These authors detail the treatment of a rare case of drug-induced neutropenia and fever in a patient who was using vancomycin for infection following an ankle fracture.
Drug-induced neutropenia is a medical condition resulting in a decreased absolute neutrophil count (ANC) <1500/µL.1-3 A normal ANC ranges between 1,700 to 7,000/µL.1–3 One can calculate this by multiplying the white blood cell (WBC) count (normal range between 4,500 to 10,500 cells/mm3) by the percent of neutrophils in the blood.
Drug-induced neutropenia can be the result of a broad range of medications including antimicrobials, analgesics, antipsychotics, anticonvulsants, antithyroid medications, cardiovascular and antihistamine drug classes.3,4 Within the antibiotic class, vancomycin is one commonly used medication with adverse effects including abdominal pain, ototoxicity, nephrotoxicity, anaphylaxis, “red man syndrome” and, as we describe here, the uncommon adverse reaction of vancomycin-induced neutropenia.1,4,5
Vancomycin-induced neutropenia reportedly occurs at a rate of 2 to 8 percent.5,6 The exact mechanism of drug-induced neutropenia and vancomycin-induced neutropenia is unknown, but authors have proposed two theories.4 One theory includes an immunologic mechanism of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) immune-mediated hypersensitivity reaction with the development of anti-neutrophil antibodies. In some instances, studies have found the concomitant presentation of a rash and fever to mirror or follow the onset of neutropenia, both of which are also immune-mediated responses.4,5,7 A second theory suggests direct bone marrow toxicity but researchers believe this is a less likely cause.5,6
Patients generally develop neutropenia and associated complications (i.e., leukocytosis, fever, rash) with the onset after seven to 12 days of drug therapy while most cases occur 20 days after initiation of medication.4–6 This point sheds light on the presumed notion that the symptoms are generally time-related rather than dose-dependent (i.e., range of dose, total cumulative dose, serum concentration) or secondary to supratherapeutic doses.4,6 Despite drug fever not being a consistently reported finding, authors have documented drug fever as a significant adverse effect with recorded temperatures up to 104.7°F.7
The patients we see are commonly on multiple drugs that share neutropenia as a risk and/or side effect, making it difficult to determine the exact underlying cause of the incident. Furthermore, with clinicians often using these trigger medications such as antibiotics to treat an infection, not only can it be difficult to differentiate drug reaction versus bacterial infection versus other fever-causing disorders, it is also challenging to diagnose drug-induced neutropenia, vancomycin-induced neutropenia and vancomycin-induced fever. Few reports discuss both entities (i.e., neutropenia and fever) occurring in tandem.7,8
Typically, resolution of the symptoms (i.e., lab results trending toward normalization, fever reduction, clearing of rash) occurs after discontinuation of the medication (range one to five days) with full neutrophil recovery three to four weeks following treatment.6 If there is an absolute need for long-term vancomycin use greater than seven days with concern for vancomycin-induced neutropenia, we recommend a WBC count with differential along with absolute neutrophil count weekly for monitoring. Discontinuation of therapy should occur with the presence of any hematological abnormality.1,4
When vancomycin-induced neutropenia occurs in a patient, it is unknown if the patient will react similarly in future situations and we recommend alternative therapeutic approaches for treatment. Other documented replacement therapy options include teicoplanin (Targocid, Sanofi) if a vancomycin equivalent is required, administration of granulocyte colony-stimulating factor with delayed administration of vancomycin or concurrent vancomycin/filgrastim (Neupogen, Amgen) therapy.3–6
A 68-year-old woman was under our care for the treatment of a left ankle fracture with secondary wound complications and infection. Her initial injury, a left trimalleolar ankle fracture and dislocation, occurred on November 10, 2017 and we performed open reduction internal fixation (ORIF) the next day. There was delayed healing of a 3 cm segment of the incision site. We treated the wound with local care but further breakdown occurred secondary to friction and pressure from a controlled ankle motion (CAM) boot while she transitioned to full weightbearing status. She received treatment in a wound care center but returned to the hospital emergency department on Dec. 27 for fevers, increasing pain, edema and cellulitis (see photo at left).
Upon hospital admission, the patient’s vitals/lab results included: 100°F, 10.84 WBC count, 89 mm/hr erythrocyte sedimentation rate (ESR) and 215.70 mg/L C-reactive protein (CRP). We started the patient on IV vancomycin 1 g and performed daily dressing changes to monitor the lateral ankle wound. The wound cultures grew methicillin-sensitive Staphylococcus aureus (MSSA) and Enterococcus. The patient had various antibiotic allergies (i.e., penicillin, cephalosporins, erythromycin and sulfur) with a history of uncomplicated use of IV vancomycin. Therefore, we continued to use IV vancomycin at this time with input/management by the hospital infectious disease team.
The clinical appearance of the wound improved each day with resolving edema and cellulitis (see figures 1b-d). However, the patient continued to have persistent fever spikes ranging from 100.5 to 101.3°F as well as a downward trend in her WBC from 11 to 5 on Dec. 31. Despite the reported fevers, the patient was asymptomatic with a non-toxic presentation. A chest X-ray was negative. Urinalysis with culture was positive for E. coli but but infectious disease reports this as likely contamination and unlikely to be the cause of the patient’s fevers as she was asymptomatic overall for a urinary tract infection. Multiple sets of blood cultures taken throughout the entire hospital stay were also negative. Due to persistent fevers, we ordered a magnetic resonance imaging (MRI) of the ankle, which demonstrated no collections in the soft tissues with only non-specific fluid in the ankle joint.
Despite no evidence of contiguous connection of the wound bed to deeper underlying structures, there was concern for a septic joint based on the MRI report. The patient had an operative arthroscopic ankle joint washout with wound debridement on Jan. 1, 2018. No intraoperative purulence was present. Operative cultures and pathology specimens revealed methicillin-sensitive Staphylococcus aureus. Unfortunately, the fevers persisted, increasing to 102.7°F and a maximum temperature of 103°F on Jan. 4 with WBC trending down to 4.61, 3.91, and finally 2.01 on Jan. 5. Her absolute neutrophil count decreased from 8.19 upon admission to 1.27 on Jan. 5.
The patient went back to the operating room on January 5 for repeat ankle joint washout and removal of all internal hardware with repeat cultures and pathology specimens again revealing MSSA (see Figure 2a). Bone cultures and pathology did not demonstrate findings consistent with osteomyelitis. The infectious disease team was concerned about the possibility of vancomycin-induced neutropenia and fevers. Accordingly, we discontinued the vancomycin and converted the patient to daptomycin 435 mg IV daily, starting on January 5.
Two days later, the patient’s WBC returned to 4.2 with resolution of the fever (see Figures 3-4). However, the patient developed a rash on her legs, arms and back. After four days of daptomycin (Cubicin, Merck), the patient’s rash persisted with WBC increasing to 6.63. Overall, though, the patient’s appearance and strength improved. On January 10, we discontinued daptomycin use due to the aforementioned rash and concern for renal and/or hepatic injury with a bump in creatine phosphokinase (251 IU/L on January 8) resolving to 72 on January 10.
We subsequently initiated IV clindamycin 300 mg q8h and PO rifampin (Rifadin, Sanofi) 300 mg BID. We discharged the patient later that day to a skilled nursing facility with wound care follow-ups. We were able to achieve wound closure approximately six weeks later with initial negative pressure wound therapy and subsequent use of Promogran Prisma™ Matrix (Acelity) (see Figures 2b-d).
The wound remains healed with no lab work irregularities related to the case as of this report’s publication.
There are limited case studies and research on the topic of vancomycin-induced neutropenia and fevers. However, it appears that our patient had such an incident. The increase in temperature and drop in WBC/ANC occurred on the same day after a total of nine days of IV vancomycin therapy, a pattern consistent with documented delayed and time-related onset of symptoms. Upon cessation of the vancomycin, symptoms typically resolve and labs/vitals normalize in the subsequent days. Again, this was consistent with our patient’s course.
Many patients take combinations of drugs that have documented neutropenia as an adverse effect, making it difficult to determine one single culprit of the incident. We hope to have highlighted vancomycin as a potential causative agent for drug-induced neutropenia and fever in our case report.
After post-case reflection, we debated whether the continued washout procedures and hardware removal were necessary due to the patient seeming to not improve with spiking fevers while on the vancomycin. We also wondered if the vancomycin-induced neutropenia presentation clouded the “appropriate” course of treatment. Additionally, was the rash a result of the daptomycin or a delayed vancomycin-induced neutropenia sequela? Nonetheless, the collaborative efforts among the medicine, infectious disease and podiatric teams worked in a stepwise fashion for infection control and medical stability with an optimal result considering the patient’s circumstances.
Dr. Hood is a fellowship-trained foot and ankle surgeon, and associate at Premier Orthopaedics and Sports Medicine in Malvern, Pa. Follow him on Twitter at @crhoodjrdpm.
Dr. Morrison is a first-year resident with the Bryn Mawr Hospital/Main Line Health System PMSR/RRA residency in Bryn Mawr, Pa.
The authors especially thank David R. Trevino, MD (Infectious Disease and Preventative Medicine, Main Line Health System) and Dr. David N. Tachna, DPM (Foot and Ankle Center and The Paoli Hospital Wound Healing & Hyperbaric Center, Main Line Health System) for their collaboration in patient care.
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