The addition of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) prevents inactivation of the parent penicillin by some, but not all, beta-lactamases. Marketed products include amoxicillin 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic acid (tablet); amoxicillin 1 g plus 62.5 mg of clavulanic acid (extended-release tablet preparation); ampicillin 1 g plus sulbactam 0.5 g, and ampicillin 2 g plus sulbactam 1 g (vial for intravenous injection); and piperacillin 3 g plus tazobactam 0.375 g, and piperacillin 4 g plus tazobactam 0.5 g (vial for intravenous injection). Amoxicillin-clavulanic acid is given orally and the others, intravenously. In Europe, amoxicillin-clavulanic acid is also available as a parenteral formulation. In general, the beta-lactamase inhibitors effectively inactivate beta-lactamases produced by Staphylococcus aureus, H influenzae, Moraxella catarrhalis, and B fragilis. In contrast, the beta-lactamase inhibitors are variably and unpredictably effective against beta-lactamases produced by certain aerobic gram-negative bacilli, such as Enterobacter. Of the available parenteral penicillin–beta-lactamase inhibitor combinations, piperacillin-tazobactam has the broadest spectrum of activity. Like ampicillin-sulbactam, piperacillin-tazobactam is active against ampicillin-susceptible enterococci. It has greater in vitro activity against P aeruginosa, Serratia, and Klebsiella species when compared with amoxicillin-clavulanic acid or ampicillin-sulbactam. While piperacillin-tazobactam is active in vitro against ESBL-producing organisms, its clinical efficacy is inconsistent compared to other agents. Carbapenem antibiotics (see below) should be considered the first-line treatment of serious infection due to ESBL-producing bacteria.
Amoxicillin-clavulanic acid is used for the outpatient treatment of comorbid patients with community-acquired pneumonia, refractory cases of otitis media and prophylaxis of infections resulting from animal and human bites. The Infectious Diseases Society of America (IDSA) considers amoxicillin-clavulanic acid to be the antibacterial of choice in the treatment of acute bacterial rhinosinusitis. The roles of the parenteral penicillin–beta-lactamase inhibitors include the treatment of polymicrobial infections such as peritonitis from a ruptured viscus, osteomyelitis in a diabetic patient, or traumatic osteomyelitis.
When piperacillin-tazobactam is used to treat Pseudomonas infections, increased dosages (200–300 mg/kg/day of the piperacillin component) should be used.
Piperacillin-tazobactam treatment of pseudomonal isolates with reduced piperacillin-tazobactam susceptibility may be associated with increased mortality. Nonpseudomonal infections can be treated with lower doses (100–200 mg/kg/day of the piperacillin component). Taking advantage of pharmacokinetics and pharmacodynamics, extended infusions of piperacillin-tazobactam may be superior to intermittent bolus dosing in the treatment of serious bacterial infections and febrile neutropenia.