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Is Ciprofloxacin in Combination With Beta-lactam Antibiotics a Recipe for Thrombocytosis?
Thrombocytosis is defined as a platelet count greater than 400,000/mcL. We report the case of a patient who developed thrombocytosis after receiving ciprofloxacin and ceftriaxone therapy. A 73-year-old African-American female presented to the hospital with altered mental status attributed to sepsis and urinary tract infection. Patient was initiated on multiple empiric antibiotic therapy and was subsequently transitioned to ciprofloxacin and ceftriaxone at different times as definitive therapy for treatment of Escherichia coli bacteremia and Escherichia coli urinary tract infection. The patient developed thrombocytosis during and/or proximally to the administration of ciprofloxacin and ceftriaxone. A myeloproliferative source for the thrombocytosis was ruled out by the hematology/oncology team with a negative Janus kinase 2 V617F mutation assay result. In addition, other nondrug reactive sources of thrombocytosis (infection and anemia) were generally ruled out because the thrombocytosis was proximally linked with ciprofloxacin and ceftriaxone administration. The Naranjo Adverse Drug Reaction Probability Scale assigned a score of 5, indicating ciprofloxacin or ceftriaxone independently or in combination as a probable cause of thrombocytosis. This case report suggests that ciprofloxacin in combination with ceftriaxone (a beta-lactam antibiotic) may be a probable cause of thrombocytosis.
Keywords: thrombocytosis, ciprofloxacin, ceftriaxone, beta-lactam antibiotics
Ciprofloxacin is an antibacterial agent with broad-spectrum activity against both gram-negative and gram-positive organisms; it has wide utility as an antimicrobial therapy for many systemic infections.1 Generally, ciprofloxacin is well tolerated except for a low incidence (1%–2.6%) of gastrointestinal side effects (nausea, diarrhea, vomiting), liver function test abnormalities, and rash.1 More recently, new warnings have been issued for ciprofloxacin, as serious adverse reactions such as tendinitis, tendon rupture, peripheral neuropathy, worsening of muscle weakness in patients with myasthenia gravis, and prolongation of the QT interval with isolated cases of torsade de pointes have occurred with ciprofloxacin use.1 Of particular note is the rare side effect of thrombocytosis that can develop with ciprofloxacin. In a study of geriatric patients receiving ciprofloxacin for treatment of infections, one patient out of 81 developed thrombocytosis.2 The incidence of this rare occurrence may possibly be increased by combining ciprofloxacin and beta-lactam antibiotics, which have their own risk of thrombocytosis. The incidence of thrombocytosis due to ciprofloxacin is not known; however, the incidence of thrombocytosis due to beta-lactams (ceftazidime, ceftriaxone, penicillin, etc.) is reported to be somewhere in the range of less than 5% to 30%.3,4 This wide range is likely due to difficulty in differentiating antibiotic-induced thrombocytosis from thrombocytosis occurring from an acute-phase reaction of an infection. Thrombocytosis is generally defined as a platelet count greater than 400,000/mcL.3 Thrombocytosis is classified as primary or secondary thrombocytosis.3 Primary thrombocytosis refers to elevated thrombocyte count, which is a manifestation of a myeloproliferative disorder, while secondary thrombocytosis is used to describe elevation in thrombocyte count not of myeloproliferative etiology, including drug-induced thrombocytosis.3 Early identification, evaluation, and treatment of thrombocytosis is essential to avoid complications of thrombocytosis such as thrombosis and bleeding.5 This case report is on a patient who developed thrombocytosis while on combination therapy of ciprofloxacin and ceftriaxone at different but proximal time points.
The patient was a 73-year-old female who presented to our hospital with altered mental status attributed to sepsis from a urinary tract infection. It was noted by her family that she had foul-smelling urine and warm skin. It was reported that she had a two-day history of somnolence, three-day history of abdominal pain with constipation, and one-day history of decreased appetite prior to admission. Her past medical history included ethanol dependence, glaucoma, hypertension, iron deficiency anemia, type-2 diabetes mellitus, and urinary incontinence. She had no known drug allergies. Her home medications included aspirin, 81 mg orally daily; ferrous sulfate, 325 mg orally daily; latanoprost 0.005% ophthalmic solution, one drop nightly; oxybutynin, 5 mg orally three times daily; polyethylene glycol, 17-g packet orally daily; glipizide, 2.5 mg orally daily; hydrocodone/acetaminophen, 10/325 mg every four hours as needed for pain; ibuprofen, 600 mg every six hours as needed for pain, and lisinopril, 20 mg orally daily.
Her vital signs were as follows: temperature, 100.4°F; heart rate, 105 beats per minute (BPM); systolic blood pressure, 108 mm Hg; diastolic blood pressure, 38 mm Hg; and respiratory rate, 16 respirations per minute (rpm). The complete metabolic panel results were as follows: sodium, 132 mmol/L; potassium, 3.1 mmol/L; chloride, 98 mmol/L; bicarbonate, 20 mmol/L; blood urea nitrogen, 57 mg/dL; serum creatinine, 2.65 mg/dL; serum glucose, 209 mg/dL; calcium, 8.6 mg/dL; albumin, 3.3 g/dL; aspartate aminotransferase, 26 U/L; alanine aminotransferase, 13 U/L; and alkaline phosphatase, 77 U/L. Complete blood count results were as follows: white blood cell (WBC) count, 20.9 x 103/mcL, hemoglobin, 6.6 g/dL; hematocrit, 22.3%; and platelets, 311,000/mcL. Other important laboratory results were as follows: lactate, 3.0 mmol/L; and C-reactive protein, 5.3 mg/dL.
Prompted by her presentation with a fever of 100.4°F, WBC count of 20.9 x 103/mcL, heart rate of 105 bpm, respiratory rate of 16 rpm, and lactate level of 3 mmol/L, the patient was given a preliminary clinical diagnosis of sepsis based on a joint assessment of systemic inflammatory response syndrome (SIRS) criteria and quick Sequential Organ Failure Assessment (qSOFA), with a SIRS score of 3/4 (leukocytosis, tachycardia, and fever) and qSOFA score of 1 (altered mental status). She also presented with an elevated serum creatinine of 2.65 mg/dL and an elevated blood urea nitrogen of 57 mg/dL, indicative of acute kidney injury. Other health problems that were diagnosed at admission included microcytic anemia, mild hyponatremia, and mild hypokalemia.
Given her clinical presentation, blood and urine cultures were obtained. A cerebrospinal fluid sample was also taken due to suspicion of meningitis as the cause for her altered mental status and infection. She was started on empiric therapy with vancomycin, piperacillin/tazobactam, and ciprofloxacin. After four days of antibiotic therapy, the patient’s vital signs and kidney function returned to normal and the WBC count began to trend downward (Table 1). The cerebrospinal fluid specimen excluded a diagnosis of meningitis with the results as follows: glucose, 107 mg/dL (normal range, 40–70 mg/dL); protein, 179.8 mg/dL (normal range, 15–45 mg/dL); and WBC count, 1/mcL (normal range 0–5/mcL). Both blood and urine cultures taken upon admission detected Escherichia coli sensitive to ciprofloxacin (Table 2). Therefore, the patient was de-escalated to ciprofloxacin alone and given a single dose. On the following day, ciprofloxacin was switched to ceftriaxone for better blood−brain barrier penetration.6 The patient was observed to be improving after three days of ceftriaxone and was switched back to ciprofloxacin alone. After eight days on a mix of antibiotic therapy (two days of vancomycin, four days of piperacillin/tazobactam, three days of ciprofloxacin, and four days of ceftriaxone), platelets began to increase significantly from 366,000/mcL to 515,000/mcL, suspected to be reactive to the infection. After four days, the patient’s platelet count continued to rise from 515,000/mcL to 957,000/mcL which prompted a medication adverse effect review that pointed to ciprofloxacin as a possible cause of thrombocytosis. With ciprofloxacin as a leading possible source of thrombocytosis because of the temporal association of its use with the platelet increase, the patient was switched from ciprofloxacin to aztreonam because both medications had similar E. coli coverage from the culture and susceptibilities result. The hematology/oncology medical team was subsequently consulted to assess the patient’s thrombocytosis; they recommended performing a Janus kinase 2 (JAK2) V617F mutation assay to rule out myeloproliferative disease. The JAK2 V617F mutation assay result returned negative. Following the switch from ciprofloxacin to aztreonam, the patient’s platelet levels continued to rise for four days, reaching a plateau from 515,000/mcL to 1,070,000/mcL, and then began to trend downward from 1,070,000/mcL to 928,000/mcL prior to being discharged. The patient completed aztreonam monotherapy and received a total course of 14 days of antibiotics from her first negative blood culture. She was discharged the following day with instructions to resume her home medications. Figure 1 depicts the patient’s platelet count during hospital stay. Table 3 contains the numerical data on the platelet count and antibiotic doses during the patient’s hospital stay.
|Table 1 Serum Creatinine (SCr) and White Blood Cell (WBC) Count During Hospital Stay|
|Date||SCr (mg/dL)||WBC x 103/mcL|
SCr normal range: 0.5–1.1 mg/dL (females) and 0.7–1.4 mg/dL (males)
WBC normal range: 4.5–11.0 x 103/mcL (males and females)
|Table 2 Cultures and Susceptibilities Results|
|January 2||Blood culture (two sets)||Escherichia coli||Resistant: ampicillin Sensitive: aztreonam, cefazolin, ciprofloxacin, gentamicin, trimethoprim/sulfamethoxazole|
|January 2||Urine||Escherichia coli (>100,000 colonies/mL)||Resistant: ampicillin Sensitive: amoxicillin/clavulanate, cefazolin, ciprofloxacin, gentamicin, nitrofurantoin, trimethoprim/sulfamethoxazole|
|January 4||Blood culture (two sets)||No growth|
|Table 3 Platelet Levels* and Total Daily Doses of Antibiotic Therapy Given During Hospital Stay|
|January 9||515,000||—||500 (orally)||—||1,000||—|
|*Platelets normal range: 130,000–400,000/mcL (males and females)|
Following the trend of the thrombocytosis (more than 400,000/mcL), the rise of the platelets was strongly associated with the following medications: ciprofloxacin and ceftriaxone, and to a very insignificant degree, piperacillin/tazobactam. Piperacillin/tazobactam was not strongly linked to the thrombocytosis because of the unlikelihood that piperacillin/tazobactam would still be present in the patient’s body. Due to its short elimination half-life of 0.7–1.2 hours7 and using a generous estimate that it takes seven elimination half-lives to eliminate 99% of a drug,8 piperacillin/tazobactam would be mostly removed from the patient’s body after 8.4 hours (i.e., January 6), which is two days prior to the thrombocytosis onset. Ciprofloxacin and ceftriaxone were the two antibiotics that were still predictably in the patient’s body proximally and during the steady rise of the patient’s platelets. Ciprofloxacin has an elimination half-life of approximately four hours and needs about 28 hours to be 99% eliminated from the patient’s body.1 Ceftriaxone has an elimination half-life of 5.8–8.7 hours and needs about 60.9 hours (approximately 2.5 days) to be 99% eliminated from the patient’s body.9 Ciprofloxacin and ceftriaxone were thought to be associated with the rise of the platelets starting January 7 (ciprofloxacin was still extrapolated to be in the patient’s system and ceftriaxone doses were administered) and leading to the thrombocytosis on January 9 (when both ciprofloxacin and ceftriaxone were administered, with ceftriaxone subsequently stopped by January 10 and ciprofloxacin continued until January 12). Upon medication review on January 12, ciprofloxacin was discontinued given its temporal association with thrombocytosis, and the patient was transitioned to aztreonam therapy to treat her E. coli bacteremia and urinary tract infection.
Table 4 is an adaptation of the Naranjo Adverse Drug Reaction Probability scale used to evaluate the likelihood of ciprofloxacin and ceftriaxone independently contributing to the thrombocytosis. The scores on the Naranjo scale can be interpreted as: a score greater than 8 is definite; a score of 5–8 is probable; a score of 1–4 is possible; and a score of less than 1 is doubtful. Based on her Naranjo scale score of 5 for ciprofloxacin and beta-lactam antibiotics individually, she had a probable likelihood of having thrombocytosis due to ciprofloxacin and ceftriaxone independently. Question number 5 (Are there alternative causes [other than the drug] that could on their own have caused the reaction?) on the Naranjo scale did not lead to a deduction, since the possibility of reactive causes of thrombocytosis due to the patient’s anemia and infection was very low, as the patient has had anemia chronically and her infection was clinically improving at the time of the development of thrombocytosis (WBC count was normal—9.4 x 103/mcL on January 9—and blood cultures were clear by January 4). Ciprofloxacin and ceftriaxone were both probable causes of the thrombocytosis. Whether one or both of these antibiotics together were responsible for the thrombocytosis is speculative and not definitive.
|Table 4 Assessing Ciprofloxacin and Beta-Lactam Induced Thrombocytosis Using Naranjo Adverse Drug Reaction Probability Scale11|
|Yes||No||Do Not Know||Ciprofloxacin||Beta-lactam (Ceftriaxone)|
Two studies have reported thrombocytosis as a clinical laboratory abnormality observed with ciprofloxacin and ceftriaxone, respectively.2,4 In an open study in a geriatric population, the efficacy and safety of oral ciprofloxacin was addressed. It concluded that oral ciprofloxacin is a well-tolerated, safe, and effective treatment option in this population. Of note, however, there was one case of reversible thrombocytosis. The study does not provide the specifics of the patient case and development of thrombocytosis, but it is suspected that this case was due more to the geriatric populations’ increased risk for adverse effects.1 Another study, by Oakes and colleagues, also identified that thrombocytosis occurred in patients receiving ceftriaxone and was higher in patients receiving twice-daily dosing of ceftriaxone (5.3%) compared to patients receiving once-daily doses (1.8%).
A review of the literature also revealed a case report by Finsterer et al. that reported thrombocytosis after initiation of ciprofloxacin and piperacillin/tazobactam combination therapy.10 The patient was a 50-year-old male who required antibiotic therapy for a bronchopulmonary infection. The thrombocytosis developed on the eighth day of hospitalization and was suspected to be an acute-phase reaction similar to that of our patient. However, the likelihood of acute-phase reaction from pulmonary infection contributing to thrombocytosis was dismissed because the patient was clinically improving before the onset of the platelet increase. The authors observed that since the platelet count increased two days following the initiation of ciprofloxacin and piperacillin/tazobactam, and the platelet count immediately declined upon discontinuation of ciprofloxacin and piperacillin/tazobactam combination therapy, that these two antibiotics were exclusively responsible for the thrombocytosis. The authors ruled out the other medications administered during his hospital stay as possible agents causing thrombocytosis. Within three weeks from discontinuation, the platelets counts returned to normal levels. The authors concluded that the rare side effect of thrombocytosis could have been due to the individual agents or the agents in combination.3 This study provided some evidence to suggest that the combination of ciprofloxacin and beta-lactams may be associated with the development of thrombocytosis, similar to our case report.
This patient experienced an episode of thrombocytosis after administration of a combination antibiotic regimen consisting of ciprofloxacin and ceftriaxone, with a remote administration of piperacillin/tazobactam. These medications were identified as the probable cause of thrombocytosis due to the downward trend that was observed with platelet levels after discontinuation of ciprofloxacin and ceftriaxone and the ensuing transition to aztreonam therapy. Our case suggests that the combination of ciprofloxacin with ceftriaxone (a beta-lactam antibiotic) may be a recipe for thrombocytosis.
Disclosure: The authors report no financial or commercial interest in regard to this article.
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