Allergic reactions to the beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are a major factor limiting their use. Immediate hypersensitivity reactions to penicillins depend on the presence of preformed allergic (IgE) antibodies to several penicillin determinants. These materials can be used in in-vivo skin testing to exclude those patients at risk for immediate or accelerated allergic reactions. The cephalosporins have not had their relevant determinants defined as related to allergic reactions. The results of in-vivo challenges of patients with IgE to penicillin suggest the incidence of reactivity of cephalosporins in patients allergic to penicillin is less than generally appreciated. The monocyclic beta-lactam antibiotic, aztreonam (a monobactam), failed to show cross-reactivity with penicillin antibodies, because immune reactivity toward the monobactam was directed against side chain rather than nuclear determinants. On the other hand, the new bicyclic carbapenem beta-lactam drugs, represented by imipenem, showed extensive in-vivo cross-reactivity with penicillins.

Immediate hypersensitivity reactions to beta-lactam antibiotics.

Over 40 years ago, several investigators attempted to establish the optimal dosage regimens of penicillin G for the treatment of infections caused by common gram-positive bacteria. In a variety of streptococcal infection models in animals, they showed that the total dose of drug required to cure infection was significantly less if the drug was administered in multiple doses at frequent intervals than if it was administered as a single dose or as multiple doses at widely spaced intervals (18, 20, 37). The aggregate time that active penicillin concentrations were maintained, rather than the magnitude of the concentration, appeared to be the important determinant of efficacy against these infections. As a result, repository formulations of penicillin G, designed to maintain continuous levels of the drug in plasma and tissues for protracted time periods, were used extensively in the early years of penicillin therapy. Studies with penicillin also demonstrated that removal of staphylococci and streptococci from penicillin exposure is not followed by immediate bacterial regrowth (19, 21, 59). Rather, a lag phase or recovery period, which can last for several hours, is observed. This persistent suppression of bacterial growth supported the development of the intermittent dosing regimens for ,B-lactam antibiotics that are currently used in clinical practice. The goal of a dosage regimen for each individual 3-lactam is to prevent the drug-free interval between doses from being long enough for the bacterial pathogen to resume growth (17). Although these intermittent dosage regimens seem to work reasonably well in clinical practice, we do not know whether we are overdosing or even underdosing patients with most drugs. The increasing number of immunocompromised patients and the rising incidence of gram-negative bacillary infections have added impetus to the development of dosage regimens that will achieve the most benefit with the least amount of drug. During the past decade, many of the issues about dosing regimens raised by the early penicillin studies have been investigated for newer antimicrobial agents and for pathogens such as gram-negative bacilli. The results of those studies as well as the availability of improved intravenous drug delivery systems for both the hospital and the outpatient settings have rekindled interest in the contin-

Continuous infusion of beta-lactam antibiotics.

beta-Lactam antibiotics can induce severe neutropenia by a hitherto unknown mechanism. Fifty cases of beta-lactam antibiotic-induced neutropenia (less than 1,000 neutrophils/mm3) from 17 hospitals were analyzed and compared with 140 literature cases. The incidence of neutropenia was 5%-greater than 15% in patients treated for greater than or equal to 10 days with large doses of any beta-lactam antibiotic but less than 0.1% with shorter duration of therapy. In greater than 95% of cases recovery occurred between one to seven days after withdrawal of beta-lactam antibiotics. Bone marrow aspirates were characterized by a lack of well-differentiated myeloid elements in the presence of numerous immature granulocyte precursors. Nine penicillins and eight cephalosporins inhibited in vitro granulopoiesis in a dose-dependent manner. There was a good correlation between the inhibitory capacity of beta-lactam antibiotics in vitro and the doses inducing neutropenia in vivo. These observations may be relevant for therapy in the granulocytopenic patient.

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Inhibition of Granulopoiesis in Vivo and in Vitro by β-Lactam Antibiotics

There are considerable laboratory data and information from animal and continuous culture in vitro models to support continuous infusion therapy for penicillins and cephalosporins, but, as yet, the only existing clinical data relate to cephalosporins. Penicillins do not exert concentration-dependent killing in the therapeutic range but have a post-antibiotic effect (PAE) against Gram-positive cocci but not Gram-negative rods. Animal models indicate the time (T) during which the serum concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen [T > MIC] determines outcomes. Pharmacokinetic studies in humans indicate that continuous infusion with penicillins is possible but there are no clinical data on efficacy. Cephalosporins have similar pharmacodynamic properties to penicillins; T > MIC determines outcome. Data related to ceftazidime indicate that the drug concentration at steady-state (Css) should exceed the pathogen MIC by > 1-fold and perhaps by 4- to 5-fold or more. Human pharmacokinetics of ceftazidime administered by continuous infusion to a wide variety of patient groups indicates that Css of > 20 mg/L can easily be achieved using conventional daily doses. Clinical data indicate increased effectiveness of a continuous regimen in neutropenic patients with Gram-negative infection. Furthermore cefuroxime administration by continuous infusion has resulted in lower doses and shorter course durations. Little is known of the pharmacodynamics of monobactams and there are few clinical data on continuous infusion therapy. Carbapenems have different pharmacodynamics to other beta-lactams as they have concentration-dependent killing and a PAE with both Gram-positive and Gram-negative bacteria. While T > MIC has a role in determining outcomes, the proportion of the dosing interval for which serum drug concentrations should exceed the pathogen MIC is less than for other beta-lactams. In vitro models have shown that continuous infusion is effective, as is less frequent dosing. There are few data on continuous infusion of carbapenems but some patients have been treated with once-daily dosing. Clinically, continuous infusion therapy with penicillins and cephalosporins should be considered in patients infected with susceptible Gram-negative rods not responding to conventional therapy. As an approximation, the same total daily dose should be given but a bolus intravenous injection should be give at the start of continuous infusion to ensure Css is reached rapidly. The Css may be difficult to predict and determination of serum drug concentrations may be indicated. Ideally, the Css should be calculated based on the MIC of the potential pathogen and may be higher or lower than the Css achieved by a conventional daily dose.

Continuous Infusion of β-Lactam Antibiotics

(1990). Drug-Protein Conjugation and its Immunological Consequences. Drug Metabolism Reviews: Vol. 22, No. 1, pp. 87-144.

AlainL. De Weck

Papers

Effect of storage of penicillin-g solutions on sensitisation to penicillin-g after intravenous administration