Novel cephalosporin-β-lactamase inhibitor combinations have been developed to combat resistant Gram-negative infections; see the subsequent section for more information on β-lactamase inhibitors. Ceftolozane-tazobactam and ceftazidime-avibactam were both FDA-approved for the treatment of complicated intra-abdominal infections and urinary tract infections. Both agents have potent in vitro activity against Gram-negative organisms, including P aeruginosa and AmpC and extended-spectrum β-lactamase producing Enterobacteriaceae. While neither agent is active against organisms producing metallo-β-lactamases, ceftazidime-avibactam may be an option for carbapenemase-producing organisms. Due to limited activity against anaerobic pathogens, both should be combined with metronidazole when treating complicated intra-abdominal infections. Both agents have short half-lives of 2–3 hours and are dosed every 8 hours. Both are primarily renally excreted and require dose adjustment in patients with impaired renal clearance.
A. Allergy
Like penicillins, cephalosporins may elicit a variety of hypersensitivity reactions, including anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia. Patients with documented penicillin anaphylaxis have an increased risk of reacting to cephalosporins compared with patients without a history of penicillin allergy. However, the chemical nucleus of cephalosporins is sufficiently different from that of penicillins such that many individuals with a history of penicillin allergy tolerate cephalosporins. Overall, the frequency of cross-allergenicity between the two groups of drugs is low (~1%). Cross-allergenicity appears to be most common among penicillin, aminopenicillins, and early-generation cephalosporins, which share similar R-1 side chains. Patients with a history of anaphylaxis to penicillins should not receive firstor second-generation cephalosporins, while thirdand fourth-generation cephalosporins should be administered with caution, preferably in a monitored setting.
B. Toxicity
Local irritation can produce pain after intramuscular injection and thrombophlebitis after intravenous injection. Renal toxicity, including interstitial nephritis and tubular necrosis, may occur uncommonly.
Cephalosporins that contain a methylthiotetrazole group may cause hypoprothrombinemia and bleeding disorders. Historically, this group included cefamandole, cefmetazole, and cefoperazone; however, cefotetan is the only methylthiotetrazole-containing agent used in the USA. Oral administration of vitamin K, 10 mg twice weekly, can prevent this uncommon problem. Drugs with the methylthiotetrazole ring can also cause severe disulfiram-like reactions; consequently, alcohol and alcohol-containing medications must be avoided.