, *St. Joseph's Hospital and Medical Center, Paterson, New Jersey, and † Wright State University School ofMedicine, Miami Valley Hospital, Dayton, Ohio.

Semin Respir Crit Care Med. 2000;21(1) 

In This Article

General Review

The penicillin family of drugs are usually well tolerated, but they have been associated with a wide range of hypersensitivity reactions, including fever, rash (maculopapular and urticarial), anaphylaxis, exfoliative dermatitis, erythema multiforme, serum sickness, and hemolytic anemia.[4] When administered intravenously in high doses, particularly to patients with renal impairment, they have the potential to cause central nervous system toxicity, manifested by myoclonic jerks, seizures or coma.[5] Specific members of the penicillin family have been identified with particular adverse reactions: ampicillin, amoxicillin, and amoxicillin/clavulanate with diarrhea and C. difficile colitis, as well as rash when prescribed to the patient with chronic lymphocytic leukemia; nafcillin-induced neutropenia; carbenicillin and ticarcillin (with/without clavulanic acid) with hypokalemia, platelet dysfunction, and fluid overload; and methicillin and ampicillin with interstitial nephritis.[6,7,8] Platelet-mediated bleeding caused by ticarcillin and piperacillin is duration-related and can be serious, and it is additive with other risk factors, including chemotherapy, thrombocytopenia and renal insufficiency.[9] Of interest is the observation that the administration of ticarcillin/ elavulanate is statistically less frequently associated with C. difficile-related disease than that attributed to the third-generation cephalosporins.

The cephalosporins have proven to be very safe compounds and this is one explanation for their wide appeal. Untoward events attributed to the cephalosporins have included diarrhea, pseudo-membranous colitis, and rarely, hypersensitivity reactions including drug fever, rash, interstitial nephritis or immediate life-threatening events. Specific members of the cephalosporin family of compounds have been identified with particular adverse reactions: ceftriaxone, cefixime, ceftibuten, cefdinir, and cefoperazone with diarrhea; ceftriaxone with reversible biliary sludge; cefoperazone, cefotetan, moxalactam, and cefamandole with hypoprothrombinemic bleeding; ceftazidime with abnormal liver function; cefoperazone, cefonicid, and cefamandole with disulfiram-like reactions following the ingestion of alcohol;and cefazolin-induced seizures in patients with renal failure who have received high doses.[10]

Imipenem and cilastatin and aztreonam have caused phlebitis, gastrointestinal untoward events, and rash. A particular concern is the development of seizures attributed to imipenem and cilastatin.[11] This adverse event usually occurs in the setting of an elderly patient, particularly when renal impairment or underlying central nervous system (CNS) disease exists.

The most notorious side effect of clindamycin is diarrhea and C. difficile-related colitis.[12] This drug has rarely caused drug fever, rash, blood dyscrasias, and hepatotoxicity. Doxycycline has been associated with diarrhea and, infrequently, photosensitivity; rash; hepatitis; and, particularly in elderly patients. esophageal ulcerations or strictures.[13] Infrequent untoward events attributed to vancomycin include rash, fever, nephrotoxicity, ototoxicity, and reversible, transient hematopoietic toxicity. The most dramatic side effect is the red man syndrome, a non-immunologically mediated reaction consisting of pruritus and erythema with or without hypotension, which appears to be dependent on dose, frequency of administration, and rate of infusion.[14] The pronounced erythema has a predilection for the face, neck, upper body, and upper extremities.

Concerns regarding administration of the aminoglycosides include nephrotoxicity, specifically nonoliguric acute renal failure, ototoxicity, both the auditory and vestibular components, and neuromuscular blockade, a rare event that has developed in patients with myasthenia gravis, renal disease, hypocalcemia, or hypermagnesemia.[15] Factors contributing to nephrotoxicity include duration of therapy, older age, liver disease, shock and the coadministration of drugs that have the potential to cause nephrotoxicity, such as amphotericin B, cisplatinum, cyclosporine, and ethacrynic acid. Limited data indicate that tobramycin is less nephrotoxic than gentamicin and that nephrotoxicity is reduced by a once per day dosing regimen. Factors contributing to ototoxicity include hypovolemia, total dose administered, renal impairment, liver dysfunction, elevated serum trough concentrations, cisplatinum, furosemide, and ethacrynic acid. Ototoxicity is a particular concern for the fetus of a pregnant woman, and it is important to appreciate that auditory and vestibular toxicity can develop in patients who received appropriate dosing and pharmacological adjustment, as determined by monitoring of serum concentrations and renal function.

Rash, fever, and gastrointestinal adverse reactions are the most common side effects precipitated by trimethoprim and sulfamethoxazole.[16] Additional rare untoward events include nephrotoxicity, hyperkalemia, hematologic derangements (neutropenia, thrombocytopenia, agranulocytosis, aplastic anemia, and megaloblastic anemia), hepatitis, pancreatitis, pseudomembranous colitis, and adverse CNS events (headache, insomnia, vertigo, ataxia, and aseptic meningitis).

Adverse events attributed to the macrolides have included nausea, vomiting, abdominal pain, diarrhea, and, rarely, antibiotic-associated colitis, pancreatitis, cholestatic jaundice, acute hepatitis, abnormal taste (clarithromycin), and reversible ototoxicity.[17] Clarithromycin and azithromycin cause fewer gastrointestinal adverse events than does erythromycin.

The most common adverse events attributed to the fluoroquinolones are gastrointestinal symptoms, nervous system complaints (headache, dizziness, insomnia, agitation, and hallucinations), and allergic reactions (rash and pruritus).[18] Rare adverse effects include seizures, elevations of liver enzymes, and tendinopathy. Photosensitivity has been a concern with lomefloxacin and sparfloxacin and very rarely with trovafloxacin. Patients receiving trovafloxacin are at risk to develop dizziness, and they should not drive a car, operate machinery, or engage in activity that requires mental alertness. Grepafloxacin and sparfloxacin should not be used in patients with known Qtc prolongation or in patients receiving Qtc prolonging drugs.


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