Pharmacokinetics and Pharmacogenomics of β-Lactam-Induced Neutropenia

Hahn, Andrea; Fukuda, Tsuyoshi; Hahn, David; Mizuno, Tomoyuki; Frenck, Robert W.; Vinks, Alexander A.

doi:10.2217/pgs-2015-0008

Cited by 7 publications

(9 citation statements)

References 35 publications

(33 reference statements)

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“…Although no clear evidence has been provided, the dose‐related inhibitory effect of beta‐lactam antibiotics on granulopoiesis has been postulated to compromise the ability of the bone marrow to compensate for the immune destruction of neutrophils . Finally, a possible pharmacogenetic polymorphism involving MRP4 3348 A to G or myeloperoxidase has been suggested .…”

Section: Discussionmentioning

confidence: 99%

Beta‐lactam‐induced severe neutropaenia: a descriptive study

Vial

Bailly

Pérault‐Pochat

et al. 2018

Fundamemntal Clinical Pharma

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The objectives of this study were to describe the characteristics and natural history of beta‐lactam‐induced severe neutropaenia and to evaluate the risk of recurrences after another beta‐lactam readministration. Reports of pure agranulocytosis associated with a beta‐lactam exposure within the 10 days preceding the neutropaenia were extracted from the French Pharmacovigilance Database over the year 2010. Cases with another evident cause or more likely attributable to another drug were excluded. Data were analyzed for demographics, clinical and biological features, prognosis factors, granulocyte colony stimulating factors administration and outcome. Sixty‐two cases were included (median age: 65 years). The median duration of treatment before neutropaenia was 16 days. In 47% of cases, the diagnosis was made on a systematic blood cell count. The median neutrophil count at nadir was 0.125 × 109/L, and bone marrow examination evidenced features of neutrophilic maturation arrest or aplasia in 21 patients, hyperplasia of granulopoietic cells in three and normal findings in five. Three patients developed severe sepsis. All but one recovered a normal blood cell count within 2–56 days after beta‐lactam discontinuation. The last patient died from recurrent severe septic shock. No significant effect of granulocyte colony stimulating factor on the mean duration of haematological recovery was found. Among the 21 patients who later received another beta‐lactam, two experienced recurrence of the neutropaenia after receiving a beta‐lactam from another subfamily. Beta‐lactam‐induced agranulocytosis was usually observed after prolonged treatment, and severe complications are uncommon. In most patients, a subsequent treatment with another beta‐lactam was well tolerated.

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Section: Discussionmentioning

confidence: 99%

Beta‐lactam‐induced severe neutropaenia: a descriptive study

Vial

Bailly

Pérault‐Pochat

et al. 2018

Fundamemntal Clinical Pharma

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“…3,4,8,[10][11][12][13][14][15][16][17][18][19]68,69 Genetic variation causing predisposition to drug-induced neutropenia has been described and may play a role by increasing risk of a reaction to a specific agent. 70,71 A recent review of drug-induced agranulocytosis concluded that the available evidence supports an immunemediated mechanism as the primary pathogenesis. 71 Specific findings from case series involving β-lactams include drug-dependent antineutrophil antibodies and leukocyte agglutination, possibly induced by accumulation of reactive metabolites over several days of therapy.…”

Section: Pathogenesismentioning

confidence: 99%

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

2020

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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.

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“…Mice lacking MRP4 and OAT3 have demonstrated increased renal and plasma concentrations of β‐lactam antibiotics, and a separate case‐control study found patients with polymorphisms to MRP4 were found to have a higher odds of developing neutropenia than those without the polymorphism . These data suggest MRP4 and OAT1/OAT3 transporters may play a role in protection against bone marrow toxicity …”

Section: Discussionmentioning

confidence: 97%

“…Other β‐lactam toxicities, such as neurotoxicity, seem to support a dose‐dependent relationship . Polymorphisms in efflux transporter multidrug resistance protein 4 (MRP4) and uptake transporters organic anion transporters 1 and 3 (OAT1/OAT3), both substrates for β‐lactam antibiotics, may also play a role in β‐lactam–associated neutropenia . Mice lacking MRP4 and OAT3 have demonstrated increased renal and plasma concentrations of β‐lactam antibiotics, and a separate case‐control study found patients with polymorphisms to MRP4 were found to have a higher odds of developing neutropenia than those without the polymorphism .…”

Section: Discussionmentioning

confidence: 99%

Comparison of Neutropenia Associated with Ceftaroline or Ceftriaxone in Patients Receiving at Least 7 Days of Therapy for Severe Infections

2019

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STUDY OBJECTIVE Ceftarolinefosamil is a cephalosporin with broad clinical utility; however, limited data suggest that prolonged ceftaroline exposure may be associated with neutropenia. The objective was to determine drug and patient factors associated with neutropenia in patients receiving ceftaroline or ceftriaxone for deep-seated infections. DESIGN Retrospective, ratio-matched cohort study. SETTING Four acute-care hospitals within an urban health care system. PATIENTS A total of 176 hospitalized adults who received definitive ceftaroline (44 patients) or ceftriaxone (132 patients) therapy for at least 7 days between January 2013 and April 2017 for any of the following indications: bone and joint infections (BJI), infective endocarditis (IE), or bloodstream infections (BSI). MEASUREMENTS AND MAIN RESULTS The primary outcome was development of neutropenia while receiving cephalosporin therapy, defined as an absolute neutrophil count (ANC) <1500 cells/mm 3 . Neutropenia severity and patient characteristics were described and compared between the ceftaroline and ceftriaxone groups. The median (interquartile range [IQR]) antibiotic prescription duration was 41 (29-44) days for the ceftaroline group and 40 (28-44) days for the ceftriaxone group (p=0.9). Cephalosporin indications were 112 (64%) BJI, 27 (15%) BSI, 16 (9%) IE, and 21 (12%) multiple infections; ceftaroline was more commonly used in BJI (p=0.03), and ceftriaxone was more commonly used in IE (p=0.01). Neutropenia developed in 16 (9%) patients: 8 (18%) in the ceftaroline group and 8 (6%) in the ceftriaxone group (p=0.03). Median (IQR) onset to neutropenia was 22 (15-28) days, and median (IQR) change in ANC was 2.86 (1.50-4.08) cells/mm 3 ; most cases of neutropenia were mild (12 patients [75%]). The median (IQR) time to mild or moderate-severe neutropenia was not significantly different (p=0.68): 22 (14-28) and 22 (21-36) days, respectively. Treatment was discontinued in 4 (25%) patients due to neutropenia. Ceftaroline use was independently associated with neutropenia (adjusted odds ratio 3.2, 95% confidence interval 1.2-10.5) after adjusting for lower body mass index strata (18.5-25 kg/m 2 ).

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Pharmacokinetics and Pharmacogenomics of β-Lactam-Induced Neutropenia

Cited by 7 publications

References 35 publications

Beta‐lactam‐induced severe neutropaenia: a descriptive study

Beta‐lactam‐induced severe neutropaenia: a descriptive study

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

Comparison of Neutropenia Associated with Ceftaroline or Ceftriaxone in Patients Receiving at Least 7 Days of Therapy for Severe Infections

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