Pulmonary Damage and Bacterial Load in Assessment of the Efficacy of Simulated Human Treatment-Like Amoxicillin (2,000 Milligrams) Therapy of Experimental Pneumococcal Pneumonia Caused by Strains for Which Amoxicillin MICs Differ

Abstract

An experimental rat pneumonia model using two amoxicillin-susceptible (MICs, <0.015 and 2 g/ml) and two non-amoxicillin-susceptible (MIC, 4 g/ml) Streptococcus pneumoniae strains was developed for testing the efficacy of amoxicillin administered to simulate human serum kinetics after treatment with amoxicillinclavulanate (2,000 and 125 mg, respectively, twice a day, for 2.5 days). The end points for efficacy were reductions in bacterial loads in the lungs and reductions in levels of pulmonary damage. For the amoxicillinsusceptible strains (serotypes 23F and 14), a decrease greater than 4.5 log 10 CFU/pair of lungs was obtained, and the time for which the serum antibiotic concentration (SAC) was higher than the MIC (T SAC>MIC ) was greater than 60% of the dosing interval. Acute pneumonia is the most frequent cause of death from infectious diseases in developed countries (16). Streptococcus pneumoniae is the leading cause of community-acquired pneumonia (2). Despite the availability of potent antimicrobial agents, pneumococcal pneumonia has a very high mortality, reaching 38% in some areas (3,19). In addition, the appearance of pneumococcal strains with decreased susceptibility to ␤-lactams and other antibiotics has caused concern because in some areas as many as 35% of pneumococcal pneumonias are caused by non-penicillin-susceptible organisms (3). In spite of this, ␤-lactams are widely and successfully used for respiratory tract infections caused by S. pneumoniae strains, even nonpenicillin-susceptible strains. However, there has been little experience with the treatment of pneumococcal pneumonia caused by strains for which amoxicillin MICs are higher than 2 g/ml, because the probability of pathogens with such a reduced susceptibility profile is too low (11) and this warrants the use of animal models for testing efficacy. To cover pneumococcal strains for which amoxicillin MICs are 4 g/ml for approximately 50% of the dosing interval with a twice-a-day (b.i.d.) regimen, a new sustained-release amoxicillin-clavulanate formulation has been developed (12). This antibiotic treatment has shown clinical efficacy in community-acquired pneumonia (8,11,22), but there was a small number of patients infected with pneumococci for which amoxicillin MICs were high.The aim of this study was to compare the efficacies of amoxicillin in an experimental model of pneumonias caused by four pneumococcal strains with different amoxicillin susceptibilities. The antibiotic was administered so as to attain an amoxicillin pharmacokinetic profile similar to that obtained in humans after administration of the new sustained-release amoxicillinclavulanic acid formulation of 2,000 and 125 mg, respectively, b.i.d. A secondary aim was to evaluate the effect of the time from inoculation to treatment initiation on antibiotic efficacy. MATERIALS AND METHODSBacteria. Four strains of S. pneumoniae with different in vitro susceptibilities to amoxicillin were selected based on their similar virulence in experimental animals. Strain AR30118 (serotype 23F)...

Delay in antibiotic therapy results in fatal disease outcome in murine pneumococcal pneumonia

“…In severe pneumonia, only early antibiotic therapy, administered prior to barrier breakdown, prevented systemic inflammation, development of pleuritis, steatitis and elevated AST levels, which was followed up by restoration of fitness and rescue of mice from fatal outcome. Gracia et al [ 41 ] have shown in S. pneumoniae -infected rats that early and late antibiotic regimens similarly eliminated bacterial burdens whereas only early therapy helped to prevent lung damage. However, the authors started early therapy just 1 h p.i., an important difference to our protocol whereby infected mice already developed pneumonia prior to antibiotic treatment.…”

Gaps in antibiotic development: the postmarketing task

“…In the postmarketing phase, animal models have been used to study pharmacodynamic prediction of efficacy in systemic infections caused by strains with decreased susceptibility using humanized models [34], the relationship of pharmacodynamic parameter values with tissue injury [35], the effects of treatment delay on pharmacodynamics [35], the significance of local (as middle ear fluid) vs. serum pharmacodynamic parameters in local infections (otitis media) [36], pharmacodynamics in mixed local infections (S. pneumoniae þ H. influenzae) [37], the effect of the disease (acute otitis media vs. otitis media with effusion) on pharmacodynamics in middle ear fluid [38], or the effect of concomitant medications as analgesics on the relationship between pharmacodynamic parameters and eradication [39,40].…”