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 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 [plasmid-mediated colistin resistance] plasmid), increasing the risk of horizontal transfer. Cross-resistance between colistin and polymyxin B is nearly 100%.
Indications for Polypeptide Antibiotics
Polypeptides are used for several types of infections (see table Some Clinical Uses of Polypeptides Some Clinical Uses of Polypeptides 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 ).
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 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 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 patients... 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 are... 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 organisms... 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.
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 (see table Aminoglycosides) have concentration-dependent bactericidal activity. These antibiotics bind to the 30S ribosome, thereby inhibiting bacterial protein synthesis. Spectinomycin... 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.