This study was designed to demonstrate the efficacy and safety of pharmacokinetically enhanced amoxicillin/clavulanic acid 2000 mg/125 mg extended release formulation (ER), than conventional formulations against community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae, with reduced susceptibility to amoxicillin. This is an open labelled, multicentric, prospective, interventional study carried out across India from June 2008 to March 2009. The study included adult patients (>18 years), weighing between 40 to 60 kg with radiologically confirmed community-acquired pneumonia (CAP). Primary efficacy parameters were clinical response (fever, cough severity, sputum characteristics and improvement in dyspnoea grades) and laboratory parameters. Secondary efficacy parameters were radiological and bacteriological findings at the end of therapy. A total, 727 clinically and radiologically confirmed community-acquired pneumonia patients were enrolled in this study. Eighteen patients were lost to follow-up during study and 709 completed the study as per the study protocol. There was a significant improvement in clinical as well as laboratory parameters at the end of therapy. There was a significant improvement in fever, cough severity, sputum characteristic and dyspnoea grades from 101.88 +/- 1.55, 2.18 +/- 0.76, 1.75 +/- 0.77 and 1.91 +/- 1.23 to 98.14 +/- 0.87 (p < 0.0001), 0.24 +/- 0.45 (p < 0.0001), 0.14 +/- 0.39 (p < 0.0001) and 0.20 +/- 0.47 (p < 0.0001) respectively. Laboratory parameters such as total WBC count and neutrophil percentage decreased significantly from 15317 +/- 662 and 80 +/- 9 to 9067 +/- 558 (p < 0.0001) and 67 +/- 9 (p < 0.0001) respectively at the end of treatment. Bacteriological success and radiological success for amoxicillin-clavulanate 1,000/62.5 mg at the end of treatment was 94.33% (150 of 159) and 98.7% (700 of 709) respectively. Mild to moderate diarrhoea was reported in 61/709 patients (8.6%). Amoxicillin-clavulanate 1,000/62.5 mg given twice daily for ten days was shown to be clinically effective and safe in the treatment of community-acquired pneumonia in adult patients. Therapy was well tolerated. [J Indian Med Assoc 2011; 109: 124-7]

Rising levels of resistance amongst the major respiratory pathogens have compromised empiric antimicrobial therapy. This, coupled with a recent lack in availability of novel classes of antibacterials, has led to a need for new approaches to combat community respiratory tract infections. Bacteriological and clinical efficacy in two trials involving patients with acute bacterial sinusitis and six trials of patients with community-acquired pneumonia has shown that the development of a pharmacokinetically enhanced formulation of amoxicillin/clavulanate (Augmentin SR, available as Augmentin XR in the USA) has allowed amoxicillin/clavulanate to retain its place in the treatment of respiratory tract infections today.

Amoxicillin/clavulanate has recently undergone formulation changes (XR and ES-600) that represent 14:1 and 16:1 ratios of amoxicillin/clavulanate. These ratios greatly differ from the 2:1 ratio used in initial formulations and in vitro susceptibility testing. The objective of this study was to determine if the reference method using a 2:1 ratio accurately reflects the susceptibility to the various clinically used amoxicillin/clavulanate formulations and their respective serum concentration ratios. A collection of 330 Haemophilus influenzae strains (300 beta-lactamase-positive and 30 beta-lactamase-negative) and 40 Moraxella catarrhalis strains (30 beta-lactamase-positive and 10 beta-lactamase-negative) were tested by the broth microdilution method against eight amoxicillin/clavulanate combinations (4:1, 5:1, 7:1, 9:1, 14:1, and 16:1 ratios; 0.5 and 2 microg/mL fixed clavulanate concentrations) and the minimum inhibitory concentration (MIC) results were compared with those obtained with the reference 2:1 ratio testing. For the beta-lactamase-negative strains of both genera, there was no demonstrable change in the MIC values obtained for all ratios analyzed (2:1 to 16:1). For the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, at ratios >or=4:1 there was a shift in the central tendency of the MIC scatterplot compared with the results of testing 2:1 ratio. As a result, there was a 2-fold dilution increase in the MIC(50) and MIC(90) values, most evident for H. influenzae and BRO-1-producing M. catarrhalis strains. For beta-lactamase-positive strains of H. influenzae, the shift resulted in a change in the interpretive result for 3 isolates (1.0%) from susceptible using the reference method (2:1 ratio) to resistant (8/4 microg/mL; very major error) at the 16:1 ratio. In addition, the number of isolates with MIC values at or 1 dilution lower than the breakpoint (4/2 microg/mL) increased from 5% at 2:1 ratio to 32-33% for ratios 14:1 and 16:1. Our results indicate that, for the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, the results of the amoxicillin/clavulanate reference 2:1 ratio testing do not accurately represent all the currently licensed formulations. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment might be compromised when higher amoxicillin/clavulanate ratios are used clinically. With a better understanding of PK/PD parameters, reevaluation of the amoxicillin/clavulanate in vitro susceptibility testing should be considered by the standardizing authorities to reflect the licensed formulations and accurately predict clinical outcomes.

Amoxicillin/clavulanic acid 2000 mg/125 mg extended release (Augmentin XR), referred to herein as amoxicillin/clavulanic acid XR, is a pharmacokinetically enhanced formulation designed to provide more effective therapy in adults and adolescents than conventional formulations against community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae, with reduced susceptibility to amoxicillin.Amoxicillin/clavulanic acid XR maintains plasma amoxicillin concentrations >4 microg/mL for a mean of 49% of the dosing interval indicating that it would be highly effective against S. pneumoniae strains with minimum inhibitory concentrations (MICs) above the National Committee for Clinical Laboratory Standard's amoxicillin +/- clavulanic acid susceptibility breakpoint of < or = 2 microg/mL. Amoxicillin/clavulanic acid XR is at least as effective as conventional amoxicillin/clavulanic acid formulations, levofloxacin, and clarithromycin in treating community-acquired pneumonia, acute bacterial sinusitis, or acute exacerbations of chronic bronchitis, and has a tolerability profile comparable to that of conventional amoxicillin/clavulanic acid formulations. While the incidence of amoxicillin- or multidrug-resistant S. pneumoniae is not currently sufficient in most regions to warrant the routine empiric use of amoxicillin/clavulanic acid XR, the drug would be extremely useful in those regions with a high incidence of resistant pathogens or in selected patients (i.e. those with S. pneumoniae isolates having amoxicillin MICs > or = 2 microg/mL but < or = 4 microg/mL).

A contemporary (2002-2003) national collection of 2100 strains of Streptococcus pneumoniae obtained from 30 sites in the nine United States (US) census regions were tested to determine the comparative antimicrobial properties of amoxicillin/clavulanate and 15 other antimicrobials. The rank order of antimicrobials with the lowest susceptibility rates was: penicillin (67.9%)<trimethoprim/sulphamethoxazole (69.5%)<macrolides (<or=73.3%)<orally administered cephalosporins (<or=78.8%). Bloodstream infection isolates were more susceptible than strains isolated from community-acquired respiratory tract infections; penicillin (11.0% difference), erythromycin (9.8%) and trimethoprim/sulphamethoxazole (6.5%). The resistance rates of nearly all tested antimicrobials increased with increasing penicillin resistance: levofloxacin (98.0%), ceftriaxone (87.4%) and clindamycin (70.7%) being the most active agents against penicillin-resistant strains. Highest resistance rates were noted for the <2 year-old age group for the macrolides (>or=41.1%), trimethoprim/sulphamethoxazole (38.9%), tetracyclines (22.2%) and clindamycin (10.0%). Geographical variation in the susceptibility patterns among US census zones was present with lowest penicillin and erythromycin susceptibility noted for West South Central and West North Central zones (<or=58.7% penicillin; <or=65.5% erythromycin). New formulations of amoxicillin/clavulanate (Augmentin XR and ES-600) had a higher percentage of potentially susceptible S. pneumoniae isolates compared with amoxicillin/clavulanate for the entire organism collection (>or=+0.9%), sinus isolates (+2.7%), middle ear fluid isolates (+5.5%), penicillin-resistant strains (>or=+5.8%) and strains from patients <2 years of age (>or=+2.4%). Local and global surveillance studies of common respiratory pathogens such as S. pneumoniae remain instrumental to guide clinicians in appropriate empirical treatments and to emphasize the need for prudent antimicrobial use.

This randomized, controlled trial was designed to show that a short, 5-day course of pharmacokinetically enhanced amoxicillin-clavulanate at 2,000/125 mg (Augmentin XR) is as effective clinically as a longer, 7-day course of conventional amoxicillin-clavulanate at 875/125 mg (both given twice daily) in the treatment of acute exacerbations of chronic bronchitis (AECB). Amoxicillin-clavulanate at 2,000/125 mg was designed to extend the therapeutic levels of amoxicillin in serum over the 12-h dosing interval, compared with conventional formulations, to eradicate bacterial strains for which amoxicillin MICs were < or =4 microg/ml while retaining efficacy against beta-lactamase-producing pathogens. A total of 893 patients were randomized and received study medication (amoxicillin-clavulanate at 2,000/125 mg for 443 patients and 875/125 mg for 450 patients). Overall, 141 patients receiving amoxicillin-clavulanate at 2,000/125 mg and 135 receiving the comparator formulation had at least one pathogen identified at screening. Amoxicillin-clavulanate at 2,000/125 mg was as effective clinically in the per-protocol (PP) population at the test of cure (days 14 to 21, primary efficacy endpoint) as amoxicillin-clavulanate at 875/125 mg (clinical success rates of 93.0 and 91.2%, respectively; treatment difference, 1.8; 95% confidence interval [CI], -2.2, 5.7). Bacteriological success in the bacteriology PP population was high for both formulations (amoxicillin-clavulanate at 2,000/125 mg, 76.7%; amoxicillin-clavulanate at 875/125 mg, 73.0%; treatment difference, 3.8; 95% CI, -7.5, 15.0). Both therapies were well tolerated, with a similar incidence of adverse events. Fewer than 5% of patients in each group withdrew from the study due to adverse events. The shorter, 5-day course of amoxicillin-clavulanate at 2,000/125 mg was shown to be as effective clinically as a longer, 7-day course of amoxicillin-clavulanate at 875/125 mg, with high bacteriological efficacy and no difference in tolerability.

Amoxicillin/clavulanic acid 2000mg/125mg extended release (Augmentin XR), referred to herein as amoxicillin/clavulanic acid XR, is a pharmacokinetically enhanced formulation designed to provide more effective therapy in adults and adolescents than conventional formulations against community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae, with reduced susceptibility to amoxicillin. Amoxicillin/clavulanic acid XR maintains plasma amoxicillin concentrations above 4 microg/mL for a mean of 49% of the dosing interval indicating that it would be highly effective against S. pneumoniae strains with minimum inhibitory concentrations (MICs) above the National Committee for Clinical Laboratory Standard's amoxicillin +/- clavulanic acid susceptibility breakpoint of < or =2 microg/mL. Amoxicillin/clavulanic acid XR is at least as effective as conventional amoxicillin/clavulanic acid formulations, levofloxacin and clarithromycin in treating community-acquired pneumonia, acute bacterial sinusitis or acute exacerbations of chronic bronchitis, and has a tolerability profile comparable to that of conventional amoxicillin/clavulanic acid formulations. While the incidence of amoxicillin- or multidrug-resistant S. pneumoniae is not currently sufficient in most regions to warrant the routine empirical use of amoxicillin/clavulanic acid XR, the drug would be extremely useful in those regions with a high incidence of resistant pathogens or in selected patients (i.e. those with S. pneumoniae isolates having amoxicillin MICs > or =2 microg/mL but < or =4 microg/mL).

The pharmacokinetic (PK) and pharmacodynamic (PD) profile of an antimicrobial agent provides important information that can be used to maximize bacteriologic and clinical efficacy, minimize selective pressure for the development of antimicrobial resistance, and determine an optimal dosing regimen. Judicious selection of an antimicrobial based on local susceptibility data and PK and PD parameters is imperative in this era of increasing resistance among Streptococcus pneumoniae, a leading cause of community-acquired respiratory tract infections. The beta-lactam antimicrobials display time-dependent bacterial killing with minimal to no persistent effects. Ketolides and fluoroquinolones display concentration-dependent bacterial killing, and tetracyclines and macrolides display time-dependent killing. All have prolonged persistent effects (e.g., postantibiotic effect) that retard or prevent bacterial regrowth when free drug levels fall below the minimum inhibitory concentration (MIC). New high-dose and/or extended-release formulations of traditional antimicrobials have been added to the current armamentarium for treatment of community-acquired respiratory tract infections. These formulations include amoxicillin-clavulanate potassium powder for oral suspension 90/6.4 mg/kg per day divided every 12 hours (Augmentin ES-600; GlaxoSmithKline, Research Triangle Park, NC), amoxicillin-clavulanate potassium extended-release tablets 2 x 1,000 mg/62.5 mg every 12 hours (Augmentin XR; GlaxoSmithKline), clarithromycin extended-release tablets 2 x 500 mg once daily (Biaxin XL; Abbott Laboratories, North Chicago, IL), and cefaclor extended-release tablets 375 mg or 500 mg every 12 hours (Ceclor CD; Eli Lilly Pharmaceuticals, Indianapolis, IN). Of these agents, only amoxicillin-clavulanate potassium powder for oral suspension and amoxicillin-clavulanate potassium extended-release tablets were designed to treat infections caused by penicillin-resistant pneumococci (penicillin MIC < or =2 microg/mL). Extended-release clarithromycin does not provide higher daily doses than its immediate-release counterpart; rather, it allows for once-daily dosing of this agent because of its slower absorption following oral administration. Extended-release cefaclor is considered clinically equivalent to 250 mg of immediate-release cefaclor pulvules administered 3 times daily; it cannot be used interchangeably with 500 mg 3-times-daily dosages of other cefaclor formulations. Thus, despite providing a similar or higher total daily dose than its immediate-release counterpart, extended-release cefaclor is indicated only for the treatment of patients with mild to moderate infections caused by susceptible strains of certain organisms.

Amoxicillin/clavulanate (Augmentin) is a broad-spectrum antibacterial that has been available for clinical use in a wide range of indications for over 20 years and is now used primarily in the treatment of community-acquired respiratory tract infections. Amoxicillin/clavulanate was developed to provide a potent broad spectrum of antibacterial activity, coverage of beta-lactamase-producing pathogens and a favourable pharmacokinetic/pharmacodynamic (PK/PD) profile. These factors have contributed to the high bacteriological and clinical efficacy of amoxicillin/clavulanate in respiratory tract infection over more than 20 years. This is against a background of increasing prevalence of antimicrobial resistance, notably the continued spread of beta-lactamase-mediated resistance in Haemophilus influenzae and Moraxella catarrhalis, and penicillin, macrolide and quinolone resistance in Streptococcus pneumoniae. The low propensity of amoxicillin/clavulanate to select resistance mutations as well as a favourable PK/PD profile predictive of high bacteriological efficacy may account for the longevity of this combination in clinical use. However, in certain defined geographical areas, the emergence of S. pneumoniae strains with elevated penicillin MICs has been observed. In order to meet the need to treat drug-resistant S. pneumoniae, two new high-dose amoxicillin/clavulanate formulations have been developed. A pharmacokinetically enhanced tablet dosage form of amoxicillin/clavulanate 2000/125 mg twice daily (available as Augmentin XR in the USA), has been developed for use in adult respiratory tract infection due to drug-resistant pathogens, such as S. pneumoniae with reduced susceptibility to penicillin, as well as beta-lactamase-producing H. influenzae and M. catarrhalis. Amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses (Augmentin ES-600) is for paediatric use in persistent or recurrent acute otitis media where there are risk factors for the involvement of beta-lactamase-producing strains or S. pneumoniae with reduced penicillin susceptibility. In addition to high efficacy, amoxicillin/clavulanate has a well known safety and tolerance profile of the two new high-dose formulations are not significantly different from those of conventional formulations. Amoxicillin/clavulanate is included in guidelines and recommendations for the treatment of bacterial sinusitis, acute otitis media, community-acquired pneumonia and acute exacerbations of chronic bronchitis. Amoxicillin/clavulanate continues to be an important agent in the treatment of community-acquired respiratory tract infections, both now and in the future.

Community-acquired bacterial respiratory tract infections are among the most common health disorders requiring medical care and are associated with substantial morbidity, mortality, and direct and indirect costs. Recent increases in the prevalence of antimicrobial resistance have resulted in reduced susceptibility of the most common respiratory tract bacterial pathogens to a number of antimicrobials. Amoxicillin/clavulanate potassium extended release (ER) tablets (Augmentin XR, GlaxoSmithKline) is a new formulation of amoxicillin/clavulanate that retains activity against betalactamase-producing organisms whilst increasing the activity against Streptococcus pneumoniae through elevated and sustained plasma amoxicillin concentrations. The bilayer tablet provides immediate release of clavulanate and both immediate and sustained release of amoxicillin to maintain therapeutic concentrations of amoxicillin over longer periods of the dosing interval. In clinical trials of acute bacterial sinusitis (ABS) and community-acquired pneumonia (CAP), amoxicillin/clavulanate ER was shown to have excellent bacteriological and clinical success rates, even in patients infected with antimicrobial-resistant pathogens, and was found to be generally well tolerated. Amoxicillin/clavulanate ER is approved in the US for the treatment of patients with ABS or CAP caused by beta-lactamase-producing pathogens (ie, Haemophilus influenzae, Moraxella catarrhalis, Haemophilus parainfluenzae, Klebsiella pneumoniae, or methicillin-susceptible Staphylococcus aureus) and S. pneumoniae with reduced susceptibility to penicillin (penicillin minimum inhibitory concentration = 2.0 microg/ml).