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Two physicians discuss how to deal with the growth of antibiotic resistance in the pediatric population
Resistance to traditional antibiotics, a growing problem for hospitalized children, was the focus of a program during the American Academy of Pediatrics annual meeting, held in New Orleans recently. Sheldon L. Kaplan, M.D., of Baylor College of Medicine and Texas Children's Hospital, and Christopher J. Harrison, M.D., of the department of pediatrics at the University of Louisville, provided compelling statistics demonstrating the proliferation of resistant organisms, described mechanisms accounting for this increasingly perplexing phenomenon, and discussed guidelines for the appropriate use of currently available antibiotics.
The first issue discussed was the development of community-acquired methicillin-resistant Staphylococcus aureus (MRSA). Kaplan noted that MRSA strains were detected soon after the introduction of methicillin, but the infections were nosocomial, not a widespread community problem. Now the incidence of community-acquired MRSA is dramatically increasing throughout the world. Because these community-acquired pathogens are genotypically distinct from MRSA strains causing nosocomial infection, epidemiologists have been studying them carefully, and, as of yet, no specific risk factors for developing community-acquired MRSA infections have been detected.
The types of infections associated with community-acquired MRSA are predominantly skin and soft tissue (80%-90%), although the incidence of pneumonia and empyema is increasing, noted Kaplan. Recurrent skin infections are common, infection in more than one family member frequently occurs, and outbreaks among students in contact sports are also common.
Fortunately, community-acquired MRSA isolates are more likely than nosocomial MRSA to be susceptible to clindamycin or trimethoprim/ sulfamethoxazole. Careful susceptibility testing is necessary, however, because different types of resistance are possible. Some strains have developed an efflux pump that pushes erythromycin out of the cell; these remain clindamycin-sensitive. Other strains have developed genetic alterations that make them resistant to both erythromycin and clindamycin, and still others have genetic changes that make them resistant to erythromycin, but become resistant to clindamycin only after exposure to the drug.
Minor skin infections caused by MRSA can usually be treated with beta-lactam antibiotics, said Kaplan, but if conventional antibiotics are ineffective, cultures should be done and switching to clindamycin or trimethoprim/sulfamethoxazole should be considered. For serious infections in areas where 10% or more of MRSA isolates are community-acquired, vancomycin or clindamycin should be used for initial empiric therapy. Kaplan emphasized that vancomycin should be reserved for very serious infections since vancomycin-resistant S. aureus has recently been reported.
One promising new class of drugs is oxazolidinones, represented by the drug linezolid (Zyvox, Pfizer), but some strains of vancomycin-resistant Enterococcus (VRE) and MRSA isolates have already shown resistance to the drug. Linezolid binds to ribosomes within the bacterial cell and prevents protein synthesis. Other drugs also bind to ribosomes, but at different sites.
The pharmacokinetics of linezolid have been studied in children, and the drug is well absorbed with almost 100% bioavailability. The spectrum of activity is equivalent to vancomycin, and side effects are also similar, although the incidence of thrombocytopenia is greater with linezolid. Linezolid is targeted for hospital use and is being prescribed cautiously for serious infections or for children who cannot tolerate vancomycin.
A combination product is Synercid (King Pharmaceuticals), two streptogramin antibiotics (quinupristin and dalfopristin) that provide synergistic inhibition of bacterial protein synthesis. Unfortunately, safety and efficacy studies have not been conducted in children.
The second issue discussed was treatment of pneumonia or bacteremia caused by Streptococcus pneumoniae, both conditions being problematic because of the development of penicillin resistance and increasingly associated with resistance to other antibiotics. No official guidelines for treating pneumonia or bacteremia due to penicillin-resistant S. pneumoniae have been published, but Kaplan recommended trying penicillin for outpatients if susceptibility testing indicates that the minimum inhibitory concentration (MIC) of penicillin is less than or equal to 2 mcg/ml. Vancomycin or clindamycin is logical when no response is seen.
Harrison then shifted gears to discuss the current controversy over appropriate therapy for acute otitis media. He noted that the same data are cited by both proponents and opponents of the use of antibiotics. Proponents of antibiotic use note that pain relief occurs earlier and the infection subsides sooner. Opponents note that analgesics can be used if needed and that otitis media is not a life-threatening problem that requires the swiftest possible resolution. He also remarked that most cases of recurrent otitis media are actually new infections, in other words, children with recurrences have a "plumbing" problem and the host fails, not the antibiotic.
Quinolones are frequently used for the treatment of otitis media, and there is grave concern about overutilization, said Harrison. Resistance to these drugs is growing very quickly and, in the pediatric setting, is expected to triple every year.
Two quinolones are approved for the treatment of pneumonia, gatifloxacin (Tequin, Bristol-Myers Squibb) and levofloxacin (Levaquin, Ortho McNeil). Studies in difficult-to-treat otitis media are being done and preliminary results indicate that they are as effective as amoxicillin/ clavulanate potassium (Augmentin ES-600, GlaxoSmithKline) and are predicted to be as effective as three-dose ceftriaxone, said Harrison. Healthcare professionals should be aware that, although no major adverse effects on hip cartilage have been reported, transient arthralgias and an increased risk for a ruptured Achilles tendon have been seen, mostly in older children.
The current list of drugs used for acute otitis media include amoxicillin; for children allergic to penicillins, cefdinir (Omnicef, Abbott), which is one of the few cephalosporins small children will take because most taste so bad; and for those allergic to cephalosporins, azithromycin (Zithromax, Pfizer) plus trimethoprim/sulfamethoxazole. Harrison noted that azithromycin could not cure bacteremia because it stays in the vascular compartment for only 12 minutes. Moreover, it is excreted very slowly and remains in the body for two weeks at subtherapeutic levels, selecting for drug-resistant bacteria.
For children who've had antibiotic therapy within the prior month, amoxicillin/clavulanate potassium is recommended; for those allergic to penicillin, ceftriaxone; and for those allergic to cephalosporins, clindamycin plus trimethoprim/sulfamethoxazole, or ceftibuten (Cedax, Schering).
Both Kaplan and Harrison closed by emphasizing the need for judicious use of antibiotics and careful community surveillance for resistant bacterial strains.
KT Porter. Why antibiotic resistance is growing in pediatric inpatients.
Dec. 8, 2003;147:HSE6.