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‘Time above MIC’ is the PD index that correlates with therapeutic efficacy of -lactams.
Animal models of infection with S. pneumoniae, using mortality as the endpoint, have demonstrated the relationship between ‘Time above MIC’, bacterial eradication and treatment outcome. When ‘Time above MIC’ is low, with serum antibacterials remaining above MIC for &lt; 25% of the dosing interval, mortality is high. However with a ‘Time above MIC’ of &gt; 40% for penicillins (&gt; 50% for cephalosporins) the rate of survival increases to almost 100%.1
Clinical evidence from studies in otitis media and sinusitis show a clear correlation between ‘Time above MIC’ and bacterial eradication of S. pneumoniae or H. influenzae.2 Bacteriological cure rates of 85–100% were obtained when serum concentrations of the antibacterial were above the MIC for approximately 40% or more of the dosing interval.
1. Craig et al. Diag Microbiol Infect Dis 1996; 25:213–217
2. Craig & Andes Pediatr Infect Dis J 1996; 15:255–259
Peak:MIC ratio and AUC:MIC ratio are the best predictors of antibacterial efficacy for concentration-dependent antibacterials such as fluoroquinolones.
Most studies have shown slightly better correlations with the AUC:MIC ratio than with the Peak:MIC ratio. Peak:MIC ratios may be more important in infections where there is a significant risk of the emergence of resistant subpopulations.1
AUC:MIC ratios &lt; 30 were associated with &gt; 50% mortality in animal infection models, whereas AUC:MIC values &gt; 100 were associated with almost no mortality. Thus, it appears that fluoroquinolone serum concentrations need to average approximately four times the MIC to produce virtually 100% survival in experimental animal infections.1
A similar relationship has been observed in clinical trials. An AUC:MIC value &gt; 125 was associated with satisfactory outcome for seriously ill patients treated with intravenous ciprofloxacin. Lower AUC:MIC values resulted in bacteriological and clinical cure rates &lt; 50%.2
Similarly, a recent clinical trial with levofloxacin demonstrated that a Peak:MIC ratio of &gt; 12 or AUC:MIC ~100 were predictive of a successful outcome. A Peak:MIC ratio of 8–10 has been demonstrated to prevent the emergence of resistant mutants during fluoroquinolone therapy both in vitro and in vivo.1
1. Craig et al. Clin Infect Dis 1998; 26:1–12
2. Forrest et al. Antimicrob Agents Chemother 1993; 37:1073–1081
The overall goal of antibacterial therapy is to ensure clinical cure, thus reducing morbidity, mortality, resource utilization and costs.
In order to prevent clinical failure, recurrence or relapse of infection and the selection of resistance it is essential that the primary goal of antibacterial therapy should be bacterial eradication or maximal reduction of bacterial load.
If bacterial eradication is to be ensured it is essential that PD indices are utilized in order to select appropriate antibacterial therapy.
Therefore, appropriate antibacterial therapy chosen using PD indices will result in bacterial eradication and, hence, clinical cure.
There is a strong correlation between early eradication of pathogens from middle ear fluid during antibacterial treatment of AOM and improved clinical outcome.1
In Dagan’s study, the study group consisted of 123 patients, of whom 57 (46%) had positive middle ear fluid 72 to 96 hours after initiation of antibacterial treatment with either azithromycin (10 mg/kg/day od x 3 days), cefaclor (40 mg/kg/day tid x 10 days) or amoxicillin (50 mg/kg/day tid x 10 days). Clinical failure was observed in 21/57 (37%) patients in whom bacteriological eradication did not occur vs. only 2/66 (3%) patients with bacteriological eradication after 3 to 4 days of treatment (P &lt; 0.001).
Clinical failures in the study population were associated with inability of the antibacterial therapy to eradicate the causative organisms of AOM from the middle ear fluid within 3–4 days after initiation of therapy.
Most patients (including those without bacteriological eradication) improved after 3–4 days of treatment. However, patients with sterile middle ear fluid (i.e. those in whom bacteriological eradication had been achieved) felt better after 3–4 days of treatment compared with patients in whom bacteriological eradication had failed.
1. Dagan et al. Pediatr Infect Dis J 1998; 17:776–782