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); ticarcillin 3 g plus clavulanate 100 mg (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, ticarcillin-clavulanic acid, or ampicillin-sulbactam. While piperacillin-tazobactam and ticarcillin-clavulanic acid are active in vitro against ESBL-producing organisms, their clinical efficacy is less clear. Carbapenem antibiotics (see below) should be considered the medication of choice in the treatment of serious infection due to ESBL-producing bacteria.
Amoxicillin-clavulanic acid is used for the treatment of refractory cases of otitis media and prophylaxis of infections resulting from animal and human bites. While controversial, 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 and ticarcillin-clavulanic acid are used to treat Pseudomonas infections, increased dosages (200–300 mg/kg/day of the piperacillin [or ticarcillin] 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 [or ticarcillin] 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 infection and febrile neutropenia.