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.
KirkwoodCFSmithLLRustagiPKSchentagJJ. Neutropenia associated with beta-lactam antibiotics. Clin Pharm. 1983;2:569-578.
2.
LemieuxPGrégoireJPThibeaultRBergeronL. Higher risk of neutropenia associated with piperacillin-tazobactam compared with ticarcillin-clavulanate in children. Clin Infect Dis. 2015;60:203-207. doi:10.1093/cid/ciu780
3.
NeftelKAHauserSPMullerMR. Inhibition of granulopoiesis in vivo and in vitro by beta-lactam antibiotics. J Infect Dis. 1985;152:90-98. doi:10.1093/infdis/152.1.90
4.
OlaisonLBelinLHogevikHAlestigK. Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis. Arch Intern Med. 1999;159:607-615. doi:10.1001/archinte.159.6.607
5.
PeraltaFGSanchezMBRoizMPPenaMATejeroMAArjonaR. Incidence of neutropenia during treatment of bone-related infections with piperacillin-tazobactam. Clin Infect Dis. 2003;37:1568-1572. doi:10.1086/379519
6.
VialTBaillyHPerault-PochatMC, et al. Beta-lactam-induced severe neutropaenia: a descriptive study. Fundam Clin Pharmacol. 2019;33:225-231. doi:10.1111/fcp.12419
7.
WhitmanCBJosephJMSjoholmLO. Cephalosporin-induced leukopenia following rechallenge with cefoxitin. Ann Pharmacother. 2008;42:1327-1332. doi:10.1345/aph.1L183
8.
UyNThiagarajanPMusherDM. Cephalosporin side chain idiosyncrasies: a case report of ceftriaxone-induced agranulocytosis and review of literature. Open Forum Infect Dis. 2015;2:ofv007. doi:10.1093/ofid/ofv007
9.
TurnerRBWilsonDESaedi-KwonH, et al. Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline. J Antimicrob Chemother. 2018; 73:772-778. doi:10.1093/jac/dkx452
ForshawJ. Penicillin-induced granulopenia. Br Med J. 1968;3:184. doi:10.1136/bmj.3.5611.184
12.
GrafMTarlovA. Agranulocytosis with monohistiocytosis associated with ampicillin therapy. Ann Intern Med. 1968;69:91-95. doi:10.7326/0003-4819-69-1-91
13.
IrvineAEFrenchADalyARanaghanLMorrisTC. Drug-induced neutropenia due to direct effects on CFU-C—ten years of culture experience. Eur J Haematol. 1994;52:21-27. doi:10.1111/j.1600-0609.1994.tb01280.x
14.
LeeDDewdneyJMEdwardsRGNeftelKAWaltiM. Measurement of specific IgG antibody levels in serum of patients on regimes comprising high total dose beta-lactam therapy. Int Arch Allergy Appl Immunol. 1986;79:344-348. doi:10.1159/000234000
MeyerOGaedickeGSalamaA. Demonstration of drug-dependent antibodies in two patients with neutrophenia and successful treatment with granulocyte-colony-stimulating factor. Transfusion. 1999;39:527-530. doi:10.1046/j.1537-2995.1999.39050527.x
17.
MurphyMFRiordanTMinchintonRM, et al. Demonstration of an immune-mediated mechanism of penicillin-induced neutropenia and thrombocytopenia. Br J Haematol. 1983;55:155-160. doi:10.1111/j.1365-2141.1983.tb01233.x
RouveixBLassouedKVittecoqDRegnierB. Neutropenia due to beta lactamine antibodies. Br Med J (Clin Res Ed). 1983;287:1832-1834. doi:10.1136/bmj.287.6408.1832
20.
SchmidLHeitWFluryR. Agranulocytosis associated with semisynthetic penicillins and cephalosporins: report of 7 cases. Blut. 1984;48:11-18. doi:10.1007/BF00320712
21.
GarbeE. Non-chemotherapy drug-induced agranulocytosis. Expert Opin Drug Saf. 2007;6:323-335. doi:10.1517/14740338.6.3.323
22.
AndersohnFKonzenCGarbeE. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007;146:657-665. doi:10.7326/0003-4819-146-9-200705010-00009
23.
AndrèsEMaloiselFZimmerJ. The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis. Br J Haematol. 2010;150:3-8. doi:10.1111/j.1365-2141.2010.08104.x
24.
Figueira-CoelhoJPereiraOPicadoBMendonçaPNeves-CostaJ. The use of granulocyte colony-stimulating factor does not appear to reduce recovery time in penicillin-related agranulocytosis during the treatment of endocarditis. J Heart Valve Dis. 2010;19:810-811.
25.
AhernMJHicksJEAndrioleVT. Neutropenia during high dose intravenous oxacillin therapy. Yale J Biol Med. 1976;49:351-360.
26.
DutroMPPiecoroJJJrWilsonHD. Nafcillin-induced neutropenia in two children. Am J Hosp Pharm. 1981;38:889-892.
ZakhirehBRootRK. Unusually high occurrence of drug reactions with nafcillin. Yale J Biol Med. 1978;51:449-455.
29.
KirkwoodCFLasezkayGM. Neutropenia associated with mezlocillin and piperacillin. Drug Intell Clin Pharm. 1985;19:112-114. doi:10.1177/106002808501900205
WilsonCGreenhoodGRemingtonJSVostiKL. Neutropenia after consecutive treatment courses with nafcillin and piperacillin. Lancet. 1979;1:1150. doi:10.1016/s0140-6736(79)91834-8
32.
RossiterMAGrayIRShintonNK. Penicillin-induced haemolytic anaemia. Br Med J. 1968;3:616-617. doi:10.1136/bmj.3.5618.616-e
33.
TimmisADCroftsMAMetcalfeJMonaghanMJSharpJJacksonG. Gonococcal endocarditis with penicillin-induced bone marrow hypoplasia: role of echocardiography. JAMA. 1981;246:672-673.
WalzBZupnickJUdenDKeatingA. Penicillin-induced agranulocytosis. West J Med. 1988;149:460-462.
36.
KaajaRValtonenVV. Leucopenia associated with beta-lactam antibiotic therapy. Acta Med Scand. 1984;216:531-534. doi:10.1111/j.0954-6820.1984.tb05042.x
37.
PengRRWuJZhaoW, et al. Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: does it really matter?PLoS Negl Trop Dis. 2017;11:e0005456. doi:10.1371/journal.pntd.0005456
38.
ColvinBRogersMLaytonC. Benzylpenicillin-induced leucopenia: complication of treatment of bacterial endocarditis. Br Heart J. 1974;36:216-219. doi:10.1136/hrt.36.2.216
39.
BenliAŞimşek-YavuzSBaşaranSÇağatayAÖzsütHEraksoyH. Hematologic adverse effects of prolonged piperacillin-tazobactam use in adults. Turk J Haematol. 2018;35:290-295. doi:10.4274/tjh.2018.0127
40.
ScheetzMHMcKoyJMParadaJP, et al. Systematic review of piperacillin-induced neutropenia. Drug Saf. 2007;30:295-306. doi:10.2165/00002018-200730040-00002
41.
KumarAChoudhuriGAggarwalR. Piperacillin induced bone marrow suppression: a case report. BMC Clin Pharmacol. 2003;3:2. doi:10.1186/1472-6904-3-2
Ruiz-IrastorzaGBarreiroGAguirreC. Reversible bone marrow depression by high-dose piperacillin/tazobactam. Br J Haematol. 1996;95:611-612. doi:10.1046/j.1365-2141.1996.d01-1952.x
44.
McDonaldCCottaMOLittlePJ, et al. Is high-dose β-lactam therapy associated with excessive drug toxicity in critically ill patients?Minerva Anestesiol. 2016;82: 957-965.
45.
ChenCCLinHAHungYJChenJH. Piperacillin-tazobactam induced bicytopenia in low cumulative treatment doses. BMJ Case Rep. 2019;12:e232944. doi:10.1136/bcr-2019-232944
46.
LambourneJKitchenJHughesCMerryC. Piperacillin/tazobactam-induced paresthesiae. Ann Pharmacother. 2006;40:977-979. doi:10.1345/aph.1G526
47.
RyePJRobertsGStaugasREMartinAJ. Coagulopathy with piperacillin administration in cystic fibrosis: two case reports. J Paediatr Child Health. 1994;30:278-279. doi:10.1111/j.1440-1754.1994.tb00635.x
48.
GoodingPGClarkBJSatheSS. Piperacillin: a review of clinical experience. J Antimicrob Chemother. 1982;9(suppl B):93-99. doi:10.1093/jac/9.suppl_b.93
UzunGOnemYHatipogluMTurhanVMutluogluMAyH. Piperacillin/tazobactam-induced neutropenia, thrombocytopenia, and fever during treatment of a diabetic foot infection. Scand J Infect Dis. 2013;45:73-76. doi:10.3109/00365548.2012.697638
51.
HeZFWuXAWangYP. Severe bone marrow suppression and hepatic dysfunction caused by piperacillin/tazobactam. Scand J Infect Dis. 2013;45:885-887. doi:10.3109/00365548.2013.805426
52.
ReichardtPHandrickWLinkeASchilleRKiessW. Leukocytopenia, thrombocytopenia and fever related to piperacillin/tazobactam treatment—a retrospective analysis in 38 children with cystic fibrosis. Infection. 1999;27:355-356. doi:10.1007/s150100050042
53.
BehbahaniRKostmanJR. Hypersensitivity reaction during prolonged use of piperacillin/tazobactam in treatment of osteomyelitis. Ann Pharmacother. 1995;29:936-937. doi:10.1177/106002809502900920
54.
KuyeOTealJDeVriesVGMorrowCATallyFP. Safety profile of piperacillin/tazobactam in phase I and III clinical studies. J Antimicrob Chemother. 1993;31(suppl A):113-124. doi:10.1093/jac/31.suppl_a.113
55.
VeveMPStuartMDavisSL. Comparison of neutropenia associated with ceftaroline or ceftriaxone in patients receiving at least 7 days of therapy for severe infections. Pharmacotherapy. 2019;39:809-815. doi:10.1002/phar.2301
56.
WongBBKoGJ. Neutropenia in patients receiving long-term cefepime therapy for osteomyelitis. Am J Health Syst Pharm. 2003;60:2229-2232. doi:10.1093/ajhp/60.21.2229
57.
FoongKSHsuehKBaileyTC, et al. A cluster of cefepime-induced neutropenia during outpatient parenteral antimicrobial therapy. Clin Infect Dis. 2019;69:534-537. doi:10.1093/cid/ciy1112
58.
FurtekKJKubiakDWBarraMVarugheseCAAshbaughCDKooS. High incidence of neutropenia in patients with prolonged ceftaroline exposure. J Antimicrob Chemother. 2016;71:2010-2013. doi:10.1093/jac/dkw062
59.
SullivanELTurnerRBO’NealHRJrCrum-CianfloneNF. Ceftaroline-associated neutropenia: case series and literature review of incidence, risk factors, and outcomes. Open Forum Infect Dis. 2019;6:ofz168. doi:10.1093/ofid/ofz168
60.
VaradaNLSakoulasGLeiLRChuaJ. Agranulocytosis with ceftaroline high-dose monotherapy or combination therapy with clindamycin. Pharmacotherapy. 2015;35:608-612. doi:10.1002/phar.1596
61.
JainRChanJDRogersLDellitTHLynchJBPottingerPS. High incidence of discontinuations due to adverse events in patients treated with ceftaroline. Pharmacotherapy. 2014;34:758-763. doi:10.1002/phar.1435
Van TuylJSJonesANJohnsonPN. Meropenem-induced neutropenia in a neonate. J Pediatr Pharmacol Ther. 2016;21:353-357. doi:10.5863/1551-6776-21.4.353
65.
EstellaJVillanuevaJCalvoM, et al. Bone marrow aplasia and meropenem in a paediatric patient. Br J Haematol. 2000;111:984-985. doi:10.1046/j.1365-2141.2000.02393.x
66.
CalandraGBWangCAzizMBrownKR. The safety profile of imipenem/cilastatin: worldwide clinical experience based on 3470 patients. J Antimicrob Chemother. 1986;18(suppl E):193-202. doi:10.1093/jac/18.supplement_e.193
67.
TepplerHGesserRMFriedlandIR, et al. Safety and tolerability of ertapenem. J Antimicrob Chemother. 2004;53(suppl 2):ii75-ii81. doi:10.1093/jac/dkh209
68.
GreeneGRCohenE. Nafcillin-induced neutropenia in children. Pediatrics. 1978;61:94-97.
HahnAFukudaTHahnDMizunoTFrenckRWJrVinksAA. Pharmacokinetics and pharmacogenomics of β-lactam-induced neutropenia. Pharmacogenomics. 2016;17:547-559. doi:10.2217/pgs-2015-0008
71.
JohnstonAUetrechtJ. Current understanding of the mechanisms of idiosyncratic drug-induced agranulocytosis. Expert Opin Drug Metab Toxicol. 2015;11:243-257. doi:10.1517/17425255.2015.985649
ChenWTChiCC. Associations of HLA genotypes with antithyroid drug-induced agranulocytosis: a systematic review and meta-analysis of pharmacogenomics studies. Br J Clin Pharmacol. 2019;85:1878-1887. doi:10.1111/bcp.13989
74.
BrownMAPileKDKennedyLG, et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis. 1996;55:268-270. doi:10.1136/ard.55.4.268
75.
LiebermanJAYunisJEgeaECanosoRTKaneJMYunisEJ. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry. 1990;47:945-948. doi:10.1001/archpsyc.1990.01810220061007
76.
HernándezRDelpianoLAmadorJAriasMCarrasco DelgadoJ. Neutropenia associated with the use of cefepime in pediatric patients with cystic fibrosis. Rev Chilena Infectol. 2019;36:112-114. doi:10.4067/S0716-10182019000100112
77.
KancirLMTuazonCUCardellaTASheagrenJN. Adverse reactions to methicillin and nafcillin during treatment of serious Staphylococcus aureus infections. Arch Intern Med. 1978;138:909-911.
78.
CouchonnalGJHinthornDRHodgesGRLiuC. Nafcillin-associated granulocytopenia. South Med J. 1978;71:1356-1358. doi:10.1097/00007611-197811000-00012
79.
ChangMOKohESKimMJ, et al. Nafcillin-induced bullous skin eruption with granulocytopenia in a patient with end-stage renal disease. Intern Med. 2012;51:287-289. doi:10.2169/internalmedicine.51.6091
80.
MalincarneLFrancisciDMartinelliLMasiniGBaldelliF. A case of severe cefepime-related neutropenia in a 15-year-old patient. Scand J Infect Dis. 2010;42:156-157. doi:10.3109/00365540903380503
81.
LeventhalJMSilkenAB. Oxacillin-induced neutropenia in children. J Pediatr. 1976;89:769-771. doi:10.1016/s0022-3476(76)80800-1
82.
FariñasMCde VegaTGarmendiaJGonzález-MacíasJ. Severe neutropenia in a patient treated with imipenem/cilastatin. Eur J Clin Microbiol Infect Dis. 1993;12:303-304. doi:10.1007/BF01967266
NorrisAHShresthaNKAllisonGM, et al. 2018 Infectious Diseases Society of America clinical practice guideline for the management of outpatient parenteral antimicrobial therapy. Clin Infect Dis. 2019;68:e1-e35. doi:10.1093/cid/ciy745
85.
MeyrePBRadosavacMBaumannLPisoRJHoffmannM. COVID-19 in a patient with accidental drug-induced neutropenia. Eur J Case Rep Intern Med. 2020;7:001848. doi:10.12890/2020_001848
86.
BlackELauTTEnsomMH. Vancomycin-induced neutropenia: is it dose- or duration-related?Ann Pharmacother. 2011;45:629-638. doi:10.1345/aph.1P583
87.
JuliáAOlonaMBuenoJ, et al. Drug-induced agranulocytosis: prognostic factors in a series of 168 episodes. Br J Haematol. 1991;79:366-371. doi:10.1111/j.1365-2141.1991.tb08042.x
88.
IbáñezLSabatéMBallarínE, et al. Use of granulocyte colony-stimulating factor (G-CSF) and outcome in patients with non-chemotherapy agranulocytosis. Pharmacoepidemiol Drug Saf. 2008;17:224-228. doi:10.1002/pds.1542
89.
McDanelJSPerencevichENDiekemaDJ, et al. Comparative effectiveness of beta-lactams versus vancomycin for treatment of methicillin-susceptible Staphylococcus aureus bloodstream infections among 122 hospitals. Clin Infect Dis. 2015;61:361-367. doi:10.1093/cid/civ308
90.
OlaisonLAlestigK. A prospective study of neutropenia induced by high doses of beta-lactam antibiotics. J Antimicrob Chemother. 1990;25:449-453. doi:10.1093/jac/25.3.449
91.
CorbettGMPerryDJShawTR. Penicillin-induced leukopenia. N Engl J Med. 1982;307:1642-1643. doi:10.1056/nejm198212233072611
92.
JoorabchiBKohoutE. Apparent penicillin-induced arrest of mature bone marrow elements. Br Med J. 1973;2:26-27. doi:10.1136/bmj.2.5857.26
93.
LekhakulaASwasdikulD. Drug-induced agranulocytosis: experience in two university hospitals. J Med Assoc Thai. 1991;74:121-130.
94.
KumarKKumarA. Reversible neutropenia associated with ampicillin therapy in pediatric patients. Drug Intell Clin Pharm. 1981;15:802-806. doi:10.1177/106002808101501015
SandbergMTuazonCUSheagrenJN. Neutropenia probably resulting from nafcillin. JAMA. 1975;232:1152-1154.
100.
FeldmanWENelsonJDStanberryLR. Clinical and pharmacokinetic evaluation of nafcillin in infants and children. J Pediatr. 1978;93:1029-1033. doi:10.1016/s0022-3476(78)81251-7
101.
NahataMCDeBoltSLPowellDA. Adverse effects of methicillin, nafcillin and oxacillin in pediatric patients. Dev Pharmacol Ther. 1982;4:117-123. doi:10.1159/000457400
102.
YoungsterIShenoyESHooperDC, et al. Comparative evaluation of the tolerability of cefazolin and nafcillin for treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting. Clin Infect Dis. 2014;59:369-375. doi:10.1093/cid/ciu301
103.
OrtbalsDWMarrJJ. Profound neutropenia caused by oxacillin. South Med J. 1977;70:1245-1246. doi:10.1097/00007611-197710000-00027
104.
BrookI. Leukopenia and granulocytopenia after oxacillin therapy. South Med J. 1977;70:565-566. doi:10.1097/00007611-197705000-00018
105.
PassoffTLSherryHS. Oxacillin induced neutropenia: a case report. Clin Orthop Relat Res. 1978;(135):69-70.
106.
ChuJYO’ConnorDMSchmidtRR. The mechanism of oxacillin-induced neutropenia. J Pediatr. 1977;90:668-669. doi:10.1016/s0022-3476(77)80413-7
107.
WalkerASCauseyMWSebestaJA. Cefazolin-induced neutropenia and thrombocytopenia following trauma: a case report. Mil Med. 2012;177:352-354. doi:10.7205/milmed-d-11-00319
108.
MaderJTReinarzJALeFrockJL. Cefotaxime treatment in patients with osteomyelitis and septic arthritis: a multicenter study. Clin Ther. 1982;5(suppl A):10-18.
109.
BaumgartnerJDGlauserMP. Tolerance study of ceftriaxone compared with amoxicillin in patients with pneumonia. Am J Med. 1984;77:54-58.
110.
HuiCHChanLC. Agranulocytosis associated with cephalosporin. BMJ. 1993;307:484. doi:10.1136/bmj.307.6902.484-a
111.
EronLJParkCHHixonDLGoldenbergRIPoretzDM. Ceftazidime in patients with Pseudomonas infections. J Antimicrob Chemother. 1983;12(suppl A):161-169. doi:10.1093/jac/12.suppl_a.161
112.
DahlgrenAF. Two cases of possible cefepime-induced neutropenia. Am J Health Syst Pharm. 1997;54:2621-2622. doi:10.1093/ajhp/54.22.2621
113.
HettmerSHeeneyMM. Cefepime-induced neutropenia in a teenager. Pediatr Blood Cancer. 2008;51:715-716. doi:10.1002/pbc.21664
114.
KalambokisGVassouABourantasKTsianosEV. Imipenem-cilastatin induced pure white cell aplasia. Scand J Infect Dis. 2005;37:619-620. doi:10.1080/00365540510040205
