A Review of β-Lactam–Associated Neutropenia and Implications for Cross-reactivity

Abstract

Objective: To review the incidence, management, and current understanding of the pathophysiology of β-lactam–induced neutropenia and to critically evaluate the practicality and safety of direct substitution to an alternative β-lactam in the setting of this reaction. Data Sources: A literature analysis using the PubMed and Ovid search engines (July 1968 to October 2020) was performed using the search terms neutropenia, leukopenia, β-lactam, nonchemotherapy, agranulocytosis, and G-CSF (granulocyte colony-stimulating factor). Study Selection and Data Extraction: The included English-language studies evaluated the incidence, mechanism, and/or management of β-lactam–induced neutropenia in pediatric or adult patients. Data Synthesis: Drug-induced neutropenia is a well-documented adverse reaction of β-lactam antibiotics, with an incidence of approximately 10% following at least 2 weeks of intravenous therapy. However, multiple gaps in knowledge remain in the mechanism of pathophysiology and optimal management of this reaction. Both direct toxic and immune-mediated mechanisms have been implicated. Although the cornerstone of management includes cessation of the offending agent, controversy exists on the appropriateness of direct substitution or future use of an alternative β-lactam. Relevance to Patient Care and Clinical Practice: Given the frequency of use and superiority of β-lactams over alternative therapy for several infectious disease states, practical recommendations are needed on the management and safe use of β-lactams following β-lactam–induced neutropenia. Conclusion: Future use of β-lactams with differing R1 side chains, particularly those from a separate class, should not be deemed contraindicated following β-lactam–induced neutropenia and may be considered when indicated, with close laboratory monitoring.

Ceftriaxone‐induced neutropenia successfully overcome by a switch to penicillin G in Cardiobacterium hominis endocarditis

“…The cornerstone of management of β‐lactam antibiotic‐induced neutropenia is the cessation of the causative agent. Direct substitution or future use of an alternative β‐lactam antibiotic is controversially discussed 7 . Because of the superiority of β‐lactam antibiotics compared to alternative therapeutic options for several infections including endocarditis, the present case suggests that the use of a β‐lactam with differing side chains should not be considered contraindicated after β‐lactam antibiotic‐induced neutropenia 7 .…”

“…Drug‐induced neutropenia probably can occur with all β‐lactam antibiotics. Both direct toxic and immune‐mediated mechanisms have been implicated 7 …”

Evaluation of the safety of piperacillin‐tazobactam extended infusion in pediatric cystic fibrosis patients

“…8 Moreover, hematologic effects of beta-lactams and serum sickness are often not seen until after 14 days of exposure on average and a repeat CBC/diff was not obtained for many patients (83/109 in TI group and 27/95 in the EI group). 8,25 This limits the interpretation of these findings, and further investigation into the effects of EI on bone marrow suppression and serum sickness with longer treatment durations is warranted.…”

Cefepime-Induced Neutropenia: A Case Report and Literature Review

“…Emerging cross-reactivity studies support the substitution to an alternative β-lactam from a different group in cases of adverse events; however, this strategy in the setting of DIN is still under scrutiny, given the noted recurrence of neutropenia in 15%–30% of cases who are reintroduced to antibiotics. 22 These data mainly include reintroducing the same agent (ie, rechallenging) or substituting to an agent with a structural similarity, which does not contradict the use of alternative antibiotics with different side chains or structure, as they are believed to be the main contributors to cross reactivity amongst β-lactams. 23 One case report of ceftriaxone-induced neutropenia reported complete resolution after substituting with cefepime.…”