Patricia M. Dowling Polymyxins, glycopeptides, bacitracin, and fosfomycin are peptide antibiotics with a variety of actions against bacteria. Streptogramins are also peptides but are discussed in Chapter 11 because of their common mechanism of action with lincosamides. Glycopeptides are important, particularly in human medicine, because of their activity against Gram‐positive bacteria, including multidrug‐resistant enterococci and staphylococci. The clinical development of polymyxins, bacitracin, and fosfomycin had not been pursued since their discovery early in the antibiotic era but because of the worldwide increase in multidrug‐resistant bacterial infections, these drugs are being used as a last resort for seriously ill patients. An increase in carbapenem‐resistant Enterobacterales infections has increased use of peptide antibiotics as a last‐line antimicrobial to treat these Gram‐negative infections, and the World Health Organization (WHO, 2024) has now listed many of these drugs as antibiotics of high priority critical importance (polymixins) or for use in humans only (glycopeptides). There is increasing use of these “last‐resort” drugs in veterinary medicine as well as human medicine. Unfortunately, there is also evidence of polymyxin‐resistant and fosfomycin‐resistant Enterobacterales isolated from animals (Kock et al., 2021; Sadek et al., 2022). Polymyxins are antibiotic products of Paenibacillus polymyxa subsp. colistinus. Polymyxin E (colistin) and polymyxin B are the only polymyxins used clinically. Colistin is a complex mixture of more than 30 components, with colistin A (polymyxin E1) and colistin B (polymyxin E2) being the two major components. When first developed in the 1940s, the polymyxins were of great interest for their activity against Pseudomonas aeruginosa. They were limited mainly to oral (colistin) or topical (polymyxin B) use due to their notable systemic toxicity. Colistin and polymyxin B are being reconsidered as last‐resort antibiotics for the treatment of multidrug‐resistant Gram‐negative bacterial infections in human medicine. At the same time, the use of polymyxins in veterinary medicine is being reconsidered due to increased reports of polymyxin‐resistant Enterobacterales (Binsker et al., 2022). Many countries have now restricted the use of colistin as a feed additive and growth promoter, while others are banning the use of colistin in food animals. In horses, dogs and cats, there is interest in the systemic and extracorporeal use of polymyxins at subantimicrobial doses for binding and inactivating endotoxin. Polymixins are listed by the WHO (2024) as high priority critically important antimicrobials. Polymyxins are basic cyclic decapeptides. Colistin is polymyxin E and is chemically related to polymyxin B. Colistin and polymyxin B differ by only a single amino acid in the peptide ring, with a phenylalanine in polymyxin B and a leucine in colistin. Colistin is available as the sulfate for oral or topical administration and as the less toxic sulfomethate prodrug (colistin methanesulfonate sodium) for parenteral use. Dosages are given in international units or metric units depending on the source: 10 units of polymyxin B = 1 μg, 10 units of colistin sulfate or colistin methanesulfonate = 0.5 μg. They are stable, highly water‐soluble drugs. Polymyxins are cationic, surface‐active agents that displace Mg2+ or Ca2+ and disrupt the structure of cell membrane phospholipids and increase cell permeability by a detergent‐like action. Polymyxins disorganize the outer membrane of Gram‐negative bacteria by binding lipopolysaccharides (LPS, endotoxin) through direct interaction with the anionic lipid A region. This action increases the permeability of the bacterial membrane, leading to leakage of the cytoplasmic content and ultimately causing cell death. Polymyxins also inhibit vital respiratory enzymes (type II NADH‐quinone oxidoreductases) in the bacterial inner membrane (Poirel et al., 2017). Polymyxins bind to and neutralize this LPS molecule released during cell lysis, reducing activation of the endotoxin‐induced proinflammatory cascade. The bactericidal activity of polymyxin B is concentration dependent and related to the ratio of the area under the concentration‐time curve to the MIC (AUC:MIC) (Ram et al., 2021). Polymyxins have minimal postantibiotic effects at clinically relevant concentrations. Polymyxin B and colistin are similarly rapidly bactericidal and highly active against many species of Gram‐negative organisms, such as Escherichia coli, Salmonella, and Pseudomonas aeruginosa, but not against Proteus, Serratia, or Providencia. Gram‐positive and anaerobic bacteria and Mycoplasma spp. are resistant. Despite the similarity of the molecular structures of colistin and polymyxin B, there are differences between their MICs. While there is a high level of agreement between the MICs for P. aeruginosa and Acinetobacter spp., MIC values are two‐fold higher for polymyxin B than for colistin for many Klebsiella spp. isolates and E. coli isolates (Sader et al., 2015). Categorical agreement of 99% is obtained when breakpoints of ≤2/≥4 μg/ml for both colistin and polymyxin B are applied. Activity against P. aeruginosa is reduced in vivo by the presence of physiological concentrations of calcium. To widen the range of antimicrobial activity, neomycin and bacitracin are combined with polymyxin B in topical preparations (e.g., Polysporin®). Neomycin and polymyxin B are also available combined in a bladder irrigation solution designed for local treatment of E. coli cystitis in women. Gram‐negative bacteria develop resistance through common mechanisms for both colistin and polymyxin B. Polymyxin resistance to antimicrobials is mediated by mutations in specific regions (pmrA/B and phoP/Q) that result in structural changes of LPS in both the cytosol and periplasm of the cell membrane in Klebsiella, E. coli, and P. aeruginosa. In P. aeruginosa, subinhibitory concentrations of polymyxins induce the ParR–ParS regulator system, resulting in adaptive resistance to various polycationic antibiotics, including aminoglycosides (Fernández et al., 2010). A temperature‐dependent mechanism occurs in other bacteria, including A. baumannii, Yersinia enterocolitica, and Salmonella spp. Colistin resistance in E. coli from animals was initially identified from mutations in chromosomal genes (e.g., pmrA and pmrB9) (Quesada et al., 2014). In 2016, a chromosomal and plasmid‐mediated colistin resistance gene, mcr‐1, was detected in Enterobacterales isolated from food animals, food, and humans in China and became a threat to public health worldwide (Liu et al., 2016). Several variants of plasmid‐mediated colistin resistance genes (e.g., mcr‐2, mcr‐3, mcr‐4 and mcr‐5) have now been detected. The mcr‐1 gene is globally distributed in many bacterial species isolated from a number of different sources, but especially from swine. In 2016, China banned the use of colistin in animals as a growth promoter and has documented a significant reduction in the prevalence of colistin resistance in both the animal and human sectors (Wang et al., 2020). However, colistin remains available by prescription for treatment of disease and metaphylaxis in animals in China. In food‐producing animals, colistin sulfate is predominantly administered orally, in a variety of different formulations (e.g., premix, powder, oral solutions). Orally administered polymyxins are not appreciably absorbed from the gastrointestinal tract, such that colistin only treats enteric infections. Oral treatment results in high enteric concentrations with minimal risk of antimicrobial residues in the meat (Mead et al., 2021). Colistin methanesulfonate sodium or polymyxin B can be administered intravenously or intramuscularly. Colistin methanesulfonate causes less pain at the injection site and less renal toxicity than polymyxin B, but polymyxin B has greater local activity. Polymyxins bind moderately to plasma proteins but extensively to muscle tissue, diffuse poorly through biologic membranes, and attain low concentrations in transcellular fluids and in milk. Because of tissue binding, accumulation occurs with chronic dosing. The strong affinity of the polymyxins to the muscle tissue results in persistent drug residues (Ziv et al., 1982). When administered IV, CSF concentrations of colistin methanesulfonate sodium reach 25% of plasma concentrations. The polymyxins are slowly excreted unchanged by glomerular filtration and tubular secretion in to urine. High concentrations accumulate in patients with renal insufficiency. Polymyxins are synergistic with a variety of antimicrobial drugs through their disorganizing effects on the outer and cytoplasmic membranes (Li et al., 2022a; Ontong et al., 2021; Scudeller et al., 2021). Other compounds that show synergism with colistin against multidrug‐resistant Gram‐negative bacteria include silver nanoparticles, melatonin, cannabidiol, resveratrol, and essential oils. Polymyxins are well tolerated after oral or topical administration, but systemic use causes nephrotoxic, neurotoxic, and neuromuscular blocking effects. Colistin is less toxic than polymyxin B, but colistin methanesulfonate has reduced antimicrobial activity compared to colistin sulfate. Polymyxin‐induced neurotoxicity involves oxidative stress and mitochondrial dysfunction. In humans, reversible peripheral neuropathy, with paresthesia, numbness around the mouth, blurring of vision, and weakness, occurs in about 7% of treated patients; neuromuscular blockade causing respiratory insufficiency occurs in about 2% of patients, particularly in those treated with high doses. Curcumin, minocycline, salidroside, and rapamycin appear to be neuroprotective (Dai et al., 2019). In an equine study of the administration of polymyxin B alone and in combination with gentamicin, all horses developed transient ataxia during drug administration and 29% showed muscle weakness (van Spijk et al., 2022). The duration of drug administration and co‐administration with gentamicin exacerbated severity of ataxia. The polymyxins are highly nephrotoxic, causing damage to the renal tubular epithelial cells. Risk factors for nephrotoxicity include age (geriatric), preexisting renal insufficiency, hypoalbuminemia, and concomitant use of nonsteroidal antiinflammatory drugs, aminoglycosides, and vancomycin. Renal failure appears dose dependent, with some studies identifying the total cumulative dose predictive of renal failure and others the daily dose (Yahav et al., 2012). Concurrent administration of antioxidants has a protective effect (Mirjalili et al., 2022). In an animal model, colistin‐induced nephrotoxicity was decreased histopathologically and serologically by the administration of intravenous lipid emulsion (Senkal et al., 2021). In the van Spijk et al. (2022) study, antiendotoxin doses of polymyxin B did not cause acute kidney injury. Colistin is mainly administered orally in the form of premix, powder, and oral solutions in feed, drinking water or in milk replacer for the treatment of gastrointestinal tract infections caused by noninvasive E. coli. Because of toxicity, parenteral polymyxins have not been used routinely in animals except in the treatment of endotoxemia. Polymyxins are given to many different animal species including dogs, cats, horses, pigs, poultry, cattle, sheep, goats, laying hens, rabbits and in aquaculture. Because of the dissemination of the mobile colistin resistance mcr‐1 gene and its variants between multidrug‐ (MDR) and extensive drug‐resistant (XDR) virulent Gram‐negative bacteria in animals, humans, and the environment, polymyxin B and colistin should no longer be routinely used in food animals. As noted, they are listed as high priority critically important antimicrobials by the WHO (2024). Polymyxins have commonly been used in some countries for the treatment of colibacillosis and salmonellosis in veal calves (Bokma et al., 2019). However, the oral use of colistin in calves resulted in horizontal transfer of the mcr‐1 gene to a human (Viñes et al., 2021). Polymyxin B has been used in intramammary (IMM) formulations in dairy cattle. However, IMM infections with multidrug‐resistant, mcr‐1‐positive, extended‐spectrum beta‐lactamase‐producing E. coli in dairy cattle have been documented (Filioussis et al., 2020; Tartor et al., 2021). The routes of selection of colistin resistance are unknown. It may result from IMM infusion of polymyxin B in the infected udder, but resistance might also have been selected in the farm environment as a consequence of oral administration of colistin to calves with resistant bacteria eliminated in the feces. Some IMM products containing polymyxin B have been pulled from the market and oral colistin use has become restricted in many countries. Colistin has been used extensively in pigs outside North America as an oral treatment for colibacillosis, mainly postweaning diarrhea. Its worldwide use in swine has been limited since 2016 as a consequence of reports of a transferable plasmid‐mediated colistin resistance gene, mcr‐1, in Enterobacterales isolates from pig production in China (Liu et al., 2016). Despite control efforts, mcr‐1 and its variants have spread globally, threatening the human use of this “last‐resort” drug (Wang et al., 2018). Polymyxin B is used locally to treat bacterial keratitis caused by Klebsiella spp. or P. aeruginosa. Polymyxin B is formulated as “triple antibiotic” ophthalmic ointment or solution, in combination with bacitracin and neomycin. Polymyxin B has been used for its endotoxin‐binding activity in horses (Werners, 2017). Polymyxin B interacts with the lipid A 2‐keto‐3‐deoxyoctulosonate region of the LPS molecule to form a stable molecular complex, preventing the endotoxin‐induced proinflammatory casacade. Due to the importance of polymyxin B in the treatment of multidrug‐resistant Gram‐negative infections in humans, its nonantimicrobial use should be carefully considered. In foals challenged with LPS, it reduced fever, respiratory rate and serum activities of tumor necrosis factor (TNF) and interleukin‐6 (Durando et al., 1994; Wong et al., 2013). In adult horses, it ameliorates clinical signs and decreases plasma TNF activity (Barton et al., 2004). Conversely, polymyxin B was ineffective in ameliorating the endotoxemia associated with carbohydrate overload (Raisbeck et al., 1989). If used, treatment should begin as soon as possible, as the LPS scavenging effects are only beneficial in the first 24–48 hours, after which tolerance to LPS develops. In equine models of endotoxemia, neuromuscular blockade and apnea were not observed, and nephrotoxicity was only observed at very high dosages. The polymyxin B concentrations that bind LPS are considerably lower (2–5 times) than the dose used for antimicrobial activity. For endotoxemia in horses, a dose of polymyxin B at 5000–10 000 IU/kg IV q8–12 h is suggested (Morresey and Mackay, 2006). Polymyxins are used in the topical treatment of bacterial keratitis, otitis externa, and other skin infections caused by susceptible Gram‐negative bacteria. Resistance to polymyxins is increasing in canine otitis cases, and isolates containing the mcr‐1 gene have been detected. Such antimicrobial resistance may increase the number of challenging otitis cases that do not respond to first‐line antimicrobials and poses a public health threat due to the close association between dogs and their owners (Martins et al., 2022). In an endotoxic dog model, colistin administration improved capillary refill time and hydration and significantly reduced serum TNF concentrations. For treatment of endotoxic shock in dogs, a colistin dose of 12 500 U/kg q12 h was safe and efficacious (Senturk, 2005). An extracorporeal hemoperfusion device using a polymyxin B‐immobilized resin column was effective in removing endotoxin and inflammatory mediators and improving survival in septic beagles (Li et al., 2022b). A dose of polymyxin B at 1000 IU/kg IV appears safe and efficacious for endotoxemia in cats (Sharp et al., 2010). Colistin is widely used in China, India, Southeast Asia, the European Union, and many other countries for the treatment of Gram‐negative infections in chickens, turkeys, and ducks. Colibacillosis in chickens is characterized by septicemia and air sacculitis. As colistin is not appreciably absorbed from the GI tract of chickens, the true use of colistin in chickens is to decolonize the GI tract E. coli population and reduce E. coli in the dust that causes air sacculitis and colibacillosis via inhalation. In turkeys, colibacillosis is an enteric infection. Countries with high use of oral colistin in poultry have seen increasing detection of mcr‐1 and its variants in live poultry and meat products (Kempf et al., 2016). Many countries now restrict or ban the use of oral colistin in food animals. The glycopeptides are actinomycete‐derived antibiotics with unique tricyclic or tetracyclic heptapeptide cores. They are divided into four distinct structural subclasses (I–IV), according to the substituents and the type of residues at positions 1 and 3 of the heptapeptide. Vancomycin, teicoplanin, and avoparcin are first‐generation glycopeptide antibiotics with activity against Gram‐positive bacteria and particularly against Gram‐positive cocci. Vancomycin and teicoplanin are currently available for human use in most parts of the world, whereas avoparcin is only available for veterinary use in some countries. Because of their outstanding activity against a broad spectrum of Gram‐positive bacteria, vancomycin and teicoplanin have often been considered the drugs of “last resort” for serious staphylococcal and enterococcal infections. The WHO (2024) classifies vancomycin and teicoplanin as authorized for human medicine only. Glycopeptides had been in clinical use for almost 30 years before high‐level resistance first emerged in enterococci. Avoparcin had been used extensively as an antibiotic growth promoter for chickens and pigs in Europe. It was withdrawn for use in Europe because it was associated with selection for vancomycin‐resistant enterococci (VRE) in farm animals, which then were a source of infection for humans. Under the Animal Medicinal Use Clarification Act of 1996, the extra‐label use of glycopeptides is banned in animals in the United States. The expense of treatment with vancomycin and teicoplanin effectively limits the veterinary use of these drugs in countries where their use is not specifically banned. Vancomycin is a high molecular weight glycopeptide, a fermentation product of Amycolatopsis orientalis. The generic name vancomycin
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Peptide Antibiotics: Polymyxins, Glycopeptides, Bacitracin, and Fosfomycin
Polymyxins
Chemistry
Mechanisim of Action
Antimicrobial Activity
Resistance
Pharmacokinetic Properties
Drug Interactions
Toxicity and Adverse Effects
Administration
Clinical Use
Cattle
Swine
Horses
Dogs and Cats
Poultry
Glycopeptides: Vancomycin, Teicoplanin, and Avoparcin
Vancomycin
Chemistry
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