Pediatrics Update: Methicillin-Resistant Staphylococcus aureus: How Best to Treat Now?

Over the past 5 years, methicillin-resistant Staphylococcus aureus (MRSA) isolates have become widespread throughout the United States as well as the world.¹ In some regions, including our own Gulf Coast, MRSA accounts for the majority of S aureus isolates recovered from patients with community-acquired infections.

Currently, most infections caused by community-acquired MRSA (CA-MRSA) are skin and soft tissue infections, but serious, life-threatening infections also may occur. Thus, physicians have to be familiar with the antibiotic susceptibility pattern of S aureus in their own communities to select antibiotics correctly for the initial empiric treatment of community-acquired infections for which S aureus is the suspected pathogen. Unfortunately, it may be difficult to know the proportion of MRSA isolates among community strains unless local health officials, hospital or commercial laboratories, or local investigators specifically determine this rate.

Currently, microbiology laboratories should routinely test S aureus isolates for susceptibility to macrolides, clindamycin, and trimethoprim-sulfamethoxazole (TMP-SMX), in addition to b-lactam antibiotics. Most CA-MRSA isolates are resistant to macrolides but remain susceptible to clindamycin. Clindamycin and TMP-SMX have become very important in the management of staphylococcal infections. In particular, to avoid any delay in selecting the most appropriate agent, isolates should be tested routinely for the inducible macrolide-lincosamide-streptogramin B (MLS_B) phenotype with the "D" test. This requires an additional step and expense for laboratories that use automated antibiotic susceptibility methods.

A positive test only indicates the possibility that a clindamycin-sensitive pathogen may become resistant during treatment. Treatment failures with clindamycin have occasionally been reported for infections caused by MRSA isolates with the inducible MLS_B phenotype.² Thus, clinicians require this information as soon as possible for the optimal treatment of patients with life-threatening staphylococcal infections.

The proportion of community staphylococcal isolates identified as MRSA that needs to be exceeded before empiric treatment is modified has not been formally addressed. Nevertheless, it seems reasonable to consider modifying empiric therapy if more than 10% of community S aureus isolates are MRSA. In New Orleans, where I practice, that rate is now 50%.

EMPIRIC TREATMENT

A b-lactam antibiotic, such as dicloxacillin or cephalexin, had been considered the initial antibiotic of choice for empiric outpatient treatment of skin and soft tissue infections. Similarly, nafcillin, oxacillin, or cefazolin had been the agents of choice for patients hospitalized with serious infections suspected to be caused by S aureus. However, these agents no longer are appropriate for empiric treatment--or for completing treatment--when CA-MRSA is a consideration or is isolated.

What are the alternative agents?

Vancomycin. Certainly, vancomycin is the gold standard for the treatment of MRSA infections and is recommended for inclusion in empiric antibiotic regimens provided to seriously ill patients with infections for which S aureus may be causative. Such patients may be children admitted to the ICU with septic shock, acute infective endocarditis, pneumonia with empyema, or bone and joint infections complicated by septic thrombophlebitis, among others. Some experts recommend adding rifampin, with or without gentamicin, for suspected life-threatening MRSA infections.

Nafcillin or oxacillin (these agents are therapeutic equivalents)is also recommended in this setting to cover optimally for methicillin-susceptible S aureus (MSSA) isolates because these agents are more rapidly bactericidal than vancomycin for these organisms. Clinical data are also available to suggest that nafcillin and oxacillin are superior to vancomycin for patients with serious MSSA infections.³

Clindamycin and TMP-SMX. CA-MRSA isolates typically are susceptible to clindamycin and TMP-SMX, although there are regions in the United States in which a large percentage of isolates are clindamycin-resistant. This is probably relat-ed to the predominant CA-MRSA clone(s) circulating in the community. Before the recent upsurge in CA-MRSA activity, published experience with clindamycin for treating MRSA infections was quite limited for several reasons:

• Many nosocomial S aureus isolates have been and are resistant to clindamycin.

• Clindamycin treatment failures were reported, especially for infective endocarditis.

• Resistance can develop during therapy, related to the inducible MLS_B mechanism of resistance.

However, clindamycin now has been shown to be quite effective in treating serious infections caused by clindamycin-susceptible CA-MRSA isolates, including osteomyelitis, septic arthritis, and pleural empyema.^2,4,5 Clindamycin is initially provided intravenously at a dosage of 30 to 40 mg/kg/d in 3 divided doses. Oral clindamycin is well absorbed, so treatment can be completed at the same dosage used for intravenous administration. However, the oral suspension of clindamycin is not particularly palatable, and some flavoring may be required.

Outcomes of treatment are comparable to those for invasive MSSA infections treated with nafcillin. Adverse effects of clindamycin are well known, especially Clostridium difficile pseudomembranous colitis, which is a relatively rare but serious complication.

SKIN AND SOFT TISSUE INFECTIONS

How best to manage simple skin and soft tissue infections is not really clear, even though these are the sites of more than 90% of the infections caused by CA-MRSA isolates.

b-Lactam antibiotics. Several investigators have reported that b-lactam antibiotics generally are associated with microbiologic and clinical cures of skin and soft tissue infections in otherwise healthy children. This is certainly the case for abscesses that are incised and drained, particularly if the abscess is less than 5 cm in diameter.⁶ It may be that in a normal host, the tissue levels of an anti-staphylococcal b-lactam antibiotic exceed the minimal inhibitory concentration for a short period that, along with normal host defenses, is sufficient to eradicate the organism.

Nevertheless, it is not appropriate to give empiric anti-staphylococcal b-lactam antibiotic treatment routinely for skin and soft tissue infections in regions in which CA-MRSA isolates account for 15% or more of community isolates. In this setting, TMP-SMX or clindamycin can be employed. In my area, TMP-SMX may be considered first-line therapy for skin and soft tissue infections, with the hope that clindamycin use--and, thus, resistance to clindamycin among our CA-MRSA isolates--will be minimized.

There are some problems with this approach. First, informa-tion regarding TMP-SMX treatment of MRSA infections is minimal, although in initial clinical studies, TMP-SMX was effective in treating MSSA infections.^7,8 Some experts suggest adding rifampin to TMP-SMX. TMP-SMX also may result in serious hypersensitivity reactions.

Linezolid. This agent provides an option for treating CA-MRSA infections in children. The first in a new class of antimicrobials called oxazolidinones, linezolid is equivalent to vancomycin for the treatment of serious MRSA infections--including bacteremia and pneumonia in children.⁹ Linezolid has not been studied in osteomyelitis, although there has been some anecdotal experience in adults.

One major advantage of linezolid is that it is very well absorbed following oral administration, and therapy can be completed with the oral formulations. The intravenous and oral dose of linezolid in children is 10 mg/kg every 8 hours for children younger than 11 years and every 12 hours for those 11 years and older. In general, linezolid is well tolerated. As with most antibiotics, diarrhea and rashes are the most common adverse effects. With prolonged use, bone marrow suppression--especially thrombocytopenia--may occur, but this seems to be more common in adults than in children. The oral suspension of linezolid is not palatable to some children, but generally, this is easily overcome by the addition of flavoring that is available in most pharmacies.

Daptomycin. This is the most recent antibiotic to gain approval for the treatment of serious staphylococcal infections in adults.¹⁰ Daptomycin has not been studied in pediatric populations; thus, its dosage and safety profile are unknown in children.

PREVENTING RECURRENCES

Recurrent CA-MRSA infections and CA-MRSA infections among multiple family members are quite common. Preventive measures include simple instructions that are well established, such as keeping fingernails clean and cut short and changing towels, washcloths, underwear, and sleepwear daily. Applying mupirocin to the anterior nares may help diminish nasal colonization by CA-MRSA. A 5- to 7-day course of nasal mupirocin is often inadequate and may not be associated with any decrease in recurrences. Some experts recommend applying mupirocin 3 times a day for a minimum of 1 month.

Finally, taking a bath twice a week for 15 minutes in water to which liquid bleach (eg, Clorox, 2 tsp per gallon of water) has been added appears to help prevent recurrent infections.

References:

REFERENCES:

1. Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant

Staphylococcus aureus

in children with no identified predisposing risk.

JAMA.

1998;279:593-598.
2. Frank AL, Marcinak JF, Mangat PD, et al. Clindamycin treatment of methicillin-resistant

Staphylococcus aureus

infections in children.

Pediatr Infect Dis J.

2002;21:530-534.
3. Gonzalez C, Rubio M, Romero-Vivas J, et al. Bacteremic pneumonia due to

Staphylococcus aureus:

a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms.

Clin Infect Dis.

1999;29:1171-1177.
4. Martinez-Aguilar G, Hammerman WA, Mason EO Jr, Kaplan SL. Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible

Staphylococcus aureus

in children.

Pediatr Infect Dis J.

2003; 22:593-598.
5. Martinez-Aguilar G, Avalos-Mishaan A, Hulten K, et al. Community-acquired, methicillin-resistant and methicillin-susceptible

Staphylococcus aureus

musculoskeletal infections in children.

Pediatr Infect Dis J.

2004;23:701-706.
6. Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant

Staphylococcus aureus. Pediatr Infect Dis J.

2004;23:123-127.
7. Ardati KO, Thirumoorthi MC, Dajani AS. Intravenous trimethoprim-sulfamethoxazole in the treatment of serious infections in children.

J Pediatr.

1979; 95(5 pt 1):801-806.
8. Adra M, Lawrence KR. Trimothoprim/sulfamethoxazole for treatment of severe

Staphylococcus aureus

infections.

Ann Pharmacother.

2004;38:338-341.
9. Kaplan SL, Deville JG, Yogev R, et al. Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.

Pediatr Infect Dis J.

2003;22:677-686.
10. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant Gram-positive pathogens.

Clin Infect Dis.

2004;38:994-1000.