e1-15: Specialized Medications Used Against Bacteria: Bacitracin, Mupirocin, Clindamycin, Metronidazole & Tinidazole, Vancomycin, Bezlotoxumab

This polypeptide is selectively active against gram-positive bacteria. Because of severe nephrotoxicity associated with systemic administration, its use has been limited to topical application on surface lesions, usually in combination with polymyxin or neomycin.

Mupirocin (formerly pseudomonic acid) is a naturally occurring antibiotic produced by Pseudomonas fluorescens active against most gram-positive cocci, including methicillin-sensitive and methicillin-resistant S aureus and most streptococci (but not enterococci). Used topically, it can decolonize staphylococcal carriage after application to the anterior nares twice daily for 5 days. However, recurrent colonization occurs (50% at the end of 1 year), and when mupirocin is used long-term over months, resistance can emerge. High rates of mupirocin resistance have been observed in methicillin-resistant S aureus isolates from surgical intensive care unit patients, despite minimal in-hospital mupirocin use. This finding suggests the benefit of mupirocin is limited. Monthly application for 5 days each month for up to a year decreases staphylococcal colonization, which in turn lowers the risk of recurrent staphylococcal skin infections. Studies demonstrate an associated reduction in postoperative staphylococcal lung infections in colonized patients treated with mupirocin. Whether it is more effective than trimethoprim-sulfamethoxazole or dicloxacillin plus rifampin for eradication of staphylococcal nasal carriage is unknown. The IDSA recommends the use of mupirocin with chlorhexidine preferentially over oral antibacterials for methicillin-resistant S aureus decolonization. Mupirocin is equal to oral beta-lactams in the treatment of mild impetigo.

Clindamycin is active against gram-positive organisms including S pneumoniae, viridans streptococci, group A streptococci, and S aureus, though resistance has been described in all of these pathogens. Pneumococci or staphylococci with an efflux-based mechanism of resistance can be effectively treated with clindamycin. However, isolates with ribosomal methylase resistance are also resistant to clindamycin. Enterococci and most S epidermidis are resistant. Susceptibility of CA-MRSA isolates to clindamycin varies regionally. In those instances, in which CA-MRSA isolates demonstrate resistance to macrolides but susceptibility to clindamycin, additional microbiologic testing (“D” test) is advised to confirm the effectiveness of clindamycin. Clindamycin is equal to trimethoprim-sulfamethoxazole in uncomplicated skin and soft-tissue infection in emergency department patients. A dosage of 150–300 mg orally every 6 hours is generally given for bacterial infection. It is widely distributed in tissues but does not achieve therapeutic levels in cerebrospinal fluid. Excretion is primarily nonrenal.

Clindamycin is currently recommended as an alternative medication for prophylaxis against endocarditis following certain dental procedures in patients allergic to amoxicillin. Clindamycin, 300 mg orally twice daily for 7 days, can be used as an alternative to metronidazole for the therapy of bacterial vaginosis. Topical application of a 2% vaginal cream once or twice daily for 7 days or 100-mg ovules intravaginally once at bedtime for 3 days is also effective. Clindamycin is active against most anaerobes, including Prevotella, Clostridium, Peptococcus, Peptostreptococcus, and Fusobacterium organisms. However, up to 25% of B fragilis isolates are resistant, and alternative agents should be considered for serious infections due to these organisms. It is frequently used to treat less severe infections in which anaerobes are significant pathogens (eg, aspiration pneumonia, pelvic and abdominal infections), usually in combination with other medications active against gram-negative aerobes. Patients with hospital-acquired infection should be given clindamycin, 600–900 mg intravenously every 8 hours. Clindamycin is effective in the treatment of staphylococcal osteomyelitis, particularly in children. Because tissue models document that clindamycin significantly decreases toxin production, the addition of clindamycin to penicillin for treatment of group A Streptococcus toxic shock syndrome is recommended. The combination of clindamycin and vancomycin is associated with decreased length of stay and reduced hospital readmission rates, probably due to this reduction in toxin production. Clindamycin in combination with primaquine is an alternative in the treatment of Pneumocystis pneumonia, and clindamycin with quinine is of value for falciparum malaria. While useful in brain abscess, clindamycin is ineffective in meningitis.

Common side effects are diarrhea, nausea, and skin rashes. Antibiotic-associated colitis has been associated with the administration of clindamycin and other antibiotics and is due to a necrotizing toxin produced by C difficile. Interestingly, antecedent use of clindamycin is not a risk factor for the hypervirulent strain of C difficile. Rather, prior receipt of fluoroquinolones is a significant risk factor. C difficile is usually susceptible to—and can be treated with—oral vancomycin (see below).

Metronidazole is an antiprotozoal medication (see Chapter 35-07) also active against most anaerobic gram-negative bacilli (ie, Bacteroides, Prevotella, Fusobacterium) as well as Clostridium species but has minimal activity against many anaerobic gram-positive and microaerophilic organisms. It is well absorbed after oral administration and is widely distributed in tissues. It penetrates well into the cerebrospinal fluid, yielding levels similar to those in serum. The medication is metabolized in the liver, and dosage reduction is required in severe hepatic insufficiency or biliary dysfunction. Tinidazole is identical in spectrum of activity to metronidazole.

Metronidazole is used to treat amebiasis and giardiasis (see Chapter 35-07 and 35-10) and in the following circumstances:

1. Vaginitis caused by Trichomonas vaginalis can be treated with a single 2-g dose of either metronidazole or tinidazole or 500 mg orally three times daily for 7 days. Bacterial vaginosis is treated with metronidazole 500 mg twice daily for 7 days. Metronidazole vaginal cream (0.75%) applied twice daily for 5 days is also effective. Resistance with metronidazole is generally low level and can be treated with tinidazole.

2. In anaerobic infections, metronidazole can be given orally or intravenously, 500 mg three times daily. In contrast to clindamycin or cefoxitin and cefotetan, metronidazole is active against virtually all B fragilis isolates.

3. Metronidazole was previously recommended for treatment of mild C difficile colitis at a dosage of 500 mg orally three times daily. However, higher rates of metronidazole-resistant C difficile and clinical failure have been reported, and metronidazole is no longer recommended as first-line treatment for this indication. If oral medication cannot be administered in the treatment of C difficile colitis, intravenous metronidazole can be tried at the same dose; however, the efficacy associated with this route is unproven. Combination therapy with oral vancomycin and intravenous metronidazole is inconsistently superior to monotherapy in the treatment of C difficile in the critically ill patient.

4. Therapy of brain abscess, often in combination with penicillin or a third-generation cephalosporin.

5. In combination with other agents in the treatment of H pylori infections.

Adverse effects include stomatitis, nausea, and diarrhea. Ingestion of alcohol while taking metronidazole occasionally results in a disulfiram reaction. With prolonged use at high doses, reversible peripheral neuropathy can develop. Metronidazole can decrease the metabolism of warfarin, necessitating dosage adjustment of warfarin. Metronidazole is carcinogenic in certain animal models and mutagenic for certain bacteria, but these effects have not resulted in an increased risk of cancer in humans.

Vancomycin is bactericidal for most gram-positive organisms, particularly staphylococci and streptococci; it is, however, bacteriostatic for most enterococci. While active against staphylococci, vancomycin kills more slowly when compared with nafcillin or cefazolin, and these agents are preferred in the treatment of serious infection associated with methicillin-resistant S aureus. Although vancomycin has retained activity against staphylococci and streptococci, vancomycin-resistant strains of enterococci (particularly E faecium) are common. S aureus both intermediately sensitive and highly vancomycin-resistant has been observed in patients receiving long-term vancomycin therapy. Vancomycin is not absorbed from the gastrointestinal tract and thus useful orally only for the treatment of antibiotic-associated enterocolitis. For systemic effect, the medication must be administered intravenously (30 mg/kg/day in two or three divided doses). Vancomycin is excreted mainly via the kidneys. In end-stage kidney disease, the half-life may extend to 8 days. Vancomycin is cleared via high-flux hemodialysis and continuous renal replacement therapy (CRRT), resulting in the need for increased dosing. In patients with impaired kidney function, the dosing interval is determined by measuring trough serum levels. When trough serum levels decline to 10–15 mcg/mL, repeat dosing is required, primarily in the treatment of severe infection. As an example, more aggressive dosing with associated troughs of greater than 15 mcg/mL has been recommended in the treatment of methicillin-resistant S aureus ventilator-associated pneumonia. However, this practice has not been proven to result in increased efficacy. Large doses (4 g daily or more) and concomitant use of piperacillin-tazobactam have been associated with mild reversible nephrotoxicity. Vancomycin likely increases the risk of aminoglycoside-associated nephrotoxicity. Vancomycin efficacy correlates with pharmacokinetics/pharmacodynamics. Specifically, an area under the curve (AUC) divided by the minimum inhibitory concentration (MIC) of greater than 400 (AUC/MIC greater than 400) has been associated with favorable outcomes in serious infection due to S aureus. Attainment of this ratio appears to be particularly important during the first 2 days of therapy of methicillin-resistant S aureus bloodstream infections. Considering this relationship, the MIC is critical regarding the decision to use vancomycin; when the MIC is greater than or equal to 2 mcg/mL (or greater than or equal to 1.5 mcg/mL by E-test), alternatives to vancomycin (including daptomycin, linezolid, and other agents, depending on the site of infection) should be considered.

Indications for parenteral vancomycin include the following: (1) severe staphylococcal infections in patients with type 1 allergy to penicillins; (2) methicillin-resistant S aureus and methicillin-resistant S epidermidis infections; (3) serious infections (pneumonia, meningitis) due to resistant S pneumoniae; (4) severe enterococcal infections in the penicillin-allergic patient or ampicillin-resistant Enterococcus; (5) other gram-positive infections in penicillin-allergic patients, eg, viridans streptococcal endocarditis; (6) surgical prophylaxis in penicillin-allergic patients in clean surgical procedures; (7) for gram-positive infections due to organisms that are multidrug-resistant, ie, Corynebacterium jeikeium; and (8) endocarditis prophylaxis in the penicillin-allergic patient. In C difficile–associated disease, vancomycin, 0.125 g, is given orally four times daily. Oral vancomycin is preferred over oral metronidazole in the treatment of most C difficile disease. Oral doses in excess of 0.125 g are not associated with improved outcomes in the treatment of this disease, although it is recommended in severe recurrent disease.

Thrombophlebitis sometimes follows intravenous injection. The medication is infrequently reversibly ototoxic when given concomitantly with aminoglycosides or high-dose intravenous erythromycins; it increases aminoglycoside-induced nephrotoxicity with coadministration. Concomitant administration of vancomycin with piperacillin-tazobactam increases the risk for nephrotoxicity; this association has not been observed when vancomycin is combined with other beta-lactams. Vancomycin doses of 4 g or greater daily and elevated trough levels are also associated with an increased incidence of mild nephrotoxicity. Rapid infusion or high doses (1 g or more) may induce diffuse hyperemia (“red man syndrome”) and can be avoided by extending infusions over 1–2 hours, by reducing the dose, or by pretreating with a histamine antagonist such as hydroxyzine.

Bezlotoxumab is a monoclonal antibody approved for use in combination with standard antibacterial therapy (metronidazole, vancomycin, or fidaxomicin) in patients at high risk for C difficile recurrence. Bezlotoxumab binds to and neutralizes toxin B produced by C difficile; bezlotoxumab does not exert antibacterial activity. With a half-life of 19 days, bezlotoxumab is administered as a one-time intravenous infusion. The drug package insert warns against the use of bezlotoxumab in patients with a history of heart failure since these patients were more likely to develop heart failure while receiving bezlotoxumab in clinical studies. Other side effects of bezlotoxumab include nausea, pyrexia, and headache. In clinical studies, lower rates of C difficile recurrent infections were recorded for patients who received bezlotoxumab compared to placebo, when used in combination with either metronidazole, vancomycin, or fidaxomicin.