Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wall—a structure that mammalian cells do not possess. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms. They have little or no effect on bacteria that are not growing and dividing. The most important members of this group of drugs are the β-lactam antibiotics (named after the β-lactam ring that is essential to their activity), vancomycin, and daptomycin.
Cell Wall Inhibitors: PENICILLINS
Focus topic: Cell Wall Inhibitors
The penicillins are among the most widely effective and the least toxic drugs known, but increased resistance has limited their use. Members of this family differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue. The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, crosshypersensitivity, and susceptibility to bacterial degradative enzymes (β-lactamases).
A. Mechanism of action
The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. These drugs are bactericidal and work in a time-dependent fashion. Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses.
- Penicillin-binding proteins: Penicillins also inactivate numerous proteins on the bacterial cell membrane. These penicillin-binding proteins (PBPs) are bacterial enzymes involved in the synthesis of the cell wall and in the maintenance of the morphologic features of the bacterium. Exposure to these antibiotics can therefore not only prevent cell wall synthesis but also lead to morphologic changes or lysis of susceptible bacteria. The number of PBPs varies with the type of organism. Alterations in some of these PBPs provide the organism with resistance to the penicillins. [Note: Methicillinresistant Staphylococcus aureus (MRSA) arose because of such an alteration.]
- Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains. Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity.
- Production of autolysins: Many bacteria, particularly the grampositive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Thus, the antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of the existing cell wall by autolysins.
B. Antibacterial spectrum
The antibacterial spectrum of the various penicillins is determined, in part, by their ability to cross the bacterial peptidoglycan cell wall to reach the PBPs in the periplasmic space. Factors that determine the susceptibility of PBPs to these antibiotics include the size, charge, and hydrophobicity of the particular β-lactam antibiotic. In general, gram-positive microorganisms have cell walls that are easily traversed by penicillins, and, therefore, in the absence of resistance, they are susceptible to these drugs. Gram-negative microorganisms have an outer lipopolysaccharide membrane surrounding the cell wall that presents a barrier to the water-soluble penicillins. However, gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry.
- Natural penicillins: Natural penicillins (penicillin G and penicillin V) are obtained from fermentations of the fungus Penicillium chrysogenum. Semisynthetic penicillins, such as amoxicillin and ampicillin (also known as aminopenicillins), are created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus. Penicillin [pen-i-SILL-in] G (benzyl-penicillin) is the cornerstone of therapy for infections caused by a number of grampositive and gram-negative cocci, gram-positive bacilli, and spirochetes. Penicillins are susceptible to inactivation by β-lactamases (penicillinases) that are produced by the resistant bacteria. Despite widespread use and increase in resistance to many types of bacteria, penicillin remains the drug of choice for the treatment of gas gangrene (Clostridium perfringens) and syphilis (Treponema pallidum). Penicillin V has a similar spectrum to that of penicillin G, but it is not used for treatment of bacteremia because of its poor oral absorption. Penicillin V is more acid stable than penicillin G and is often employed orally in the treatment of infections.
- Antistaphylococcal penicillins: Methicillin [meth-i-SILL-in], nafcillin [naf-SILL-in], oxacillin [ox-a-SILL-in], and dicloxacillin [dye-klox-a-SILL-in] are β-lactamase (penicillinase)-resistant penicillins. Their use is restricted to the treatment of infections caused by penicillinase-producing staphylococci, including methicillinsensitive Staphylococcus aureus (MSSA). [Note: Because of its toxicity (interstitial nephritis), methicillin is not used clinically in the United States except in laboratory tests to identify resistant strains of S. aureus. MRSA is currently a source of serious community and nosocomial (hospital-acquired) infections and is resistant to most commercially available β-lactam antibiotics.] The penicillinase- resistant penicillins have minimal to no activity against gram-negative infections.
- Extended-spectrum penicillins: Ampicillin [am-pi-SILL-in] and amoxicillin [a-mox-i-SILL-in] have an antibacterial spectrum similar to that of penicillin G but are more effective against gramnegative bacilli. Ampicillin (with or without the addition of gentamicin) is the drug of choice for the gram-positive bacillus Listeria monocytogenes and susceptible enterococcal species. These extended-spectrum agents are also widely used in the treatment of respiratory infections, and amoxicillin is employed prophylactically by dentists in high-risk patients for the prevention of bacterial endocarditis. Resistance to these antibiotics is now a major clinical problem because of inactivation by plasmid-mediated penicillinases. [Note: Escherichia coli and Haemophilus influenzae are frequently resistant.] Formulation with a β-lactamase inhibitor, such as clavulanic acid or sulbactam, protects amoxicillin or ampicillin, respectively, from enzymatic hydrolysis and extends their antimicrobial spectra. For example, without the β-lactamase inhibitor, MSSA is resistant to ampicillin and amoxicillin.
- Antipseudomonal penicillins: Piperacillin [pip-er-a-SILL-in] and ticarcillin [tye-kar-SILL-in] are called antipseudomonal penicillins because of their activity against Pseudomonas aeruginosa. These agents are available in parenteral formulations only. Piperacillin is the most potent of these antibiotics. They are effective against many gram-negative bacilli, but not against Klebsiella because of its constitutive penicillinase. Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam, respectively, extends the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms (for example, most Enterobacteriaceae and Bacteroides species).
Natural resistance to the penicillins occurs in organisms that either lack a peptidoglycan cell wall (for example, Mycoplasma pneumoniae) or have cell walls that are impermeable to the drugs. Acquired resistance to the penicillins by plasmid-mediated β-lactamases has become a significant clinical problem. Multiplication of resistant strains leads to increased dissemination of the resistance genes. By obtaining resistance plasmids, bacteria may acquire one or more of the following properties, thus allowing survival in the presence of β-lactam antibiotics.
- β-Lactamase activity: This family of enzymes hydrolyzes the cyclic amide bond of the β-lactam ring, which results in loss of bactericidal activity. They are the major cause of resistance to the penicillins and are an increasing problem. β-Lactamases either are constitutive, mostly produced by the bacterialchromosome or, more commonly, are acquired by the transfer of plasmids. Some of the β-lactam antibiotics are poor substrates for β-lactamases and resist hydrolysis, thus retaining their activity against β-lactamase–producing organisms. [Note: Certain organisms may have chromosome- associated β-lactamases that are inducible by β-lactam antibiotics (for example, second and third generation cephalosporins).] Gram-positive organisms secrete β-lactamases extracellularly, whereas gram-negative bacteria inactivate β-lactam drugs in the periplasmic space.
- Decreased permeability to the drug: Decreased penetration of the antibiotic through the outer cell membrane of the bacteria prevents the drug from reaching the target PBPs. The presence of an efflux pump can also reduce the amount of intracellular drug (for example, Klebsiella pneumoniae).
- Altered PBPs: Modified PBPs have a lower affinity for β-lactam antibiotics, requiring clinically unattainable concentrations of the drug to effect inhibition of bacterial growth. This explains MRSA resistance to most commercially available β-lactams.
1. Administration: The route of administration of a β-lactam antibiotic is determined by the stability of the drug to gastric acid and by the severity of the infection.
- Routes of administration: The combination of ampicillin with sulbactam, ticarcillin with clavulanic acid, and piperacillin with tazobactam, and the antistaphylococcal penicillins nafcillin and oxacillin must be administered intravenously (IV) or intramuscularly (IM). Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations. Others are effective by the oral, IV, or IM routes. [Note: The combination of amoxicillin with clavulanic acid is only available in an oral formulation in the United States].
- Depot forms: Procaine penicillin G and benzathine penicillin G are administered IM and serve as depot forms. They are slowly absorbed into the circulation and persist at low levels over a long time period.
2. Absorption: Most of the penicillins are incompletely absorbed after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal flora. Food decreases the absorption of all the penicillinase-resistant penicillins because as gastric emptying time increases, the drugs are destroyed by stomach acid. Therefore, they should be taken on an empty stomach.
3. Distribution: The β-lactam antibiotics distribute well throughout the body. All the penicillins cross the placental barrier, but none have been shown to have teratogenic effects. However, penetration into bone or cerebrospinal fluid (CSF) is insufficient for therapy unless these sites are inflamed. [Note:Inflamed meninges are more permeable to the penicillins, resulting in an increased ratio of the drug in the CSF compared to the serum.] Penicillin levels in the prostate are insufficient to be effective against infections.
4. Metabolism: Host metabolism of the β-lactam antibiotics is usually insignificant, but some metabolism of penicillin G may occur in patients with impaired renal function.
5. Excretion: The primary route of excretion is through the organic acid (tubular) secretory system of the kidney as well as by glomerular filtration. Patients with impaired renal function must have dosage regimens adjusted. Nafcillin and oxacillin are exceptions to the rule. They are primarily metabolized in the liver and do not require dose adjustment for renal insufficiency. Probenecid inhibits the secretion of penicillins by competing for active tubular secretion via the organic acid transporter and, thus, can increase blood levels. The penicillins are also excreted in breast milk.
E. Adverse reactions
Penicillins are among the safest drugs, and blood levels are not monitored. However, adverse reactions may occur.
- Hypersensitivity: Approximately 5% percent of patients have some kind of reaction, ranging from rashes to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis. Cross-allergic reactions occur among the β-lactam antibiotics.To determine whether treatment with a β-lactam is safe when an allergy is noted, patient history regarding severity of previous reaction is essential.
- Diarrhea: Diarrhea is a common problem that is caused by a disruption of the normal balance of intestinal microorganisms. It occurs to a greater extent with those agents that are incompletely absorbed and have an extended antibacterial spectrum. Pseudomembranous colitis from Clostridium difficile and other organisms may occur with penicillin use.
- Nephritis: Penicillins, particularly methicillin, have the potential to cause acute interstitial nephritis. [Note: Methicillin is therefore no longer used clinically.]
- Neurotoxicity: The penicillins are irritating to neuronal tissue, and they can provoke seizures if injected intrathecally or if very high blood levels are reached. Epileptic patients are particularly at risk due to the ability of penicillins to cause GABAergic inhibition.
- Hematologic toxicities: Decreased coagulation may be observed with high doses of piperacillin, ticarcillin, and nafcillin (and, to some extent, with penicillin G). Cytopenias have been associated with therapy of greater than 2 weeks, and therefore, blood counts should be monitored weekly for such patients.
Cell Wall Inhibitors: CEPHALOSPORINS
Focus topic: Cell Wall Inhibitors
The cephalosporins are β-lactam antibiotics that are closely related both structurally and functionally to the penicillins. Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid. Cephalosporins have the same mode of action as penicillins, and they are affected by the same resistance mechanisms. However, they tend to be more resistant than the penicillins to certain β-lactamases.
A. Antibacterial spectrum
Cephalosporins have been classified as first, second, third, fourth, and advanced generation, based largely on their bacterial susceptibility patterns and resistance to β-lactamases. [Note: Commercially available cephalosporins are ineffective against MRSA, L. monocytogenes, C. difficile, and the enterococci.]
- First generation: The first-generation cephalosporins act as penicillin G substitutes. They are resistant to the staphylococcal penicillinase (that is, they cover MSSA) and also have activity against Proteus mirabilis, E. coli, and K. pneumoniae.
- Second generation: The second-generation cephalosporins display greater activity against three additional gram-negative organisms: H. influenzae, Enterobacter aerogenes, and some Neisseria species, whereas activity against gram-positive organisms is weaker. Antimicrobial coverage of the cephamycins (cefotetan [sef-oh-TEE-tan] and cefoxitin [sef-OX-i-tin]) also includes anaerobes (for example, Bacteroides fragilis). They are the only cephalosporins commercially available with appreciable activity against gram-negative anaerobic bacteria. However, neither drug is first line because of the increasing prevalence of resistance among B. fragilis to both agents.
- Third generation: These cephalosporins have assumed an important role in the treatment of infectious diseases. Although they are less potent than first-generation cephalosporins against MSSA, the third-generation cephalosporins have enhanced activity against gram-negative bacilli, including those mentioned above, as well as most other enteric organisms plus Serratia marcescens. Ceftriaxone [sef-trye-AKS-own] and cefotaxime [sef-oh-TAKSeem] have become agents of choice in the treatment of meningitis. Ceftazidime [sef-TA-zi-deem] has activity against P. aeruginosa; however, resistance is increasing and use should be evaluated on a case-by-case basis. Third-generation cephalosporins must be used with caution, as they are associated with significant “collateral damage,” essentially meaning the induction and spread of antimicrobial resistance. [Note: Fluoroquinolone use is also associated with collateral damage.]
- Fourth generation: Cefepime [SEF-eh-peem] is classified as a fourth-generation cephalosporin and must be administered parenterally. Cefepime has a wide antibacterial spectrum, with activity against streptococci and staphylococci (but only those that are methicillin susceptible). Cefepime is also effective against aerobic gram-negative organisms, such as Enterobacter species, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa. When selecting an antibiotic that is active against P. aeruginosa, clinicians should refer to their local antibiograms (laboratory testing for the sensitivity of an isolated bacterial strain to different antibiotics) for direction.
- Advanced generation: Ceftaroline [sef-TAR-oh-leen] is a broadspectrum, advanced-generation cephalosporin that is administered IV as a prodrug, ceftaroline fosamil. It is the only commercially available β-lactam in the United States with activity against MRSA and is indicated for the treatment of complicated skin and skin structure infections and community-acquired pneumonia. The unique structure allows ceftaroline to bind to PBP2a found with MRSA and PBP2x found with Streptococcus pneumoniae. In addition to its broad gram-positive activity, it also has similar gramnegative activity to the third-generation cephalosporin ceftriaxone. Important gaps in coverage include P. aeruginosa, extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, and Acinetobacter baumannii. The twice-daily dosing regimen also limits use outside of an institutional setting.
Mechanisms of bacterial resistance to the cephalosporins are essentially the same as those described for the penicillins. [Note: Although they are not susceptible to hydrolysis by the staphylococcal penicillinase, cephalosporins may be susceptible to ESBLs. Organisms such as E. coli and K. pneumoniae are particularly associated with ESBLs.]
- Administration: Many of the cephalosporins must be administered IV or IM because of their poor oral absorption.
- Distribution: All cephalosporins distribute very well into body fluids. However, adequate therapeutic levels in the CSF, regardless of inflammation, are achieved with only a few cephalosporins. For example, ceftriaxone and cefotaxime are effective in the treatment of neonatal and childhood meningitis caused by H. influenzae. Cefazolin [se-FA-zo-lin] is commonly used as a single prophylaxis dose prior to surgery because of its 1.8-hour half-life and its activity against penicillinase-producing S. aureus. Cefazolin is effective for most surgical procedures, including orthopedic surgery because of its ability to penetrate bone. All cephalosporins cross the placenta.
- Elimination: Cephalosporins are eliminated through tubular secretion and/or glomerular filtration. Therefore, doses must be adjusted in cases of renal dysfunction to guard against accumulation and toxicity. One exception is ceftriaxone, which is excreted through the bile into the feces and, therefore, is frequently employed in patients with renal insufficiency.
D. Adverse effects
Like the penicillins, the cephalosporins are generally well tolerated. However, allergic reactions are a concern. Patients who have had an anaphylactic response, Stevens-Johnson syndrome, or toxic epidermal necrolysis to penicillins should not receive cephalosporins. Cephalosporins should be avoided or used with caution in individuals with penicillin allergy. Current data suggest that the cross-reactivity between penicillin and cephalosporins is around 3% to 5% and is determined by the similarity in the side chain, not the β-lactam structure. The highest rate of allergic cross-sensitivity is between penicillin and first-generation cephalosporins.
Cell Wall Inhibitors: OTHER β-LACTAM ANTIBIOTICS
Focus topic: Cell Wall Inhibitors
Carbapenems are synthetic β-lactam antibiotics that differ in structure from the penicillins in that the sulfur atom of the thiazolidine ring has been externalized and replaced by a carbon atom. Imipenem [i-mi-PEN-em], meropenem [mer-oh-PEN-em], doripenem [dore-i-PEN-em], and ertapenem [er-ta-PEN-em] are the drugs of this group currently available. Imipenem is compounded with cilastatin to protect it from metabolism by renal dehydropeptidase.
- Antibacterial spectrum: Imipenem resists hydrolysis by most β-lactamases, but not the metallo-β-lactamases. This drug plays a role in empiric therapy because it is active against β-lactamase–producing gram-positive and gram-negative organisms, anaerobes, and P. aeruginosa (although other pseudomonal strains are resistant and resistant strains of P. aeruginosa have been reported to arise during therapy). Meropenem and doripenem have antibacterial activity similar to that of imipenem. Unlike other carbapenems, ertapenem lacks coverage against P. aeruginosa, Enterococcus species, and Acinetobacter species.
- Pharmacokinetics: Imipenem/cilastatin and meropenem are administered IV and penetrate well into body tissues and fluids, including the CSF when the meninges are inflamed. Meropenem is known to reach therapeutic levels in bacterial meningitis even without inflammation. They are excreted by glomerular filtration. Imipenem undergoes cleavage by a dehydropeptidase found in the brush border of the proximal renal tubule. This enzyme forms an inactive metabolite that is potentially nephrotoxic. Compounding the imipenem with cilastatin protects the parent drug and, thus, prevents the formation of the toxic metabolite. The other carbapenems do not require coadministration of cilastatin. Ertapenem can be administered via IV or IM injection once daily. [Note: Doses of these agents must be adjusted in patients with renal insufficiency.]
- Adverse effects: Imipenem/cilastatin can cause nausea, vomiting, and diarrhea. Eosinophilia and neutropenia are less common than with other β-lactams. High levels of imipenem may provoke seizures; however, the other carbapenems are less likely to do so.
The monobactams, which also disrupt bacterial cell wall synthesis, are unique because the β-lactam ring is not fused to another ring. Aztreonam [az-TREE-oh-nam], which is the only commercially available monobactam, has antimicrobial activity directed primarily against gram-negative pathogens, including the Enterobacteriaceae and P. aeruginosa. It lacks activity against grampositive organisms and anaerobes. Aztreonam is resistant to the action of most β-lactamases, with the exception of the ESBLs. It is administered either IV or IM and can accumulate in patients with renal failure. Aztreonam is relatively nontoxic, but it may cause phlebitis, skin rash and, occasionally, abnormal liver function tests. This drug has a low immunogenic potential, and it shows little cross-reactivity with antibodies induced by other β-lactams. Thus, this drug may offer a safe alternative for treating patients who are allergic to other penicillins, cephalosporins, or carbapenems.
Cell Wall Inhibitors: β-LACTAMASE INHIBITORS
Focus topic: Cell Wall Inhibitors
Hydrolysis of the β-lactam ring, either by enzymatic cleavage with a β-lactamase or by acid, destroys the antimicrobial activity of a β-lactam antibiotic. β-Lactamase inhibitors, such as clavulanic [cla-vue-LAN-ick] acid, sulbactam [sul-BACK-tam], and tazobactam [ta-zoh-BACK-tam], contain a β-lactam ring but, by themselves, do not have significant antibacterial activity or cause any significant adverse effects. Instead, they bind to and inactivate β-lactamases, thereby protecting the antibiotics that are normally substrates for these enzymes. The β-lactamase inhibitors are therefore formulated in combination with β- lactamase–sensitive antibiotics. [Note: Clavulanic acid alone is nearly devoid of any antibacterial activity.]
Cell Wall Inhibitors: VANCOMYCIN
Focus topic: Cell Wall Inhibitors
Vancomycin [van-koe-MYE-sin] is a tricyclic glycopeptide that has become increasingly important in the treatment of life-threatening MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE) infections, as well as enterococcal infections. With the emergence of resistant strains, it is important to curtail the increase in vancomycin-resistant bacteria (for example, Enterococcus faecium and Enterococcus faecalis) by restricting the use of vancomycin to the treatment of serious infections caused by β-lactam resistant, gram-positive microorganisms or gram-positive infections in patients who have a serious allergy to the β-lactams. Intravenous vancomycin is used in individuals with prosthetic heart valves and in patients undergoing implantation with prosthetic devices, especially in those hospitals where there are high rates of MRSA or MRSE. Serum drug concentrations (troughs) are commonly measured to monitor and adjust dosages for safety and efficacy. Vancomycin is not absorbed after oral administration, so the use of the oral formulation is limited to the treatment of severe antibioticassociated C. difficile colitis.
Cell Wall Inhibitors: DAPTOMYCIN
Focus topic: Cell Wall Inhibitors
Daptomycin [DAP-toe-mye-sin] is a bactericidal concentration-dependent cyclic lipopeptide antibiotic that is an alternative to other agents, such as linezolid and quinupristin/dalfopristin, for treating infections caused by resistant gram-positive organisms, including MRSA and vancomycin-resistant enterococci (VRE). Daptomycin is indicated for the treatment of complicated skin and skin structure infections and bacteremia caused by S. aureus, including those with right-sided infective endocarditis. Efficacy of treatment with daptomycin in left-sided endocarditis has not been demonstrated. Additionally, daptomycin is inactivated by pulmonary surfactants; thus, it should never be used in the treatment of pneumonia.
Cell Wall Inhibitors: TELAVANCIN
Focus topic: Cell Wall Inhibitors
Telavancin [tel-a-VAN-sin] is a bactericidal concentration-dependent semisynthetic lipoglycopeptide antibiotic that is a synthetic derivative of vancomycin. Like vancomycin, telavancin inhibits bacterial cell wall synthesis. Moreover, telavancin exhibits an additional mechanism of action similar to that of daptomycin, which involves disruption of the bacterial cell membrane due to the presence of a lipophilic side chain moiety. It is an alternative to vancomycin, daptomycin, and linezolid, in treating complicated skin and skin structure infections caused by resistant gram-positive organisms (including MRSA). It is also an agent of last choice for hospital-acquired and ventilator-associated bacterial pneumonia when alternative treatments are not suitable. The use of telavancin in clinical practice is limited by significant adverse effects (for example, renal impairment), interaction with anticoagulation laboratory assays, risk of fetal harm in pregnant women, and interaction with medications that can prolong the QTc interval (for example, fluoroquinolones, azole antifungals, macrolides).
Cell Wall Inhibitors: FOSFOMYCIN
Focus topic: Cell Wall Inhibitors
Fosfomycin [fos-foe-MYE-sin] is a bactericidal synthetic derivative of phosphonic acid. It blocks cell wall synthesis by inhibiting the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase, which catalyzes the first step in peptidoglycan synthesis. It is indicated for urinary tract infections caused by E. coli or E. faecalis. Due to its unique structure and mechanism of action, cross resistance with other antimicrobial agents is unlikely. Fosfomycin is rapidly absorbed after oral administration and distributes well to the kidneys, bladder, and prostate. The drug is excreted in its active form in the urine and feces. It maintains high concentrations in the urine over several days, allowing for a one-time dose for the treatment of urinary tract infections. [Note: A parenteral formulation is available in select countries and has been used for the treatment of systemic infections.] The most commonly reported adverse effects include diarrhea, vaginitis, nausea, and headache.
Cell Wall Inhibitors: POLYMYXINS
Focus topic: Cell Wall Inhibitors
The polymyxins are cation polypeptides that bind to phospholipids on the bacterial cell membrane of gram-negative bacteria. They have a detergent-like effect that disrupts cell membrane integrity, leading to leakage of cellular components and ultimately cell death. Polymyxins are concentration-dependent bactericidal agents with activity against most clinically important gram-negative bacteria, including P. aeruginosa, E. coli, K. pneumoniae, Acinetobacter species, and Enterobacter species. However, alterations in the cell membrane lipid polysaccharides allow many species of Proteus and Serratia to be intrinsically resistant. Only two forms of polymyxin are in clinical use today, polymyxin B and colistin (polymyxin E). Polymyxin B is available in parenteral, ophthalmic, otic, and topical preparations. Colistin is only available as a prodrug, colistimethate sodium, which is administered IV or inhaled via a nebulizer. The use of these drugs has been limited for a long time, due to the increased risk of nephrotoxicity and neurotoxicity (for example, slurred speech, muscle weakness) when used systemically. However, with the increase in gram-negative resistance,they have seen a resurgence in use and are now commonly used as salvage therapy for patients with multidrug-resistant infections. Careful dosing and monitoring of adverse effects are important to maximize the safety and efficacy of these agents.[/sociallocker]