Vancomycin-Induced Leukopenia and Neutropenia: Time Will Tell

Abstract

Purpose: Neutropenia is an uncommon adverse effect associated with prolonged vancomycin therapy. Methods: This was a case report on a 62-year-old African American male with hypertension, paranoid schizophrenia, and a history of polysubstance abuse developed foot osteomyelitis. The patient was initially maintained on intravenous Vancomycin & Ceftriaxone for ~3 weeks but adjusted to Daptomycin & Ceftriaxone while in hospital due to neutropenia. Patient’s neutropenia quickly resolved once discontinuation of Vancomycin occurred. Results: Vancomycin is a potential cause of drug induced leukopenia and neutropenia. Monitoring of leukocytes and neutrophils is warranted in patients receiving long term intravenous Vancomycin therapy. Conclusion: Vancomycin is a bactericidal glycopeptide antibiotic with activity against gram-positive organisms such as Staphylococci. Well-known adverse drug events include nephrotoxicity and ototoxicity. Vancomycin-induced neutropenia on the other hand is less common and reported at lower rates. It is defined as an ANC less than 1000 µL in patients maintained on Vancomycin infusions. According to Black et al, neutropenia is more likely associated with prolonged therapy; generally occurring at least 20 days after initiation.

Case Summary

A 62-year-old African American male with hypertension, paranoid schizophrenia, and a history of polysubstance abuse was initially admitted to the inpatient psychiatric unit for evaluation and management of acute psychosis. Admission labs were unremarkable including WBC count of 4.3 K/µL. During the first week of admission, the patient was switched from oral risperidone to intramuscular paliperidone depot injections. This was a re-initiation of paliperidone depot injections since a review of the health record showed that he had completed an initiation series 6 weeks prior but was outside of the window to resume maintenance doses. The WBC count remained normal in the psychiatric unit and monthly maintenance doses were continued throughout this patient’s entire hospital stay.

This patient was also found to have a right second toe ulcer that was concerning for chronic osteomyelitis based on magnetic resonance imaging (MRI) but bone biopsy had no growth. He was afebrile and hemodynamically stable. No operative intervention was recommended but given the lack of growth on bone culture and the uncertainty for patient’s compliance with oral antibiotics, infectious disease team recommended empiric therapy with 6 weeks of inpatient intravenous (IV) vancomycin and ceftriaxone. This patient was then transferred from the psychiatric unit to hospital medicine on day 27 of admission and ceftriaxone 2 g IV daily and vancomycin 1500 mg IV twice daily was initiated. WBC count at this point was normal at 5.1 K/µL. Serum vancomycin troughs ranged from 8.8 mg/L to 23.9 mg/L with most levels remaining between target trough of 15 and 20 mg/L.

On day 23 of IV vancomycin and ceftriaxone therapy and day 47 of paliperidone therapy, a low total WBC count of 2.1 K/µL was found with differential showing low neutrophil count of 147 cells/µL (Table 1). This was significantly decreased from the pre-antibiotic counts of 4.3 K/µL and 1892 cells/µL, respectively. Leukocytes and neutrophils continued to decrease the next day and reached nadirs of 2.0 K/µL and 30 cells/µL, respectively. The patient remained hemodynamically stable and denied any symptoms.

Table 1.

Clinical Course of Patient Before, During, and After Vancomycin Therapy.

Event a	Paliperidone therapy
	Vancomycin and ceftriaxone therapy								Vancomycin switched to daptomycin
Hospital Day b	8	13	27	31	34	42	49	50	52	53	56	58	62	70
White Blood cells (K/µL)	4.3		5.1	5.6	5.1	4.1	2.1	2.0	3.4	3.8	4.0	5.8	5.7	4.8
Neutrophil (cells/µL)	1892						147	30	102		1432	2790	3004

^aEvent = therapy events include medication initiation, discontinuation, and changes as specified.

^bHospital Day = day of hospital stay out of the total 70-day duration.

This patient was concurrently receiving paliperidone, ceftriaxone, and vancomycin, which have all been associated with leukopenia and neutropenia. Based on the temporal relationships between therapy initiation and neutropenia occurrence as well as the frequency at which neutropenia occurs for each, it was determined that paliperidone and ceftriaxone were less likely causes.

Previous case reports have shown that paliperidone-induced neutropenia typically occurs within 14 to 29 days of exposure while this patient’s low counts did not occur until after 46 days of re-initiation and after 98 days of first paliperidone initiation.^2-5 Ceftriaxone induced agranulocytosis is extremely rare and less common than paliperidone and vancomycin induced leukopenia. In most case reports, it has occurred in a patient on ceftriaxone 2 g IV daily for >21 days.^6,7 The cumulative dose potentially leads to an immune-mediated mechanism that induces antibody formation against neutrophils in a dose-dependent inhibition of granulopoiesis. ⁸

Vancomycin-induced neutropenia typically occurs with prolonged exposure of at least 7 days, usually after 20 days of therapy, and resolves within 48 to 72 hours of vancomycin withdrawal.^9,10 Although the exact mechanism of vancomycin-induced neutropenia is unclear, it has been proposed that this is duration-dependent, immunological reaction rather than direct bone marrow destruction.^9,11,12 Previous case reports have reported similar findings in various indications requiring long duration of Vancomycin.^1,9,11,12 Particularly, a meta-analysis conducted by Black et al that included 26 case reports which assessed dose versus duration of vancomycin-induced neutropenia. This meta-analysis found that most incidents occurred after ≥20 days of vancomycin therapy. ⁹ While this is promising for this patient, he was also on 2 other medications that could have potentiated this event.^2-5

Vancomycin was determined to be the most likely cause for neutropenia since neutropenia associated with ceftriaxone is less common. Additionally, one change was made at a time since adjusting multiple medications simultaneously would have confounded findings as to the causative agent. Gram-positive bacterial coverage was switched to daptomycin while ceftriaxone remained active. No other interventions were performed. After 3 days without vancomycin, WBC count and neutrophils increased and normalized after 1 week to 4.0 K/µL and 1432 cells/µL, respectively (Table 1). These counts remained within normal range for the remaining 18 days of antibiotic therapy and he was discharged. Unfortunately, the patient missed his follow up appointment with the infectious disease clinic and attempts at rescheduling were unsuccessful.

The Naranjo Scale is scale that was developed in 1999 to help standardize the causality of all adverse drug reactions. ¹³ This is a validated too that was used to assess the causality of vancomycin and this patient’s leukopenia had a total score of 5 points which quantifies that it was the probable cause of this drug-induced reaction (Tables 2 and 3). WBC count and neutrophils increased despite continued administration of paliperidone and ceftriaxone, confirming that vancomycin, not these medications, was affecting this low patient’s counts.

Table 2.

Naranjo Algorithm – Adverse Drug Reaction Probability Scale. ¹³

Question	Yes	No	DK/NA	Score
1. Are there previous conclusive reports on this reaction?	+1	0	0
2. Did the adverse event appear after the suspected drug was administered?	+2	−1	0
3. Did the adverse event improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0
4. Did the adverse event reappear when the drug was readministered?	+2	−1	0
5. Are there alternative causes that could on their own have caused the reaction?	-1	+2	0
6. Did the reaction reappear when a placebo was given?	−1	+1	0
7. Was the drug detected in blood or other fluids in concentrations known to be toxic?	+1	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0
10. Was the adverse event confirmed by any objective evidence?	+1	0	0
Total Score:				5

Table 3.

Naranjo Algorithm – Adverse Drug Reaction Probability Scale Interpretation. ¹³

Interpretation of Scores	Score
Definite. The reaction (1) followed a reasonable temporal sequence after a drug or in which a toxic drug level had been established in body fluids or tissues, (2) followed a recognized response to the suspected drug, and (3) was confirmed by improvement on withdrawing the drug and reappeared on reexposure.	Total Score ≥9
Probable. The reaction (1) followed a reasonable temporal sequence after a drug, (2) followed a recognized response to the suspected drug, (3) was confirmed by withdrawal but not by exposure to the drug, and (4) could not be reasonably explained by the known characteristics of the patient’s clinical state.	Total Score 5 to 8
Possible. The reaction (1) followed a temporal sequence after a drug, (2) possibly followed a recognized pattern to the suspected drug, and (3) could be explained by characteristics of the patient’s disease.	Total Score 1 to 4
Doubtful. The reaction was likely related to factors other than a drug.	Total Score ≤0

What is New and Conclusion?

Vancomycin-induced neutropenia is a rare but serious complication of therapy. Close monitoring of leukocytes and neutrophils is necessary in patients receiving vancomycin beyond 7 days. Deciphering the likely causative agent in patients with multiple neutropenia-inducing medications can be difficult. Considering the temporal relationship remains a useful determinant for attempting to identify causality when multiple medications have been associated with similar complications. Assessing other potential options for treating indications that require long term use of antibiotics will help prevent adverse related outcomes. In this case daptomycin was an appropriate choice for treating this patient’s bacteremia.