Does rifampin cause neutropenia? If so, what are the options to manage neutropenia?

Does rifampin cause neutropenia? If so, what are the options to manage neutropenia?

Comment by InpharmD Researcher

Though scant evidence exists to determine whether rifampin is directly linked to incidence of neutropenia, prescribing information for generic rifampin warn of signs and symptoms of hypersensitivity reactions (e.g., neutropenia) and case reports suggest compounding severity of neutropenia with rifampin exposure (see Tables 1-3). In these limited case reports, discontinuation of rifampin treatment led to resolution of neutropenia.

Pubmed: rifampin + neutropenia

Background

In addition to more focused case reports, rifampin has been linked to incidence of neutropenia in other studies. In a 2022 retrospective chart review focused on assessing the incidence of myelosuppression in pediatric patients receiving nafcillin or a combination of nafcillin and rifampin therapy, patients receiving combination treatment with rifampin were observed to have a significantly increased risk of neutropenia (10.42% vs. 19.80%; p= 0.0003). The significance of rifampin-associated neutropenia was also acknowledged in another case report, which focused on use of rifampin combined with ofloxacin, noting that rifampin may increase severity of neutropenia. [1], [2]

Relevant Prescribing Information

Warnings [3]
Systemic hypersensitivity reactions were reported with rifampin capsules administration. Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). Manifestations of hypersensitivity, such as fever, lymphadenopathy or laboratory abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. Monitor patients receiving rifampin capsules for signs and/or symptoms of hypersensitivity reactions. If these signs or symptoms occur, discontinue rifampin capsules and administer supportive measures.

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Does rifampin cause neutropenia? If so, what are the options to manage neutropenia?

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-3 for your response.

Leukopenia induced by anti-tuberculosis treatment
Design	Case report
Case presentation	A 43-year-old male patient presented with pleural tuberculosis. All biological tests ordered prior to treatment were normal. The patient was started on a regimen of rifampicin (rifampin) 600 mg once daily, isoniazid 300 mg once daily, pyrazinamide 1500 mg once daily, and ethambutol 1200 mg once daily. After one month of treatment, the patient developed leukopenia, neutropenia, elevated transaminases, and cholestasis. All medications were discontinued and the treatment regimen was adjusted to ethambutol, isoniazid, ciprofloxacin, and rifampicin (rifampin). Rifampicin (rifampin) was the last drug that was re-introduced. Two days later, neutrophils dropped from 1600 to 600 cells/mm³. Rifampin was deemed to be a causative agent of the neutropenia and was discontinued. The final treatment regimen consisted of isoniazid, ethambutol, and ciprofloxacin for eight months. After the medication adjustment, the patient did not experience recurrent pleural effusion.
Study Author Conclusions	Identifying the specific drug responsible for neutropenia in patients on anti-tuberculosis regimens is often challenging. In this case, rifampin was considered the most likely causative agent of neutropenia.

References:
[1] Belloumi N, Ben Bdira B, Bachouche I, Kacem M, Abdallah FC. Leukopenia induced by anti-tuberculosis treatment. J Tuberc. 2018;1:1005.

Neutropenia probable secundaria al tratamiento con rifampicina
Design	Case report
Case presentation	A 46-year-old woman with psoriatic arthritis receiving methotrexate and prednisone who was being evaluated for certolizumab therapy. Screening revealed latent tuberculosis infection based on a positive Mantoux test (6 mm) with normal chest imaging. She was started on rifampicin 600 mg/day plus isoniazid with pyridoxine (300/50 mg/day) for three months. One month later, certolizumab was initiated, after which her neutrophil count declined from 2.8 to 1.7 × 10⁹/L, progressing to severe neutropenia (0.3 × 10⁹/L) within 15 days. Rifampicin and isoniazid were discontinued, while certolizumab was continued; neutrophil counts increased to 0.8 × 10⁹/L within one week and returned to normal after one month. Isoniazid monotherapy was later resumed for nine months without recurrence of neutropenia. Using the modified Karch–Lasagna algorithm, the association between rifampicin and neutropenia was deemed probable (score 6).
Study Author Conclusions	Drug-induced neutropenia from antituberculous agents is rare (<1%) but potentially serious. The chronology, reversibility after withdrawal, and tolerance to isoniazid suggest rifampicin as the causative agent. This case highlights the need to monitor the complete blood count, in addition to liver transaminases, at least during the first month of treatment of latent tuberculosis infection with rifampicin, especially in patients with risk factors, in order to detect hematological alterations early and prevent progression to agranulocytosis.

References:
[1] España-Marí G, Álvarez-Arroyo L, Alentado-Mateu A, Limón-Ramírez R, Montañés-Pauls B. Neutropenia probable secundaria al tratamiento con rifampicina [Probable neutropenia secondary to treatment with rifampicin]. Rev Esp Quimioter. 2025;38(5):444-446. doi:10.37201/req/062.2025

Neutropenia Secondary to Tuberculosis Treatment. Neutropenia secundaria al tratamiento de la tuberculosis.
Design	Case report
Case presentation	A 43-year-old previously healthy man presented with a month of fever, constitutional symptoms, and radicular low back pain. Imaging revealed disseminated extrapulmonary and pulmonary tuberculosis, including cervical lymphadenopathy, pulmonary nodules, L1–L2 spondylodiscitis with intra- and perivertebral collections, and extensive psoas–iliac and adductor muscle abscesses. Microbiological evaluation of a drained psoas abscess confirmed rifampicin-susceptible Mycobacterium tuberculosis. The patient was initially treated with standard four-drug therapy (isoniazid, rifampicin, ethambutol, pyrazinamide), extended to three months because of extensive disease and residual undrained collections, followed by isoniazid and rifampicin continuation. During month 5, he developed severe neutropenia, complicated by intolerance to G-CSF. Sequential drug withdrawals and reintroductions demonstrated recurrent neutropenia clearly associated with rifampicin, with resolution upon discontinuation. Ultimately, a rifampicin-free regimen of isoniazid, ethambutol, and moxifloxacin was tolerated and continued to complete 12 months of therapy. The patient remained clinically stable and asymptomatic throughout neutropenia, achieved radiological resolution of collections, and had normalization of blood counts after treatment completion. Given the favorable clinical response, partial exposure to rifampicin, and persistent hematologic toxicity, treatment was not extended to 18 months despite rifampicin intolerance.
Study Author Conclusions	Our patient’s neutropenia reappeared unequivocally after isolated reintroduction of rifampicin and in the absence of other drugs, so its association with neutropenia can be defined as “certain” according to the WHO causality classification. However, his neutrophil count did not completely normalize until the antituberculous treatment including isoniazid was completed, so it is reasonable to think that both drugs contributed to the etiology of the neutropenia. In short, our intention is to warn of this hematological toxicity that may appear with tuberculosis treatment (especially isoniazid and rifampicin) and to share our particular experience on its progress and management, in case it could be of help to the rest of the scientific community.

References:
[1] Pérez Catalán I, Roig Martí C, Andrés Soler J, et al. Neutropenia Secondary to Tuberculosis Treatment. Neutropenia secundaria al tratamiento de la tuberculosis. Arch Bronconeumol (Engl Ed). 2021;57(5):375-377. doi:10.1016/j.arbres.2020.08.021