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Antibiotic choices for CA-MRSA infections
Treatment options for community-associated MRSA differ from those of health care-associated MRSA.
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Infectious illness due to community-associated methicillin-resistant Staphylococcus aureus is increasingly being addressed in the medical news media. This month’s Pharmacology Consult column will review the use of antibiotics in the treatment of infection with this pathogen, including their role and selection, in the pediatric population.
Definition of MRSA
By the CDC’s definition, MRSA infection is classified as community-associated in individuals who have not been hospitalized or undergone a medical procedure within the past 12 months. Previously, infection with MRSA typically occurred in hospitalized patients, known as health care-associated MRSA infection. To differentiate these strains, patients with CA-MRSA infection must meet one of the following criteria:
- diagnosis of MRSA was made in the outpatient setting or by culture positive for MRSA within 48 hours after hospital admission;
- no medical history of MRSA infection or colonization;
- no medical history in the past year of hospitalization, admission to a nursing home, skilled nursing facility, or hospice, or surgery;
- no permanent indwelling catheters or medical devices that pass through the skin into the body.
Other differences between HA-MRSA and CA-MRSA exist. Fortunately, CA-MRSA isolates are usually susceptible to more antibiotic agents than HA-MRSA isolates, which tend to be resistant to multiple antibiotics. CA-MRSA isolates are more likely to produce specific virulence factors or exotoxins. An important virulence factor produced by many MRSA strains is Panton-Valentine leukocidin (PVL), a cytotoxin. Infection with a PVL-producing strain can result in serious clinical illness, such as osteomyelitis or hemorrhagic necrotizing pneumonia.
Illness due to CA-MRSA most commonly results in skin and soft tissue infections, such as cellulitis, abscess formation or folliculitis. Patients may initially present to primary care clinicians complaining of “spider bites.” However, CA-MRSA infection may also result in serious or fatal disease. Case reports or series of necrotizing pneumonia, empyema, osteomyelitis or sepsis occurring in adults and children have been published. In 1999, the CDC published case reports of fatal CA-MRSA infection in four infants and children.
Genotype differences
Genotypes of CA-MRSA strains are distinct from HA-MRSA isolates. The mecA gene in staphylococci is responsible for resistance to beta-lactam antibiotics. The mecA gene is transported on a mobile genetic element known as a staphylococcal cassette chromosome (SCC). Five SCCmec complex types have been found for Staphylococcus aureus.
HA-MRSA strains contain primarily SCCmec types I, II and III. These genes are associated with resistance to multiple drug classes, in addition to beta-lactam antibiotics. SCCmec types IV and V encode for resistance to beta-lactam antibiotics and are found primarily in CA-MRSA isolates.
Another important characteristic differentiating CA-MRSA strains from HA-MRSA strains is the production of unique toxins and virulence factors. Analyses have revealed differing genes and toxins isolated from CA-MRSA strains that have not been found in HA-MRSA isolates. A clinically significant virulence factor unique to CA-MRSA strains is the PVL toxin. This cytotoxin damages human leukocytes and can produce severe tissue necrosis. Case reports of previously healthy children and adults affected with CA-MRSA infection and the resulting necrotic clinical manifestations, which have been fatal in some cases, have been published. Although the true prevalence of PVL toxin production in CA-MRSA is not known, some reports indicate that the majority of CA-MRSA isolates are able to secrete this highly potent toxin. The most common CA-MRSA clone circulating in the United States, USA300, carries the genes encoding PVL. However, the USA 300 CA-MRSA clone is being increasing recognized as a nosocomial pathogen and so the molecular characteristics of CA-MRSA and HA-MRSA strains are becoming blurred.
Antibiotic treatment
Due to the genotypic differences described above, CA-MRSA isolates are primarily resistant to beta-lactam antibiotics (penicillins, cephalosporins, carbapenems) and macrolides. Thus, additional treatment options are available to clinicians treating CA-MRSA infection. However, no data from controlled trials are available assessing which antibiotics are most likely to be effective when treating infants and children. Data available come primarily from case reports and retrospective studies. Treatment choice is guided by strain-specific antibiotic susceptibilities, clinical severity, patient allergy status, cost, tolerability and age.
Initiation of antibiotic therapy may not be necessary in all children with skin and soft tissue infections caused by CA-MRSA. Lee and colleagues described an observational study of 62 children (mean age 5.5 years) with culture-proven CA-MRSA skin and soft tissue abscess infection. All children received antibiotics and 96% of children received wound incision and drainage. Initial antibiotic therapy for 62 children, prior to culture results, consisted of an ineffective antibiotic (based upon susceptibility studies). For 37 children, therapy was not changed to an antibiotic to which the pathogen was susceptible, whereas therapy was changed to an appropriate antibiotic for 21 children.
There was no difference in outcome in children who received an appropriate antibiotic compared with children who did not receive an appropriate antibiotic. Of the four children hospitalized on the first follow-up visit, none had received an appropriate antibiotic. A significant predictor of hospitalization was initial lesion size – children with a lesion more than 5 cm were more likely to be admitted. Receipt of an initial antibiotic to which the CA-MRSA isolate was not susceptible was not a significant predictor of hospitalization. Thus, incision and drainage without adjunctive antibiotic treatment was an effective therapy in children with CA-MRSA skin and soft tissue abscess infection when the lesion was five cm or less. Other published studies have also concluded that incision and drainage, without antibiotic therapy, can be employed as successful treatment of skin and soft tissue abscess formation, including CA-MRSA infection.
Oral antibiotic choices most likely to be used by pediatric clinicians include clindamycin, trimethoprim-sulfamethoxazole, doxycycline, minocycline, rifampin and linezolid. Data describing the effectiveness of these agents in children with CA-MRSA infection come primarily from observational studies and case reports. Data are not available from controlled trials, and thus more definitive treatment recommendations and guidelines are not currently available. The 2006 Red Book lists TMP-SMX or clindamycin as antibiotic choices for skin/soft tissue infection or pneumonia, and vancomycin for life-threatening infection.
TMP-SMX, clindamycin, vanco
TMP-SMX is a viable initial antibiotic for CA-MRSA infection, as many, but not all, isolates have been reported to be susceptible to this agent. Documentation of the effectiveness of TMP-SMX comes from case reports and anecdotal recommendations. Sensitivity studies documenting the susceptibility of CA-MRSA to TMP-SMX should be obtained with its use. Because TMP-SMX contains a sulfonamide antibiotic, it should not be used in children with a history of a documented true allergic reaction to previous sulfonamide use. As CA-MRSA infection may also occur in newborns, caution should be used when prescribing TMP-SMX in these patients. As TMP-SMX may displace bilirubin from albumin binding sites, this antibiotic should not be used in newborns with increased bilirubin. Because TMP-SMX does not provide adequate activity toward group A streptococcus, it should not be used if this pathogen is suspected (eg, infection associated with lymphangitis, concomitant streptococcal pharyngitis, erysipelas) or is grown upon culture.
Clindamycin is another antibiotic frequently recommended as an initial therapeutic option. Most CA-MRSA isolates are susceptible to clindamycin. However, it is important that inducible resistance be tested for when using clindamycin. Resistance may develop rapidly with clindamycin use, despite an initial sensitivity report indicating that the MRSA isolate is susceptible. Most, if not all, microbiology laboratories can utilize the disk diffusion method (D-zone test) to test for inducible macrolide-lincosamide-streptogramin B (MLSB) resistance. Clindamycin should not be used if the D-test is positive, which indicates inducible resistance. Clindamycin is a viable option for infants aged younger than 2 months with CA-MRSA infection. Clindamycin is available in liquid formation, although it is not particularly palatable. Parenthetically, many pharmacies are able to flavor liquid medication products with commercially available flavoring systems.
Vancomycin is generally considered the drug of choice for severe CA-MRSA infections. Although MRSA is usually sensitive to vancomycin, strains with intermediate susceptibility, or, more rarely, resistant strains have been reported.
Doxycycline, minocycline, linezolid and rifampin
Doxycycline and minocycline have been reported in a small number of adult case reports to be effective therapy for MRSA infection, including skin and soft tissue infections caused by CA-MRSA. As both of these agents are members of the tetracycline class, they should not be used in children aged younger than 9 years. No data are available for their use in children. Minocycline may rarely cause significant adverse effects.
Linezolid (Zyvox) is a unique antibiotic, a member of the oxazolidinone class. Linezolid provides good in vitro activity toward MRSA, although resistance has been reported. Data on its use and effectiveness in treating CA-MRSA are limited. As linezolid is FDA-labeled for use in newborn infants and older, this agent is an option for very young patients. Linezolid should not be used initially for mild CA-MRSA treatment as it is expensive and is limited by its adverse effect profile, including thrombocytopenia and peripheral neuropathy. Pyridoxine at a dosage of 50 mg daily may modify linezolid-induced thrombocytopenia. Linezolid can be used for serious infection and is equivalent in efficacy to vancomycin for serious MRSA infection. Linezolid is available in an oral liquid formulation and intravenous formulation.
An important theoretical but unproven beneficial effect of linezolid and clindamycin may be the ability of these agents to modify CA-MRSA toxin production. A case report published in 2005 (Micek) described four adults with severe respiratory CA-MRSA infection, in which all the isolates were positive for PVL. Three patients failed therapy with vancomycin but responded to linezolid or clindamycin. As linezolid and clindamycin both function to inhibit protein synthesis, this mechanism may be valuable in modifying exotoxin production.
Rifampin may possess good in vitro activity toward CA-MRSA. Case reports have been published describing the use of rifampin in combination with another antibiotic, such as TMP-SMX, clindamycin, or doxycycline/minocycline. There are no data documenting increased efficacy by adding rifampin compared with single drug therapy. Rifampin should not be used as monotherapy as resistance may develop rapidly. As rifampin is a potent hepatic drug metabolizing enzyme inducer, the potential for drug-drug interactions should be considered when it is employed.
Conclusion
Culture and susceptibility studies should be obtained in all patients with suspected CA-MRSA infection. Incision and drainage is helpful, and it may be sufficient alone without antibiotics in mild cases. In children with mild-moderate illness (eg, febrile, systemic symptoms), it is appropriate to add systemic antibiotic therapy. TMP-SMX, doxycycline/minocycline or clindamycin are reasonable antibiotics to use empirically, prior to susceptibility study results. However, if local or regional CA-MRSA susceptibility data indicate that resistance to clindamycin is greater than 15%, it has been recommended to avoid using clindamycin empirically. Treatment for severe illness should include vancomycin or linezolid. Clindamycin may be used empirically if local resistance patterns are low. Some evidence suggests that therapy with linezolid or clindamycin may be beneficial in PVL-positive CA-MRSA infection. Consideration may be given to adding rifampin or gentamicin to vancomycin for serious illness. When using vancomycin empirically, it is appropriate to initially prescribe nafcillin or oxacillin additionally, as these agents provide more rapid bactericidal action toward methicillin-susceptible Staphylococcus aureus. Nasal application of mupirocin may be beneficial in some patients to prevent recurrence of infection. However, it is likely that recolonization will occur shortly.
For more information:
- Edward A. Bell, PharmD, BCPS, is a Professor of Pharmacy Practice at Drake University College of Pharmacy and a Clinical Specialist at Blank Children’s Hospital, Des Moines, Iowa.
- Lee MC. 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.
- Mieck ST. Pleuropulmonary complications of Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus. Chest. 2005;128:2732-2738.
- Kaplan SL. Community-acquired methicillin-resistant Staphylococcus aureus infections in children. Semin Pediatr Infect Dis. 2006;17:113-119.
- Chen SF. Staphylococcus aureus decolonization. Pediatr Infect Dis J. 2005;24:79-80.