Polypeptide antibiotics Overview of Antibacterial Drugs Antibacterial drugs are derived from bacteria or molds or are synthesized de novo. Technically, “antibiotic” refers only to antimicrobials derived from bacteria or molds but is often (including... read more disrupt bacterial cell walls.
Bacitracin is a polypeptide antibiotic that inhibits cell wall synthesis and is active against gram-positive bacteria.
Colistin (polymyxin E) and polymyxin B are cationic polypeptide antibiotics that disrupt the outer bacterial cell membrane by binding to the anionic outer membrane and thereby neutralizing the bacteria’s toxicity and causing bacterial cell death.
Colistin methane sulfonate (colistimethate sodium [CMS]) is a parenteral preparation of a prodrug that is transformed in blood and urine to colistin. CMS is less toxic than colistin.
Polypeptides other than colistin are usually used topically; systemic absorption is negligible.
Resistance to colistin and polymyxin B is typically acquired via modifications to the lipid A moiety of the lipopolysaccharide outer membrane; these modifications lead to a more positively charged cell surface, which lacks affinity for the positively charged polymyxins. Acquired resistance can be carried on mobile genetic elements (eg, mcr-1, 2, 3 [mobilized colistin resistance] plasmid), increasing the risk of horizontal transfer. Cross-resistance between colistin and polymyxin B is nearly 100%.
Indications for Polypeptide Antibiotics
Bacitracin is used mainly as a topical treatment for
Polymyxin B and colistin have rapid concentration-dependent bactericidal activity Time vs concentration of a single dose of a theoretical antibiotic against
Most facultative and aerobic gram-negative bacilli, including Pseudomonas aeruginosa Pseudomonas and Related Infections Pseudomonas aeruginosa and other members of this group of gram-negative bacilli are opportunistic pathogens that frequently cause hospital-acquired infections, particularly in ventilator... read more and Acinetobacter Acinetobacter Infections Acinetobacter species are gram-negative organisms that can cause suppurative infections in any organ system; these bacteria are often opportunists in hospitalized patients. Acinetobacter... read more species
These drugs are not active against Proteus, Providencia, Burkholderia, and Serratia species and some obligate anaerobes, including Bacteroides fragilis and gram-positive bacteria ( 1 Indications reference Polypeptide antibiotics disrupt bacterial cell walls. Bacitracin is a polypeptide antibiotic that inhibits cell wall synthesis and is active against gram-positive bacteria. Colistin (polymyxin... read more ).
The increasing prevalence of extensively drug-resistant gram-negative bacilli in hospitals has led to a resurgence of the use of IV colistin for serious systemic infections (eg, ventilator-associated pneumonia Hospital-Acquired Pneumonia Hospital-acquired pneumonia (HAP) develops at least 48 hours after hospital admission. The most common pathogens are gram-negative bacilli and Staphylococcus aureus; antibiotic-resistant... read more , bacteremia Bacteremia Bacteremia is the presence of bacteria in the bloodstream. It can occur spontaneously, during certain tissue infections, with use of indwelling genitourinary or IV catheters, or after dental... read more ). However, IV polymyxin B and colistin should typically be used only when there are no less toxic options. When polymyxins are used, they should be used in combination with other drugs such as meropenem, not as monotherapy. Colistin is often combined with other antibiotics to treat infections caused by multidrug-resistant bacteria; effectiveness of these combinations has not yet been rigorously assessed in clinical trials. Some of the newer combination beta-lactam plus inhibitor drugs are preferable to polymyxin-based therapy whenever possible.
Some Clinical Uses of Polypeptides
Ointment containing bacitracin plus neomycin, polymyxin B, or both
Spray containing neomycin, bacitracin, and polymyxin
Prevention of postoperative wound infections
Appears to help
Polymyxin B ophthalmic ointments and solutions with other antimicrobials (eg, bacitracin, neomycin, trimethoprim/sulfamethoxazole) and corticosteroids
Significantly improved rates of early clinical remission (although acute bacterial conjunctivitis is frequently self-limited)
Otic suspension with polymyxin B, neomycin, and hydrocortisone or with colistin, neomycin, and hydrocortisone
Otitis externa External Otitis (Acute) External otitis is an acute infection of the ear canal skin typically caused by bacteria (Pseudomonas is most common). Symptoms include pain, discharge, and hearing loss if the ear canal... read more (commonly due to Pseudomonas aeruginosa Pseudomonas and Related Infections Pseudomonas aeruginosa and other members of this group of gram-negative bacilli are opportunistic pathogens that frequently cause hospital-acquired infections, particularly in ventilator... read more )
Clinically effective, but may be no more effective than 2% acetic acid with hydrocortisone
In patients with a tympanostomy tube or known perforation of the tympanic membrane, must use a nonototoxic topical preparation (no aminoglycoside or alcohol)
Eradication of Staphylococcus aureus Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more nasal carriage
Less effective than other treatments
Aerosolized colistin methane sulfonate (colistimethate sodium [CMS])
Cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more
Occasionally hospital-acquired pneumonia Hospital-Acquired Pneumonia Hospital-acquired pneumonia (HAP) develops at least 48 hours after hospital admission. The most common pathogens are gram-negative bacilli and Staphylococcus aureus; antibiotic-resistant... read more caused by multidrug-resistant gram-negative bacilli
Associated with fewer adverse effects (eg, chest tightness, throat irritation, cough) than colistin sulfate
Aerosolized colistin sulfate
Same as for aerosolized colistin methane sulfonate
May be beneficial for patients with cystic fibrosis or nosocomial pneumonia (ventilator-associated or not) due to multidrug-resistant gram-negative bacteria
Severe infections due to multidrug-resistant gram-negative bacilli such as P. aeruginosa or Acinetobacter Acinetobacter Infections Acinetobacter species are gram-negative organisms that can cause suppurative infections in any organ system; these bacteria are often opportunists in hospitalized patients. Acinetobacter... read more species
Reduced dose in patients with renal insufficiency
Severe infections due to multidrug-resistant gram-negative bacilli such as P. aeruginosa or Acinetobacter species
Contraindications to Polypeptide Antibiotics
All polypeptides are contraindicated in patients who have had an allergic reaction to them.
Whenever possible, CMS and polymyxin B should not be given simultaneously with drugs that block neuromuscular transmission (eg, rocuronium) or are nephrotoxic (eg, aminoglycosides Aminoglycosides Aminoglycosides have concentration-dependent bactericidal activity. These antibiotics bind to the 30S ribosome, thereby inhibiting bacterial protein synthesis. Spectinomycin is a bacteriostatic... read more ).
Use During Pregnancy and Breastfeeding
Bacitracin may pose minimal risk during pregnancy and breastfeeding because systemic absorption is minimal; however, safety has not been established.
Polymyxin B has not been adequately evaluated in animal reproduction studies. No well-controlled studies have been done in pregnant women. Safety of polymyxin B in pregnant women has not been determined.
Colistin methane sulfonate (CMS) showed some risk in animal reproduction studies. Data related to pregnancy in humans are inadequate. Whether it is safe to use colistin or CMS during breastfeeding is unknown.
Adverse Effects of Polypeptide Antibiotics
Adverse effects of polypeptides include
Central and peripheral neurotoxicity
Polymyxins are nephrotoxic. CMS and polymyxin B may cause circumoral and extremity paresthesias, vertigo, slurred speech, and muscle weakness and respiratory difficulty due to neuromuscular blockade, especially in patients with renal insufficiency.
Dosing Considerations for Polypeptide Antibiotics
Because colistin was released before the advent of modern pharmacokinetic/pharmacodynamic analysis, appropriate dosing has not been studied as rigorously as for many modern antibiotics. In addition, manufacturers do not use a uniform method of describing drug amount; some use international units, and others use milligrams of colistin base activity or milligrams of actual colistimethate.
Whatever units are used, many experts believe that the manufacturer-recommended dose of 2.5 to 5 mg/kg of colistin base activity per day divided into 2 to 4 doses is too low and recommend higher dosing regimens, including the use of a loading dose ( 1 Dosing considerations reference Polypeptide antibiotics disrupt bacterial cell walls. Bacitracin is a polypeptide antibiotic that inhibits cell wall synthesis and is active against gram-positive bacteria. Colistin (polymyxin... read more ). However, nephrotoxicity is dose-dependent and becomes a greater concern with higher doses. Dosing should be discussed with an expert.