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10 Craig50Cephalosporins40T>MIC (%)3020100PenicillinsCarbapenems0.008 0.03 0.12 0.5 2 8MIC (mg/L)FIGURE 6 Relationshipbetween time above MICrequired for a bacteriostaticeffect and in vitro MIC forcephalosporins, penicillins,and carbapenems againstpenicillin-susceptible, -intermediate,and -resistantstrains of Streptococcuspneumoniae. Abbreviation:MIC, minimum inhibitoryconcentration. Source: FromRefs. 24, 38, 39, 41.spectrum b-lacatamases (39,47). Mutations primarily in parC and gyrA haveelevated the in vitro MICs of different fluoroquinolones with S. pneumoniae, but the24-hour AUC/MIC ratio for a bacteriostatic effect has remained very constant (48).In general, the magnitude of the PK/PD indice required for efficacy issimilar for different sites of infection. The one exception can be pneumonia wherepenetration into epithelial lining fluid (ELF) is the major determinant of efficacy.For example, vancomycin, which has decreased penetration into ELF, was aboutthreefold less potent in a lung infection model compared to a thigh infection in thesame neutropenic mice (49). Drugs like the macrolides, which have increasedpenetration into ELF have shown enhanced efficacy in pneumonia models inanimals (50).Human InfectionsBacteriological cure in patients with acute otitis media and acute maxillarysinusitis provides a sensitive model for determining the relationship betweenoutcome and time above MIC for multiple b-lactam antibiotics. A variety ofclinical trials have included pretherapy and repeat sinus puncture or tympanocentesisof middle ear fluid after two to seven days of therapy to determine whetherthe initial organism isolated had been eradicated (51–53). Figure 7demonstratesthe relationship between time above MIC and bacteriological cure rate for manyb-lactams against S. pneumoniae and Haemophilus influenzae in patients with thesetwo infections.Several of the recent studies have included penicillin-intermediate andpenicillin-resistant strains. In general, percentages for time above MIC greater than40% were required to achieve an 85% to 100% bacteriological cure rate for bothorganisms including resistant pneumococci.Commonly used parenteral doses of ceftriaxone, cefotaxime, penicillin G,and ampicillin provide free drug concentrations above the MIC 90 for penicillinintermediatestrains of S. pneumoniae for at least 40% to 50% of the dosing interval.A variety of clinical trials in severe pneumococcal pneumonia including bacteremiccases have demonstrated that these b-lactams are as effective against these