltophilia isolates.

Abstract licence: CC BY

Purpose: Antibiotic combination therapy is commonly used for empiric treatment of microbial keratitis, a potentially blinding infection of the cornea. Pseudomonas aeruginosa (P. aeruginosa) is a major cause of severe keratitis, and the 2023 outbreak linked to artificial tears involved a strain resistant to aminoglycosides and fluoroquinolones, resulting in widespread vision loss. Despite various proposed treatments, no consensus exists for management of keratitis caused by the outbreak strain. The purpose of this study was to evaluate the efficacy of cefiderocol (FDC) combined with polymyxin B (PB) against ocular P. aeruginosa keratitis isolates, including extensively drug-resistant (XDR) strains from the 2023 artificial tear-associated outbreak. Methods: Time-kill assays and epsilometer (E-test) synergy testing were performed on a panel of keratitis isolates. Genetic analysis was conducted on mutants with reduced FDC susceptibility. Results: Time-kill assays demonstrated synergy for two XDR outbreak isolates (P < 0.05), whereas the E-test used across diverse keratitis isolates showed additive to indifferent interactions. Quorum-sensing-deficient, sheen-positive strains showed reduced responsiveness (P < 0.01). Non-antagonistic interactions were observed for Serratia marcescens (S. marcescens) and Staphylococcus aureus (S. aureus) keratitis isolates, with synergy for some S. marcescens strains. Mutants with reduced FDC susceptibility harbored mutations in baeS and fepA, yet remained responsive to the antibiotic combination. Conclusions: FDC combined with PB demonstrates promising activity against drug-resistant Gram-negative keratitis pathogens, including XDR P. aeruginosa. Translational Relevance: These findings support the further development of FDC with PB as a candidate therapy for drug-resistant ocular infections.

Abstract licence: CC BY

Multidrug-resistant Klebsiella pneumoniae represents a critical global public health threat, with limited therapeutic options available due to its biofilm-forming capacity. This study investigated the antimicrobial and antibiofilm potential of benzoic acid (BA), an organic acid, and highly soluble polypyrrole (Hs-PPy), a synthetic polymer, against K. pneumoniae isolates. Forty-seven clinical isolates from infected/colonized patients and one reference strain were evaluated. Antimicrobial susceptibility was determined for 16 antibiotics. Antimicrobial activity was assessed via broth microdilution against 25/47 isolates and the reference strain. Biofilm formation and substance interference were evaluated using crystal violet staining. All isolates demonstrated multidrug resistance, with >91% showing resistance to ampicillin, cefepime, ceftriaxone, levofloxacin, ertapenem, piperacillin-tazobactam, ampicillin-sulbactam, cefoxitin, ciprofloxacin, meropenem, imipenem, and trimethoprim-sulfamethoxazole, while 57.44% were resistant to polymyxin B. Susceptibility to amikacin and gentamicin was observed in 95.74% and 51.06% of isolates, respectively. Hs-PPy showed no intrinsic antimicrobial activity, whereas BA exhibited inhibitory and bactericidal effects at 2–4 mg/mL. Among biofilm producers, one isolate demonstrated strong formation, while others showed weak production. The Hs-PPy/BA combination effectively inhibited biofilm formation in the strong producer. These findings suggest that Hs-PPy/BA combination therapy offers significant advantages for controlling biofilm formation in multidrug-resistant K. pneumoniae infections.

Abstract licence: CC BY

Purpose: The 2023 Pseudomonas aeruginosa keratitis outbreak linked to contaminated artificial tears underscored the need for new therapies against extensively drug-resistant ocular pathogens. In vitro data suggested additive or synergistic activity between the siderophore-cephalosporin cefiderocol (FDC) and either moxifloxacin (MOX) or polymyxin B sulfate (PB). Here, we tested whether combining FDC with the commercial formulations of MOX (0.5%) or PolyTrim (PT; PB 10,000 U/mL + trimethoprim 0.1%) improved in vivo outcomes. Methods: New Zealand White rabbits were injected intrastromally with 5000 CFU of Pseudomonas aeruginosa strain CDC1270. After 16 hours, established infections were treated every 30 minutes for 8 hours with FDC, followed 5 minutes later by MOX or PT. Additional groups received monotherapies or saline. Bacterial burden (CFU/cornea) and anterior chamber cultures were determined, and ocular inflammation was assessed. Results: FDC + MOX reduced bacterial burden by 2.8 log10 CFU, outperforming FDC and MOX monotherapies, although no eyes were sterilized. PT monotherapy produced a significant 3.2 log10 reduction in CFU. The FDC + PT combination yielded the most potent activity, with almost 6.9 log10 reduction and sterilization of 10 of 12 corneas. Notably, anterior chamber invasion occurred in saline and MOX groups but in none of the FDC-containing groups, and perforations were absent in all FDC and PT treatments. Conclusions: FDC + PT was superior to monotherapies and to FDC + MOX, achieving frequent sterilization and preventing intraocular spread and corneal perforations. These data support PT alone or in combination with FDC as promising therapeutic candidates for the treatment of XDR P. aeruginosa keratitis.

Abstract licence: CC BY-NC-ND

Introduction. Antibiotic heteroresistance presents a growing public health concern, as the phenotype is associated with treatment failure and is hard to detect using conventional diagnostic testing. Gap Statement. Heteroresistance in Klebsiella oxytoca , an opportunistic pathogen associated with hospital-acquired infections, has not been characterized. Aim. In this study, we characterized polymyxin B heteroresistance in a collection of six clinical and environmental isolates of K. oxytoca . Methodology. We assessed heteroresistance using population analysis profile assays and LPS modifications using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF). Results. All six isolates tested exhibited heteroresistance, indicated by an 8–16-fold difference between the MIC of the bulk population and the MIC of the resistant sub-population, as determined using population analysis profiling. Heteroresistance was found to be due to the presence of a stable sub-population of resistant bacteria, the size of which was unaffected by growth phase or the presence of host antimicrobial factors present in human serum. MALDI-TOF analysis revealed 4-amino- l -arabinose modifications of the lipid A of resistant sub-populations. Conclusion. This pilot study identifies that polymyxin heteroresistance in K. oxytoca may complicate the treatment of infections caused by this organism.

Abstract licence: CC BY

Objective: To describe the patient characteristics, resistance trends of Klebsiella pneumoniae (Kpn), and the prevalence of carbapenem-resistant Kpn (CRKP) in Hebei (2019– 2023), and to explore genetic characteristics of CRKP underlying resistance shifts. Methods: WHONET 5.6 was employed to analyze patient characteristics of Kpn infections, resistance variations and CRKP prevalence using data from all 59 tertiary hospitals participating in Hebei Provincial Antimicrobial Resistance Surveillance System (HBARSS), 2019– 2023. A total of 424 CRKP isolates from four hospitals across northern, central, and southern Hebei were subjected to antimicrobial susceptibility testing and whole-genome sequencing. Genomic analyses were performed using Kaptive, Kleborate, and PlasmidFinder. Results: Surveillance data showed that a total of 114,166 non-duplicate Kpn isolates were identified, including 16,681 CRKP. Kpn infections were more common in males (63.4%) and mainly occurred in elderly (54.1%) and ICU patients (20.2%). Resistance rates to most antimicrobials declined overall, except for minocycline, tigecycline and polymyxin B, which fluctuated. CRKP prevalence fell from 15.3% (2019) to 12.8% (2023), averaging 14.6%. Analysis of 424 clinical CRKP showed that bla KPC-2 ST11-KL64 was the predominant type in both CRKP and hypervirulent CRKP (hv-CRKP), accounting for 40.1% and 69.1%, respectively. Notably, hv-CRKP among CRKP rose from 36.5% (2019) to 69.8% (2023), averaging 55.0%. Within ST11 hv-CRKP, 84.8% of KL64 isolates carried the iucABCDiutA + rmpA + rmpA2 + virulence profile, and 97.6% harbored IncHI1B or IncHI1B(pNDM-MAR)/repB plasmids. In contrast, 92.3% of KL47 isolates carried iucABCDiutA + rmpA − rmpA2 +, and 89.7% lacked IncHI1B or IncHI1B(pNDM-MAR)/repB. Furthermore, the proportion of ST11-KL64 hv-CRKP among ST11 CRKP increased from 38.7% in 2019 to 49.2% in 2023, while that of ST11-KL47 rose from 0% to 20.0%. Conclusion: Males, the elderly and ICU patients are susceptible populations. Despite declining resistance rate and CRKP prevalence in Hebei Province, China, hv-CRKP increased rapidly. And ST11-KL64 hv-CRKP and ST11-KL47 hv-CRKP showed different evolutionary patterns, with KL47 increasing more prominently. Keywords: Klebsiella pneumoniae , bacterial resistance surveillance, carbapenem resistance, hypervirulence, molecular epidemiology

Abstract licence: CC BY-NC

The emergence and persistence of plasmid-mediated polymyxin resistance in Brazilian poultry production pose a significant One Health challenge. Here, cloacal swabs from 202 broilers across four farms in the State of Rio de Janeiro yielded 125 Enterobacteriaceae isolates growing on polymyxin-EMB agar. Escherichia coli accounted for 99% of resistant isolates, with one Klebsiella pneumoniae. Multidrug resistance (MDR) was observed in 75% of polymyxin-resistant strains. PCR screening revealed mcr-1 and mcr-5 genes. Conjugation assays demonstrated horizontal transfer of mcr-1 plasmids (48.5–194 kb). MLST assigned key strains to ST10 and ST48, both within the high-risk CC10 lineage. These findings underscore the entrenched nature of polymyxin resistance despite regulatory bans, highlight the risk of zoonotic transmission of MDR determinants, and call for enhanced surveillance, biosecurity and alternative interventions to mitigate the spread of mobile polymyxin resistance in poultry environments.

Abstract licence: CC BY

Multidrug-resistant Gram-negative bacteria (MDR-GNB) pose a severe threat to global public health, particularly in critically ill patient populations, where they are associated with high mortality and morbidity (Cassini et al., 2019;Leone et al., 2023). Polymyxin B sulfate (PBS) and colistin sulfate (CS) remain important antimicrobial agents for managing MDR-GNB infections in clinical practice, especially in regions with limited access to novel anti-infective drugs (Infectious Diseases Society of China et al., 2021). Given their narrow therapeutic window and inherent nephrotoxicity, therapeutic drug monitoring (TDM) has become a key clinical strategy to optimize polymyxin dosing and balance efficacy and safety (Tsuji et al., 2019;Abdul-Aziz et al., 2020). Zhang et al. recently published a valuable real-world retrospective study that compared the efficacy, safety, and TDM applications of PBS and CS in 180 critically ill patients with MDR-GNB infections (Zhang et al., 2025). The study employed propensity score matching (PSM) to balance baseline characteristics between the PBS (n=100) and CS (n=80) cohorts and identified no significant differences in clinical efficacy, 30-day mortality, or overall acute kidney injury (AKI) incidence between the two agents. Notably, the study found a higher incidence of stage 3 AKI in the PBS cohort and established TDM trough concentration (Cmin) thresholds for clinical efficacy: ≥0.91 mg/L for PBS and ≥0.53 mg/L for CS. Additionally, the authors' conclusion that TDM significantly improves clinical efficacy and reduces AKI risk for both drugs is a clinically meaningful finding.This single-center retrospective study provides some useful data on polymyxin clinical use.However, the findings raise several questions regarding their interpretation and highlight potential uncertainties in the methodology, presentation of TDM and pharmacokinetic data. These uncertainties require further clarification to refine our understanding of polymyxin TDM in critically ill patients and guide future clinical research and practice.In the abstract, the authors' conclude that TDM significantly improves clinical efficacy and reduces acute kidney injury (AKI) incidence for both drugs-a clinically meaningful finding that aligns with international consensus guidelines on polymyxin use (Tsuji et al., 2019;Infectious Diseases Society of China et al., 2021). However, several details in the study design and data presentation create uncertainties in interpreting the causal relationship between TDM implementation and treatment outcomes, which require further contextualization.First, the study does not report whether and how drug regimens were adjusted based on TDM results. The clinical value of TDM relies on using drug concentrations to guide dose adjustments.However, because this study lacks data on specific dose modifications and their timing, it is difficult to assess TDM's true impact on treatment outcomes. Second, potential selection bias could confound the association between TDM and improved outcomes, as physicians who routinely order TDM may also provide more intensive clinical monitoring and supportive care for patients. Clarifying the TDM-guided dosing adjustment strategies used in the study would help isolate the true effect of drug monitoring on treatment efficacy and safety.In the methods section, the study reports off-label high-dose CS use (1.0 million units q12h), which exceeds the maximum dosage specified in the Chinese product insert. While off-label dosing is common in critically ill patients with MDR-GNB infections to achieve therapeutic concentrations, the study does not contextualize the rationale for this dosing strategy-e.g., whether it was based on TDM results, disease severity, bacterial resistance patterns, or other factors. The relationship between this off-label dosing and TDM implementation remains unclear, and exploring this association would provide valuable insights into the clinical utility of TDM for guiding high-dose CS use in critically ill patients.A notable finding is the significant difference in TDM practice rates between the PBS and CS cohorts, both before (70.0% vs. 42.5%, p=0.001) and after (81.4% vs. 55.9%, p=0.003) propensity score matching (Table 1 of the original article). Given the study's conclusion that TDM enhances clinical efficacy and reduces AKI incidence, the absence of a corresponding difference in these clinical outcomes between the two cohorts is an unexpected observation that points to potential unmeasured confounding factors. These factors may include variations in the timing of TDM sampling or differences in concomitant supportive care between the two groups, all of which could mask the expected relationship between TDM rate and treatment outcomes. Further exploration of these confounding factors in subgroup analyses would help refine the interpretation of TDM's impact.A novel finding of this study is the identification of the distinct Cmin efficacy thresholds (≥0.91 mg/L for PBS and ≥ 0.53 mg/L for CS), which offers practical guidance for TDM in Chinese critically ill patients. However, this finding warrants further discussion in relation to other studies in the field. Current research shows similar minimum inhibitory concentration (MIC) values for both drugs against MDR-GNB (Chew et al., 2017;Behera et al., 2018;Yildiz et al., 2021). In addition, the Clinical and Laboratory Standards Institute (CLSI) has indicated that MICs obtained from testing CS predict MICs to PBS and vice versa (CLSI., 2020), demonstrating the crosssusceptibility expected of agents within the same class. The China Antimicrobial Surveillance Network (2023) demonstrates comparable resistance rates against Gram-negative bacteria, with PBS demonstrating slightly higher in vitro sensitivity than CS (Fupin et al., 2023), as shown in Table 1. Additionally, recent research has found that PBS and CS exhibit similar synergistic effects when combined with common clinical antimicrobials against MDR-GNB, with PBS showing marginally better combined efficacy (Wang et al., 2024). Notably, the study states that the Cmin values of PBS and CS are significantly correlated with the clinical efficacy and AKI incidence, a key finding for understanding the polymyxin therapeutic window. However, these correlation data are not presented in the Results section. Presenting this data would provide a more comprehensive understanding of the trade-off between efficacy and nephrotoxicity at different polymyxin concentrations, a critical consideration for TDM-guided dosing.The finding of a significantly higher incidence of stage 3 AKI in the PBS cohort (11.0% vs.2.5% before PSM; 10.2% vs. 3.4% after PSM) is a clinically important and consistent with recent studies (Zhang et al., 2024). The Kaplan-Meier curve for stage 3 AKI (Figure 3 of the original article) further shows a notable difference: stage 3 AKI in the CS cohort occurs only in the early treatment phase, while it increases over time in the PBS cohort, suggesting potential drug accumulation in the PBS group. This result raises several pharmacokinetic and dose-related questions. First, the study reports no significant difference in baseline creatinine clearance between the PBS and CS cohorts, a key factor influencing polymyxin elimination (Fiaccadori et al., 2016;Xie et al., 2022;Fang et al., 2024). In healthy populations, PBS and CS have reported half-lives of 5.44 h and 4 h, respectively (Fang et al., 2024;Huang et al., 2024)-a small but potentially meaningful difference that could lead to cumulative drug exposure in critically ill patients with impaired renal function. However, the study does not report serial Cmin measurements in patients with multiple TDM samplings, particularly before and after 7 days of treatment. Analyzing these longitudinal concentration data would help determine whether the increased late-stage 3 AKI in the PBS cohort is associated with rising drug concentrations. Second, the study does not present detailed data on the dosing frequency of PBS and CS in the two cohorts, a factor that can influence drug accumulation and nephrotoxicity.While the study lists the common dosing regimens for both agents, it does not report the distribution of dosing frequencies (e.g., q8h vs. q12h) in the PBS and CS groups. Given PBS's longer half-life, more frequent dosing in the PBS cohort could contribute to cumulative exposure and late-stage AKI, and exploring this association would provide valuable insights into the impact of cumulative exposure on polymyxin nephrotoxicity. It is important to note that the absolute number of stage 3 AKI cases in both cohorts is small (11 in PBS, 2 in CS before PSM), which limits the statistical power to identify the exact causes of the observed difference. Additionally, MDR-GNB infections in critically ill patients are almost always treated with combination antimicrobial therapy, and the study reports concomitant use of other nephrotoxic agents (e.g., amikacin, sulfamethoxazole/trimethoprim) in both cohorts. While the study controls for some confounding factors via PSM, the potential synergistic nephrotoxicity of polymyxin-combination therapy remains an unmeasured factor that may influence the observed AKI rates. Future large-sample studies are needed to explore the interaction between polymyxin type, dosing frequency, cumulative exposure, and concomitant nephrotoxic drugs on AKI risk in critically ill patients.The original study states that PBS and CS are the last-line treatments for MDR-GNB infections due to a lack of more effective alternatives. However, newer β-lactam/β-lactamase inhibitor combinations (e.g., ceftazidime-avibactam, imipenem-relebactam, aztreonam-avibactam, ceftolozane-tazobactam, among others) have demonstrated superior efficacy and safety to polymyxins and are now recommended as first-line options in many settings for CRKP and CRPA infections (Paul et al., 2022;Pintado et al., 2023). Similarly, for CRAB infections, sulbactam-based strategies have emerged as first-line options in many settings (Zeng et al., 2023). Polymyxins remain important salvage therapies for MDR-GNB infections, particularly in regions with limited access to novel antimicrobials.The original study notes that CS is only available in China but does not clarify the critical pharmacological and clinical distinction between CS and colistin methanesulfonate sodium (CMS)-the internationally more common colistin formulation. They have similar chemical structures and mechanisms of action, but their pharmacokinetics, dosing, and nephrotoxicity differ.CMS is a prodrug that is converted to the active moiety colistin in vivo, whereas CS is administered in its active form (Fiaccadori et al., 2016;Xie et al., 2022). CMS is mainly eliminated by the kidneys, while CS is primarily excreted through non-renal pathways (Tran et al., 2016). The conversion factor is 1 million IU, equivalent to approximately 33 mg CBA. Dose adjustment is recommended for CMS in patients with decreased creatinine clearance, but not for CS (Tsuji et al., 2019;Zhang et al., 2024). Nephrotoxicity is the most common and prominent adverse effect of polymyxins. The reported rates of nephrotoxicity associated with CMS and CS vary extensively in previous studies (Yang et al., 2025;Zeng et al., 2025). As reported in previous studies, the incidence of acute kidney injury is15.6-59.3% for CMS (Rosas Espinoza et al., 2021;Simon et al., 2023;Yang et al., 2025) and 5.9-28.8% for CS (Liu et al., 2024;Zhang et al., 2024;Zeng et al., 2025;Zhang et al., 2025).In conclusion, Zhang et al.'s study is a valuable contribution to polymyxins research, and addressing the identified uncertainties will further strengthen the value of its findings for clinical practice and future research. As polymyxins remain core agents for MDR-GNB infections in China as well as in other countries, real-world studies combining TDM data with pharmacokinetic, microbiological, and clinical outcomes will be critical to optimizing their use and balancing efficacy and safety in critically ill patients.

Abstract licence: CC BY