The Treatment of Community-Acquired Methicillin-Resistant Staphylococcus aureus Infections

Jaime Fergie, MD; Kevin Purcell, MD, PharmD, Mha

Disclosures

Pediatr Infect Dis J. 2008;27(1):67-68. 

The rapid emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has required important changes in the empiric choice of antibiotics for infections in which S. aureus is a potential pathogen. Deciding on antibiotic therapy for CA-MRSA infections is complicated by the scarcity of pediatric clinical trials that compare various antibiotics for the treatment of different types of infections. This problem is especially troubling when physicians are faced with the management of life-threatening infections. Which antibiotic or combination of antibiotics will produce a faster resolution of clinical symptoms and/or bacteriological cure? Is there a survival advantage of any given antibiotic or antibiotic combination? Is faster eradication of bacteremia a good surrogate marker of morbidity and mortality? Should antibiotic selection be based on the location of the infection, and which antibiotics should be used when multiple organs are involved?

Another important question is whether newer antibiotics are better than vancomycin for treating severe infections, and does the answer depend on the type of infection? Recently the issue of vancomycin obsolescence was debated in the literature. In point-counterpoint articles, and based on a presentation at the Infectious Diseases Society of America 2006 Annual Meeting in Toronto, Mohr and Murray[1] advocated for the continued role of vancomycin whereas Deresinski[2] presented evidence against the continued use of vancomycin for serious infections. Important information discussed by the authors included the recent change on the breakpoint for vancomycin for S. aureus from ≤4 µg/mL to ≤2 µg/mL on the basis of a high clinical failure rate for vancomycin in patients with organisms with an MIC of 4 µg/mL, a progressive increase in S. aureus MIC over time, and the fact that for methicillin-susceptible S. aureus, vancomycin is inferior to some ß-lactams for the treatment of bacteremia and endocarditis. Also, there seems to be a disconnect between in vitro and in vivo susceptibilities in the treatment of serious infections such as pneumonia and bacteremia. In part, the problem may be because of the presence of S. aureus that display heteroresistance to vancomycin (hVISA). These isolates contain a subpopulation of organisms that exhibit reduced killing with vancomycin in vitro.

Perhaps an even more important reason for the apparent high rate of vancomycin failures in the treatment of severe infections relates to the relative low concentration achieved by vancomycin at the site of infection. For example, vancomycin concentration in lung epithelial lining fluid in adults undergoing mechanical ventilation is only ~18% of that in serum.[3] In this study, the vancomycin concentration achieved in lung epithelial lining fluid was >1 µg/mL for 13 out of 14 patients, and the vancomycin dose was adjusted to obtain serum trough concentrations of about 15-20 µg/mL. These findings are troubling because of the reported increases in S. aureus minimum inhibitory concentration (MIC) and because these trough levels are not the usual target range for children.

Beyond theoretical pharmacokinetic and pharmacodynamic considerations, physicians want to know if clinical trials have demonstrated superiority of alternative antibiotics over vancomycin. Unfortunately, in this critical area there have not been many peer-reviewed publications, and few were pediatric trials. In a pediatric multinational study comparing linezolid to vancomycin in the treatment of nosocomial pneumonia, complicated skin and skin structure infections, or bacteremia of unknown source, the cure rates were similar by age and diagnosis.[4] Linezolid treated patients required significantly fewer days of intravenous therapy and had significantly fewer drug-related adverse events. A smaller neonatal trial compared linezolid to vancomycin and reported similar results with a decrease in drug-related adverse events in the linezolid recipients.[5] A few adult studies have shown differences between the effectiveness of various antibiotics. In a study of bacteremia and endocarditis caused by S. aureus, daptomycin was compared with low dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. Success rates favored daptomycin over vancomycin only among patients who were infected with MRSA, but the difference did not reach statistical significance.[6] A post hoc pooled analysis that combined the results of 2 clinical trials comparing linezolid and vancomycin in patients with healthcare associated pneumonia caused by MRSA showed improved survival for the linezolid treated patients (80% versus 64%; P = 0.022).[7] Also, superiority was demonstrated in a study of linezolid versus vancomycin in the treatment of complicated skin and soft tissue infections (89% versus 67%; P < 0.0001).[8]

As a result of the absence of large pediatric clinical trials, treatment recommendations are based on adult data, pharmacokinetic and pharmacodynamic properties, and clinical experience. For children managed on an outpatient basis for CA-MRSA skin and soft tissue infections, oral trimethoprim-sulfamethoxazole (TMP-SMX) or clindamycin should be considered for empiric therapy. Additionally, if an abscess is present, incision and drainage is the most important intervention and is likely effective without antibiotic therapy. Incision and drainage without adjunctive antibiotic therapy was found to be effective in the management of abscesses with a diameter <5 cm in a study of immunocompetent children.[9] In the same study, having a lesion initially >5 cm was a significant predictor for hospitalization. TMP-SMX may be the preferred drug if the rate of clindamycin resistance, including inducible clindamycin resistance, is more than 15%. However, the potential effectiveness of TMP-SMX is based mainly on in vitro data because very few clinical studies have evaluated the effectiveness of this drug in treating MRSA infections. Also, physicians need to keep in mind that TMP-SMX is not effective against Streptococcus pyogenes. Other oral alternatives include minocycline, doxycycline, ciprofloxacin, and linezolid. Drug selection can be based on age, price, convenience of dosing, taste, and local antibiogram data.

For children hospitalized with nonlife-threatening CA-MRSA infections and without a toxic appearance, intravenous clindamycin can be prescribed and has been shown to be effective. Additionally, incision and drainage should be performed if an abscess is present. For critically ill children hospitalized with severe sepsis, pulmonary infections, or multifocal infections suspected to be caused by S. aureus, we are now frequently using linezolid. This is based on the absence of large pediatric clinical trials and the above mentioned concerns with vancomycin efficacy and adverse drug events. Our policy differs from a recent recommendation to use vancomycin plus nafcillin with or without gentamicin, and to discontinue nafcillin if MRSA is recovered, or vancomycin if methicillin-susceptible S. aureus (MSSA) is recovered.[10] We also have used combination therapy with vancomycin and daptomycin, vancomycin and rifampin, or linezolid and daptomycin.

Although intravenous clindamycin can be used for treating critically ill children with CA-MRSA infections,[11] it may be prudent to administer linezolid, vancomycin, or an alternative drug until antibiotic susceptibility is reported and a negative D-test is documented. Several treatment failures caused by inducible clindamycin resistance have been reported. Also, clindamycin resistance has been increasing in the United States.[12] Other antibiotics that may be prescribed include TMP-SMX, quinupristin-dalfopristin, and tigecycline. TMP-SMX has been used in the management of severe infections, however the clinical trial data are limited. In a study that compared TMP-SMX with vancomycin in 101 intravenous drug users, vancomycin was shown to be superior to TMP-SMX.[13] Newer antibiotics not yet licensed include dalbavancin, telavancin, oritavancin, and ceftobipirole. A detailed review on antibiotic therapy for invasive MRSA infections was recently published by Drew.[14]

Physicians should keep in mind that children with severe CA-MRSA infections need to be managed by a multispecialty team in a pediatric intensive care unit. Multiple and duplicate radiologic studies are often required during the hospitalization as new foci of infection appear and need to be drained.

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