An overview of harms associated with beta-lactam antimicrobials: where do the carbapenems fit in?

Abstract

The US Institute of Medicine's focus on patient safety has motivated hospital administrators to facilitate a culture of safety. As a result, subcommittees of the pharmacy and therapeutics committee have emerged in many hospitals to focus on adverse events and patient safety. Antimicrobial harms have gained the attention of practicing clinicians and hospital formulary committees, because they top the list of drugs that are associated with adverse events and because of certain serious harms that have ultimately led to the withdrawal of some antimicrobial agents. In the near future, several antimicrobials in the late phase of development will become available for clinical use (ceftobiprole, ceftaroline, and telavancin), and others (doripenem and dalbavancin) have recently joined the armamentarium. Because new antimicrobials will become part of the treatment armamentarium, it is important to discuss our current understanding of antimicrobial harms in general. Although not thought of as traditional adverse events, Clostridium difficile infection and development of resistance during therapy are adverse events that occur as a result of antimicrobial exposure and therefore are discussed. In addition, a distillation of our current understanding of beta-lactam specific adverse events will be provided. Finally, new methods of administration are being evaluated that may influence peak concentration-related antimicrobial adverse events.

Figure 1

Pooled odds ratios and 95% confidence intervals for Clostridium difficile infection by antibiotic type. Adapted with permission from Bignardi. Reprinted with permission [23]. Copyright ^© 1998 The Hospital Infection Society.

Figure 2

Approach to antibiotic selection in patients with a history of penicillin allergy. ^aIt is often difficult to obtain an accurate history; if in doubt, assume that reaction could have been an urticarial rash. ^bAvoid use of first-generation cephalosporins. Stevens-Johnson syndrome and toxic epidermal necrolysis are not IgE mediated. If the suspected drug reaction was either of these, then avoid skin testing and use of penicillins. ^cSkin testing with amoxicillin is sometimes used if the reaction was to amoxicillin, but the incidence of false negatives is unknown. ^dIf the reaction was serious, then one may challenge in a supervised setting using a 'graded challenge' with escalating oral doses followed by intravenous administration, if applicable. Reprinted with permission [3]. Copyright ^© 2002 the Infectious Diseases Society of America.

Figure 3

Concentrations of various penems and their displacement of GABA from their receptor sites. Illustrated is the concentration-dependent displacement of muscimol by meropenem, panipenem, and imipenem at the γ-aminobutyric acid (GABA) receptor in mouse cerebral cortical membranes [66].

Figure 4

Cumulative risk for emergence of Gram-negative resistant organisms by treatment and duration of hospitalization. Adapted with permission [70]. Copyright ^© 2001 the Infectious Diseases Society of America.