Beta-lactam antibiotics have compiled an excellent safety profile in pediatrics during the past four decades. Both enzymatic degradation and altered transpeptidase binding sites have resulted in resistance to penicillins, cephalosporins, and carbap-enems. However, with structural modifications of the beta-lactam molecule, both of these mechanisms of resistance in Staphylococcus aureus which produce MRSA have been overcome (see Figure 13.6). Ceftobiprole is stable to the current staphy-lococcal beta-lactamases, similar to many cephalosporins. However, unlike any of the currently available beta-lactam antibiotics, ceftobiprole is also capable of binding to the PBP2a transpeptidase to inhibit growth of Staphylococcus aureus. It also
exhibits extended activity against Gram-negative pathogens, closely resembling that of cefepime. It is bactericidal in ways characteristic of beta-lactams, with antibacterial activity based on time-above-MIC pharmacodynamics. It demonstrates a serum elimination half-life of 3.4 hours, protein binding of 38%, and is excreted by the kidney, suggesting a dosing interval of every 12 hours. Thus far, the toxicity profile is similar to other cephalosporins. Should subsequent clinical trials support the development of ceftobiprole for clinical use, the safety profile of cephalosporins for parenteral therapy of serious MRSA infections would be an advantage for children (Issa et al., 2004; Jones et al., 2002; Kosowska et al., 2005; Schmitt-Hoffmann et al., 2004).
The increase in macrolide resistance in pneumococcus, group A streptococcus, and Staphylococcus aureus has lead to discovery efforts to produce a macrolide antibiotic which is not affected by the alterations in the binding site which leads to macrolide-streptogramin B-lincosamide resistance. Substitutions on the 14-member macrolide structure have produced the ketolides (see Figure 13.7). One compound of this class has recently been approved for use in respiratory tract infections in
Figure 13.7. Telithromycin.
Figure 13.7. Telithromycin.
Figure 13.8. Tigecycline.
adults. Telithromycin binds to the ribosome at two sites. Erythromycin binds at a single site in domain V, which can be methylated to prevent macrolide binding. However, a second binding site of telithromycin in domain II allows the antibiotic to persist in binding to the active site, thus preventing protein synthesis. The antibiotic is bactericidal, with pharmacodynamics activity best described by the ratio of the antibiotic AUC (area under the serum antibiotic concentration vs. time curve) to the MIC of the organism. The antibiotic is only available in an oral form, with excellent bioavailability of 57%. Telithromycin is metabolized by the cytochrome P450 system (both CYP 3A4 and non-CYP3A4 isoenzymes), yielding a serum halflife of 9.8 hours. Protein binding is moderate at 65%. The drug is well-tolerated in adults, with diarrhea and nausea occurring in 8-10% of those in prospective clinical trials involving respiratory tract infections including pneumonia and sinusitis. Telithromycin is currently approved for use in adults in certain countries, but data on safety and efficacy in children are lacking (Fogarty et al., 2005; Roos et al., 2005; Shi et al., 2005; Wellington and Noble, 2004).
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