carbapenems. Seizures are a dose-limiting toxicity for both imipenem and meropenem. Clostridium difficile-related diarrhea may occur in people treated with carbapenems or other broad spectrum antibiotics. Those with an allergy to penicillin may develop a cross sensitivity to carbapenems. Examples Approved for clinical use Imipenem, the first clinically used carbapenem, was developed at Merck and Co. It was approved for use in the United States in 1985. Imipenem is hydrolyzed in the mammalian kidney by a dehydropeptidase enzyme to a nephrotoxic intermediate, and thus is co-formulated with the dehydropeptidase inhibitor cilastatin. Imipenem is available in both intravenous and intramuscular formulations. Meropenem is stable to mammalian dehydropeptidases and does not require co-administration of cilastatin. It was approved for use in the United States in 1996. In most indications it is somewhat more convenient to administer than imipenem, 3 times a day rather than 4. Doses of less than one gram may be administered as an IV bolus, whereas imipenem is usually administered as a 20-minute to one hour infusion. Meropenem is somewhat less potent than imipenem against gram-positive pathogens, and somewhat more potent against gram-negative infections. Unlike imipenem, which produced an unacceptable rate of seizures in a phase 2 trial, meropenem is effective for the treatment of bacterial meningitis. A systematic review performed by an employee of the company that markets meropenem concluded that it provides a higher bacterial response and lower adverse event rates than imipenem in people with severe infections, but no difference in mortality rate. Ertapenem is administered once daily as an intravenous infusion or intramuscular injection. It lacks useful activity against the P. aeruginosa and Acinetobacter species, both of which are important causes of hospital-acquired infections. Doripenem has a spectrum of activity very similar to that of meropenem. Its greater stability in solution allows the use of prolonged infusions and it is somewhat less likely to produce seizures than other carbapenems. Panipenem/betamipron (Japanese approval 1993) Biapenem (Japanese approval 2001) exhibits similar efficacy and adverse event rates as other carbapenems. Tebipenem (Japanese approval 2015) is the first carbapenem whose prodrug form, the pivalyl ester, is orally available. Unapproved/experimental Razupenem (PZ-601) PZ-601 is a carbapenem antibiotic currently being tested as having a broad spectrum of activity including strains resistant to other carbapenems. Despite early Phase II promise, Novartis (who acquired PZ-601 in a merger deal with Protez Pharmaceuticals) recently dropped PZ-601, citing a high rate of adverse events in