Bacitracin A

Extensive use of colistin in food animals is deemed a major driving force for the emergence and transmission ofmcr-1However, a non-colistin usage factor(s) contributing to mobile colistin resistance may also exist in animal production systems. Given that polymyxin, a bacterium-derived peptide antibiotic, has been successfully used as a surrogate to study bacterial resistance to antimicrobial peptides (AMPs), acquisition of MCR-1 may confer cross-resistance to the unrelated AMPs implicated in practical applications. To test this, we first constructedEscherichia colirecombinant strains differing only in the presence or absence of functional MCR-1. Among diverse tested AMPs, MCR-1 was observed to confer cross-resistance to bacitracin, an in-feed antibiotic widely used in animal industry. The significantly (2-fold) increased bacitracin MIC was confirmed by using different bacitracin products, broth media, and laboratory host strains for susceptibility tests. Subsequently, an originalmcr-1gene-bearing plasmid, pSLy21, was conjugatively transferred to eight clinicalE. colirecipient strains isolated from diarrheic pigs, which also led to significantly increased MICs of both colistin (4-fold to 8-fold) and bacitracin (2-fold). Growth curve examination further demonstrated that MCR-1 provides a growth advantage to variousE. colistrains in the presence of bacitracin. Given that bacitracin, a feed additive displaying low absorption in the intestine, can be used in food animals with no withdrawal required, imprudent use of bacitracin in food animals may serve as a risk factor to enhance the ecological fitness of MCR-1-positiveE. colistrains, consequently facilitating the persistence and transmission of plasmid-mediated colistin resistance in agricultural ecosystem.IMPORTANCEPolymyxins (e.g., colistin) are the drugs of last resort to treat multidrug-resistant infections in humans. To control mobile colistin resistance, there is a worldwide trend to limit colistin use in animal production. However, simply limiting colistin use in animal production may still not effectively mitigate colistin resistance due to an overlooked non-colistin usage factor(s). Using controlled systems, in this study, we observed that MCR-1 confers cross-resistance to bacitracin, a popular in-feed antibiotic used in food animals. Thus, imprudent and extensive usage of bacitracin in food animals may serve as a non-colistin usage risk factor for the transmissible colistin resistance. Further comprehensivein vitroandin vivostudies are highly warranted to generate science-based information for risk assessment and risk management of colistin resistance, consequently facilitating the development of proactive and effective strategies to mitigate colistin resistance in animal production system and protect public health.

The Accelerated Stability Assessment Program (ASAP) was applied for the first time to a peptide, the antibiotic active pharmaceutical ingredient bacitracin. Bacitracin and its complex with zinc were exposed to temperature and relative humidity conditions from 50 to 80°C and from 0 to 63% for up to 21 days. High-performance liquid chromatography was used to analyze the stressed samples for both degradant formation and loss of the active (bacitracin A) and two inactive isoforms, with identities confirmed by mass spectrometry. These data were then analyzed using a humidity-corrected Arrhenius equation and isoconversion approach to create a shelf-life predicting model for typical storage conditions. Model fitting was found to be good with low residuals in both temperature and relative humidity axes for all parameters examined. The generated model's predictions for both the native and zinc complex of bacitracin for both formation of the major degradation product (F) and loss of the active isoform (A) were consistent with longer-term measured values at 30°C/53%RH and 40°C/75%RH, validating this approach for accelerating the determination of long-term stability of a peptide.

Topical bacitracin appears to be unique for the following reasons: (1) It is becoming a frequent sensitizer, particularly when used after surgery. (2) It may cause not only a delayed, eczematous contact dermatitis but an immediate urticarial reaction and, rarely, anaphylactic shock. (3) Positive patch test reactions to bacitracin often do not appear at the usual 48-hour test reading but may be positive when read at 96 hours. (4) Zinc bacitracin and "plain" bacitracin are two forms of topical bacitracin available, with possibly different degrees of sensitizing potential. (5) Bacitracin injected intradermally has been reported to be a histamine-releasing agent. (6) Bacitracin often coreacts but does not cross-react with neomycin. In this presentation we document the clinical and patch test findings of nine patients seen in the past year with allergic contact dermatitis to bacitracin ointment.