Risks of Prescribing Cephalosporins

Skin reactions to cephalosporins (e.g., urticaria, rash, pruritis) occur at a frequency of 1% to 3%. Anaphylaxis is rare (0.0001% to 0.1%). Because cephalosporins also contain the £-lactam ring (Figure 1), there is potential for cross-reactivity in penicillin-allergic patients. Complicating the issue is the fact that hypersensitivity reactions with cephalosporins may be due to the various side chains as well as the £-lactam nucleus. In addition, the original cephalosporins (cephalothin and cephaloridine) were contaminated with minute quantities of penicillin, which might have resulted in overestimates of cross-allergy.

…Read the rest of this article

Penicillin Allergy

The true incidence of penicillin allergy is unknown, although 5% to 20% of the population report this type of allergy, often with a vague or unconfirmed history. The penicilloyl derivative is the most frequently implicated metabolite in IgE-mediated reactions to penicillin. Anaphylaxis, the most severe of the type I reactions, occurs in 0.01% to 0.05% of penicillin courses and is fatal in 10% of such cases. It occurs most commonly in people 20 to 49 years old and in patients who have undergone parenteral administration of the drug. Fear of anaphylaxis may prevent the clinician from prescribing penicillin and other £-lactam agents to patients with a history of penicillin allergy, which in turn may result in the use of less effective, more toxic, more expensive or broader-spectrum alternatives.

The most common reactions to penicillin are type IV delayed hypersensitivity reactions. These present most frequently as a maculopapular or morbilliform rash and occur in 1% to 4% of patients taking penicillin. The incidence of rashes due to the aminopenicillins (ampicillin or amoxicillin) is generally higher (5.2% to 9.5%) and is significantly higher (69% to 100%) among patients with viral illness, the most common example being infectious mononucleosis caused by Epstein-Barr virus. Until recently, delayed reactions were considered idiopathic, with an unknown immunological mechanism, but it is now thought that they are caused by T cell stimulation; these reactions are subclassified on the basis of the specific T cells activated.

…Read the rest of this article

Classification of Allergic Reactions

Allergic reactions to 6-lactams have been categorized by clinical syndrome, immune mechanism, or time to onset (Table 1). Type 1 reactions are mediated by IgE antibodies directed at specific combinations of metabolites and serum proteins. When the metabolite-protein complex is recognized and cross-links with specific preformed IgE antibodies bound to tissue mast cells, inflammatory mediators such as histamine and leukotrienes are released, which results in the signs and symptoms of an allergic reaction. IgE-mediated reactions can be classified as immediate or accelerated. Immediate reactions are manifested by anaphylaxis with or without hypotension and usually occur within minutes to 1 h of administration of the allergen. Accelerated reactions may present within 48 to 72 h and are characterized by laryngeal edema, angioedema, and/or urticaria. Patients may report a feeling of shortness of breath, chest tightness, throat tightening, pruritis, dizziness, or feelings of warmth or impending doom; rarely, they may experience severe nausea, vomiting, abdominal pain, or diarrhea. …Read the rest of this article

Two databases — MEDLINE (from 1994 to 2004 for penicillins and cephalosporins and from 1985 to 2004 for carbapenems) and Reactions (from 1983 to 2003) — were searched for pertinent English- language articles (limited to human studies). The MeSH terms “drug hypersensitivity”, “penicillins”, “cephalosporins”, and “carbapenems” and the key words “allergy”, “imipenem”, “meropenem”, and “ertapenem” were used. The bibliographies of articles identified in this way were also reviewed and pertinent references retrieved. Because true “allergic” reactions are IgE-mediated, this mechanism was the focus of the review.

…Read the rest of this article

INTRODUCTION

B-Lactam antibiotics, which comprise the penicillin, cephalosporin, and carbapenem families, are so called because they all have a £-lactam ring (Figure 1). £-Lactam agents are frequently prescribed because they are bactericidal, relatively inexpensive, effective against a wide range of pathogens, and well tolerated. The most frequent side effect reported with £-lactam antibiotics, particularly penicillin, is allergy.

…Read the rest of this article

DRUG INTERACTIONS: Didanosine: Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When administered with VIREAD, Cmax and AUC of didanosine (administered as either the buffered or enteric-coated formulation) increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir disoproxil fumarate (tenofovir DF) with didanosine 400 mg daily. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions. Atazanavir: Atazanavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. VIREAD decreases the AUC and Cmm of atazanavir. When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with VIREAD. Lopinavir/Ritonavir: Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. Drugs Affecting Renal Function: Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum concentrations of tenofovir. In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

…Read the rest of this article

WARNINGS AND PRECAUTIONS:

Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Exacerbation of Hepatitis after Discontinuation of Treatment: Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD (See Adverse Reactions). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 m L/m in (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent. Coadministration with Other Products: VIREAD should not be used in combination with the fixed-dose combination products TRUVADA® (emtricitabine/tenofovir disoproxil fumarate) or ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil fumarate) since tenofovir disoproxil fumarate is a component of these products. VIREAD should not be administered in combination with HEPSERA® (adefovir dipivoxil) (See Drug Interactions). …Read the rest of this article