Comparative Bacteriological Efficacy of Pharmacokinetically Enhanced Amoxicillin-Clavulanate against Streptococcus pneumoniae with Elevated Amoxicillin MICs and Haemophilus influenzae

Abstract

A new pharmacokinetically enhanced formulation of amoxicillin-clavulanate (2,000 mg of amoxicillin/125 mg of clavulanate twice a day; ratio 16:1) has been designed, with sustained-release technology, to allow coverage of bacterial strains with amoxicillin-clavulanic acid MICs of at least 4/2 g/ml. The bacteriological efficacy of amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was compared in a rat model of respiratory tract infection versus four other amoxicillin-clavulanate formulations: 8:1 three times a day (1,000/125 mg), 7:1 three times a day (875/125 mg), 7:1 twice a day (875/125 mg), and 4:1 three times a day (500/125 mg); levofloxacin (500 mg once a day); and azithromycin (1,000 mg on day 1 followed thereafter by 500 mg once a day). Bacterial strains included Streptococcus pneumoniae, with amoxicillin-clavulanic acid MICs of 2/1 (one strain), 4/2, or 8/4 g/ml (three strains each), and Haemophilus influenzae, one ␤-lactamase-positive strain and one ␤-lactamasenegative, ampicillin-resistant strain. Animals were infected by intrabronchial instillation. Antibacterial treatment commenced 24 h postinfection, with doses delivered by computer-controlled intravenous infusion to approximate the concentrations achieved in human plasma following oral administration. Plasma concentrations in the rat corresponded closely with target human concentrations for all antimicrobials tested. Amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was effective against all S. pneumoniae strains tested, including those with amoxicillin-clavulanic acid MICs of up to 8/4 g/ml and against ␤-lactamase-producing and ␤-lactamase-negative ampicillin-resistant H. influenzae. These results demonstrate the bacteriological efficacy of pharmacokinetically enhanced amoxicillin-clavulanate 2,000/125 mg twice a day (ratio 16:1) against S. pneumoniae with amoxicillin-clavulanic acid MICs of at least 4/2 g/ml and support clavulanate 125 mg twice a day as sufficient to protect against ␤-lactamase in this rat model.Antimicrobial agent-resistant strains of the key respiratory tract pathogens are widespread, and their prevalence is increasing in many areas (12,15). For Haemophilus influenzae collected in the Alexander Project in 2001, the prevalence of ␤-lactamase production exceeded 24% in the United States and was more than 10% in 9 of the 16 countries included within the study (27). In the same study, the prevalence of penicillin-resistant Streptococcus pneumoniae in 2001 was approximately 20% in the United States and over 30% in Spain, Japan, France, and Hong Kong. The prevalence of macrolideresistant S. pneumoniae was also high in the United States (28%) and was at least 10% in 12 of the 16 countries included within the study (27). Data from the 1998 to 2000 Alexander Project and other surveillance studies have reported similar findings (15)(16)(17)26).Amoxicillin-clavulanate is a combination of the ␤-lactam antibiotic amoxicillin and the ␤-lactamase inhibitor clavulanic acid in the potassium form. Clavulanic acid protect...

Effects of packaging and storage conditions on the quality of amoxicillin-clavulanic acid – an analysis of Cambodian samples

“…A combination of amoxicillin and clavulanic acid was introduced in the United Kingdom in 1981 as Augmentin and eventually became the treatment of choice for many infections [11,12]. Amoxicillin–clavulanic acid is available in a variety of doses: 250/125 mg (2:1), 500/125 mg (4:1), 875/125 mg (7:1), 1000/125 mg (8:1), and 2000/125 mg (16:1).…”

A Robust Pneumonia Model in Immunocompetent Rodents to Evaluate Antibacterial Efficacy against <i>S. pneumoniae</i>, <i>H. influenzae</i>, <i>K. pneumoniae</i>, <em>P. aeruginosa</em> or <em>A. baumannii</em>

“…The multi-purpose utility of the model is demonstrated in Figures 3 and 4 and Tables 1 and 2. These studies are part of a large collection of published and unpublished data that has been generated with this model to support lead optimization efforts 16,17,[22][23][24] , for comparison and confirmation of proposed human dosing regimens 19,[25][26][27][28][29] and for PK/PD characterization It may be noted in some studies that the bacterial burden at baseline was lower than that typically targeted in other lung infection models. This is due in large part to the required dilution into agar and the small challenge volume, particularly in mice.…”

“…Reductions in bacterial burden are routinely observed for isolates considered susceptible to the agent being tested, while those considered resistant exhibit no change or bacterial growth above baseline 16,17,19,[24][25][26][27][28][29] . Studies in rats evaluating two quinolones and a macrolide using this model 32 have…”

“…Coupling this infection model with a drug delivery system to recreate human pharmacokinetic profiles in rats creates a powerful tool for evaluating human dosing regimens prior to clinical studies. An example of this is summarized in Table 2, which demonstrates that an extended-release formulation of amoxicillin-clavulanate was more effective than existing dose regimens for organisms with elevated MIC values 19 . …”

Cefotaxime and Amoxicillin-Clavulanate Synergism against Extended-Spectrum-β-Lactamase-Producing Escherichia coli in a Murine Model of Urinary Tract Infection

“…Pharmacokinetic (PK) studies were performed on uninfected mice in order to determine the therapeutic regimen of CTX and AMC that best reproduced the same percentage of time of free drug concentrations above the MIC (fTՆMIC) and the same plasmatic peak concentrations of antibiotics as those obtained in humans with standard regimens according to the current practice: i.e., CTX, 1 g every 8 h (q8h), AMC, 1 g q8h; and IMP, 1 g q8h (17)(18)(19)(20)(21)(22)(23).…”