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Pharmacotherapeutic monitoring for MRSA treatment
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Earlier this year, the Infectious Diseases Society of America published evidence-based guidelines for the treatment of infections due to methicillin-resistant Staphylococcus aureus in adults and children.
Summary and detailed documents were separately published. Pharmacotherapeutic treatment options for a wide range of clinical infectious diseases from MRSA are discussed in these guidelines, including skin and soft-tissue; infectious bacteremia; infective endocarditis; pneumonia; bone and joint infections; meningitis and neonatal infections. Specific pediatric considerations, including dosing, are reviewed where appropriate. This month’s column will further discuss antibiotic selection factors and monitoring parameters that can be important considerations when using antibiotics to treat infants and children with MRSA infection.
For ambulatory children with suspected or proven MRSA infection, such as purulent cellulitis, several orally available antibiotics are recommended in these guidelines, including clindamycin, trimethoprim-sulfamethoxazole, doxycycline or minocycline and linezolid (Zyvox, Pharmacia & Upjohn). For complicated skin and soft-tissue infections requiring hospitalization, IV vancomycin is recommended. Optional antibiotics include linezolid and clindamycin (without bacteremia or intravascular infection and when resistance is less than 10%). Children with bacteremia and infective endocarditis may be treated with vancomycin or daptomycin, although few data are available for the pediatric use of daptomycin, nor is it FDA-labeled for this use in children. Vancomycin is recommended for the treatment of pneumonia and joint infections, with clindamycin and linezolid as optional therapeutic choices. Vancomycin is also recommended for children with meningitis from MRSA.
Antibiotic choice and monitoring
Antibiotic choices for the various clinical infections caused by MRSA as recommended in these guidelines are evidence-based. For the majority of the clinical infections reviewed, several antibiotics are offered as optional treatment choices. Antibiotic choice depends upon local antimicrobial resistance patterns, underlying medical conditions, age of the patient, oral dosage form availability, concomitant drug therapy (ie, potential for drug-drug interactions), antibiotic adverse effect profiles and drug cost.
Orally available antibiotic choices for treating infection from MRSA include clindamycin, TMP-SMX, linezolid, and doxycycline or minocycline. Drug characteristics important to consider for these agents include dosage form availability and taste, adverse effect and drug-drug interaction profiles and cost (see Table).
Vancomycin is recommended initially for many of the clinical infections from MRSA discussed in the guidelines. Although non-susceptibility to vancomycin has been reported in some staphylococci, vancomycin continues to maintain good activity against MRSA. Vancomycin is administered intravenously because it is not significantly absorbed when given orally. Recommended IV dosing is 60 mg/kg/day with attainment of trough blood levels of 15 mcg/mL to 20 mcg/mL for serious infection. Although few data are available to support use of these trough levels in children, additional adult data support dosing to these trough levels.
Clindamycin and linezolid may also be given intravenously in specific clinical scenarios. Local resistance patterns to clindamycin should be less than 10% to warrant its use, as recommended in the guidelines. Linezolid displays excellent oral bioavailability, with similar IV and oral dosing. There is no clinical advantage to administering linezolid intravenously vs. orally when gastrointestinal function is normal.
Linezolid is an oxazolidinone antibiotic and is FDA-labeled for use in infants and children. It has good activity toward MRSA and other common gram-positive bacterial pathogens. Potential disadvantages of linezolid include its high cost (as compared with optional orally available agents), its poor taste rating, potential for drug-drug interactions and its adverse effect profile, especially with longer treatment courses.
The most commonly reported adverse effects in children from linezolid use include diarrhea, headache and nausea/vomiting. Thrombocytopenia and anemia have also been reported in pediatric clinical trials. Treatment courses longer than 2 weeks in children increase the risk for these adverse effects. Clinicians should consider monitoring complete blood counts in children receiving linezolid for 2 weeks or longer, or in children with underlying hematologic abnormalities, concomitant therapy with additional drugs having hematologic toxicity, or in children with chronic infection receiving additional antibiotic therapy.
Linezolid use also has been associated with peripheral and optic neuropathy. These adverse effects may not be reversible and the most significant risk factor seems to be length of therapy. Package labeling for linezolid states that visual function should be monitored when linezolid is given for 3 months or longer or when visual symptoms occur, even with shorter treatment courses.
Linezolid is a weak nonselective inhibitor of monoamine oxidase. Monoamine oxidase metabolizes dopamine, epinephrine, serotonin and other biogenic amines. Thus, it has the potential for clinically significant drug-drug interactions with various adrenergic and serotonergic medications, including pressor agents and antidepressants. The potential for serotonin syndrome (autonomic instability, hyperpyrexia, mental status changes, neuromuscular abnormalities) exists. Although case reports of serotonin syndrome from concomitant use of linezolid and various antidepressants have been reported, authors of a retrospective chart review of hospitalized adult patients (n=72) during a 4-year period concluded that serotonin syndrome uncommonly occurs when linezolid is used together with selective serotonin reuptake inhibitors (SSRI) antidepressants, and that these agents can be given concomitantly with careful monitoring.
Conclusions
Pharmacotherapy evidence-based recommendations for infection with MRSA in children were published recently. Vancomycin is a mainstay of therapy for serious clinical infections. Several oral agents are additionally available for use in children. Their choice and use depends upon evidence from clinical trials, local resistance patterns, patient age, cost and taste of oral dosage forms.
Clindamycin and TMP-SMX are acceptable options for some children; they are inexpensive, although taste may limit use of their oral liquid dosage forms in younger children. Linezolid, a unique and relatively new antibiotic, has good activity toward MRSA and is also available as an oral liquid dosage form. However, its high cost, potential for poor acceptance of the oral liquid and adverse effects may limit its use.
For more information:
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- Antimicrob Agents Chemother. 2002;46:2723-2726.
- Liu C. Clin Infect Dis. 2011;52:285-292.
- Liu C. Clin Infect Dis. 2011;52:e18-e55.
- Meissner HC. Pediatr Infect Dis J. 2003;22(9 Suppl):S186-S192.
- Ryback M. Am J Health Syst Pharm. 2009;66:62-98. Steele RW.
- Clin Pediatr. 2006;45:245-250. Taylor JJ.
- Clin Infect Dis. 2006;43:180-187.
Edward A. Bell, PharmD, BCPS, is Professor of Clinical Sciences at Drake University College of Pharmacy and Blank Children’s Hospital and Clinics in Des Moines, Iowa, and a member of the Infectious Diseases in Children Editorial Board.
Disclosure: Bell reports no relevant financial disclosures.