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Sulfa antibiotics for treatment of MRSA
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With recent increases in skin and soft-tissue infections due to community-associated methicillin-resistant Staphylococcus aureus, clinicians are more commonly faced with decisions over choices for antibiotic therapy.
Six orally available antibiotics as outpatient treatment options are available to pediatric clinicians, each with unique advantages and disadvantages. The optimal antibiotic choice among these treatment options has not been determined. This month’s column will focus on one of these antibiotics, trimethoprim-sulfamethoxazole, including efficacy and adverse effects (severe skin adverse reactions).
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Reports of community skin and soft-tissue infections (SSTIs) have demonstrated increased incidence rates of CA-MRSA as the cause of illness in recent years, with several reports from large metropolitan areas documenting CA-MRSA responsible for more than 50% of community SSTIs. Infection caused by CA-MRSA differs from infection caused by health care-associated MRSA by several characteristics: individuals with illness from CA-MRSA typically present with fewer risk factors for infection, CA-MRSA displays less resistance to antibiotics, and infections caused by CA-MRSA are typically less invasive and more commonly involve the skin and soft tissues.
TMP-SMX well tolerated
Sulfa antibiotics (ie, TMP-SMX) represent a class of orally available antibiotics frequently chosen by clinicians as a treatment option for SSTIs from CA-MRSA. Advantages of TMP-SMX include low cost, availability of liquid (with generally acceptable taste) and tablet dosage forms, and twice daily dosing. Although TMP-SMX has the potential for several potentially severe adverse effects, including hematologic suppression and drug rashes, these adverse effects uncommonly occur.
TMP-SMX is generally well tolerated by children, although it may cause nausea or vomiting. TMP-SMX compares favorably to other orally available antibiotics for treatment of CA-MRSA: TMP-SMX can be used in children aged younger than 9 years (as opposed to the tetracyclines doxycycline and minocycline); TMP-SMX liquid is more taste-tolerable than clindamycin; TMP-SMX is much less expensive than linezolid; and TMP-SMX can be used as single therapy (as compared with rifampin). These advantages allow TMP-SMX to be considered a useful treatment option.
Role of cultures
The role of antibiotics in the treatment of CA-MRSA SSTIs has not been clearly delineated and can be controversial. Recently published guidelines from the CDC for treatment of CA-MRSA infection state that incision and drainage (I/D) for purulent lesions alone may be sufficient therapy for previously healthy individuals without signs of systemic infection. Some published data indicate that I/D therapy alone can be clinically effective, especially when abscess size is smaller (< 5 cm). Cultures of purulent material can provide useful information to help guide antibiotic choice. However, cultures may not be commonly obtained because of practical reasons. Cultures may be especially useful for those with clinically severe local infections or when infection is suspected to be associated with a cluster or outbreak of infections.
In an interesting study recently published, Elliot and colleagues compared the clinical effectiveness of single-agent therapy with a beta-lactam antibiotic, clindamycin or TMP-SMX in the treatment of non-drained, non-cultured SSTIs in ambulatory children living in a MRSA-endemic region. Treatment failure was the primary outcome measure in this retrospective, case-control study. Of 2,096 children with non-drained, non-cultured SSTIs, 104 experienced treatment failure and were matched to 480 control participants.
Treatment with clindamycin was found to be equally effective as use of a beta-lactam antibiotic, and TMP-SMX was associated with an increased risk of treatment failure (OR=2.35). The presence of induration or abscess was additionally identified as a risk factor for treatment failure. Assessment of these data by the study authors includes the potential for bacterial pathogens other than CA-MRSA to be a cause of infection in these children, including group A streptococci (Streptococcus pyogenes). TMP-SMX is not active toward group A streptococci.
Limited data available
Clinical data from controlled trials supporting the efficacy of TMP-SMX for treatment of children with infection from CA-MRSA are very limited. Recommendations for consideration of use of TMP-SMX largely include microbiological data from multiple studies demonstrating good activity of TMP-SMX toward many strains of MRSA, including CA-MRSA.
A potential adverse effect of TMP-SMX use, which may cause some prescribers to shy away from its use, includes severe skin reactions, notably Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), two similar mucocutaneous disorders. Some experts have suggested that these severe adverse effects may become more prevalent with increasing rates of TMP-SMX use for treatment of CA-MRSA. No data, however, yet support this contention.
Fortunately, SJS and TEN rarely occur — incidence rates have been estimated to be 0.4 to six per million person-years. Medications are responsible for most cases of SJS and TEN (50% and 80%, respectively), and mortality rates are significant (< 5% and 30%, respectively). Some data indicate that mortality rates .might be lower for children vs. adults. More than 100 medications have been implicated as causes of SJS and TEN, with TMP-SMX identified as a leading cause (one to three cases per 100,000 users).
Additional data on SJS and TEN occurrences in children have recently been published. Levi and colleagues assessed the relationship of medication use to risk for SJS and TEN in children aged younger than 15 years hospitalized for SJS or TEN, using data from two multicenter, international, case-control studies. Eighty children with SJS or TEN were identified as cases and were compared with 216 matched controls. Sulfonamides, phenobarbital, carbamazepine and lamotrigine were strongly associated with SJS and TEN, and they were identified as independent risk factors.
Finkelstein and colleagues evaluated all children admitted to two institutions for SJS or TEN during an 8-year period (n=55). Medications (antiepileptics, followed by sulfonamide antibiotics) were deemed to be responsible for most cases (53%). Infection with mycoplasma and herpes virus was additionally identified as a common cause. Interesting data from this study include identification of 10 children (18%) who had recurrence of SJS up to 7 years after the index case, and 26 children (47%) who suffered long-term sequelae, mostly involving the skin and eyes.
Conclusions
Few data are available to document the optimal oral antibiotic treatment choice for CA-MRSA SSTI in ambulatory children. TMP-SMX offers several advantages over other orally available antibiotics. Although TMP-SMX provides good microbiological activity toward CA-MRSA, it is not active toward group A streptococci, which can also cause SSTI and illness. Incision and drainage alone may be sufficient therapy for some children, although this has not been well defined. TMP-SMX has the potential to result in severe adverse skin reactions, although such reactions rarely occur.
References:
- Daum RS. N Engl J Med. 2007;357:380-390.
- Elliott DJ. Pediatrics. 2009;123:e959-e966.
- Finkelstein Y. Pediatrics. 2011;128:723-728.
- Gorwitz RJ. Strategies for clinical management of MRSA in the community: summary of an experts’ meeting convened by the Centers for Disease Control and Prevention. 2006. Available at www.cdc.gov/ncidod/dhqp/ar_mrsa_ca.html.
- Levi N. Pediatrics. 2009;123:e297-e304.
- Odell CA. Curr Opin Pediatr. 2010;22:273-277.
- Roujeau JC. N Engl J Med. 1994;331:1272-1285.
Edward A. Bell, PharmD, BCPS, is professor of clinical sciences at Drake University College of Pharmacy, Blank Children’s Hospital, in Des Moines, Iowa. He is also a member of the Infectious Diseases in Children Editorial Board. Disclosure: Dr. Bell reports no relevant financial disclosures.