Imipenem–cilastatin-induced thrombocytosis: A probable rare case report

Abstract

Drug-induced thrombocytosis is difficult to identify and is rarely reported. Here, we report a probable rare case of imipenem–cilastatin-induced thrombocytosis in a 51-year-old female. The patient received imipenem–cilastatin treatment because of an intra-abdominal infection, following which the platelet count increased to a peak value of 1058×10⁹ cells/L in 14 days. When imipenem–cilastatin was replaced by levofloxacin and amikacin, the platelet count decreased progressively and remained within the normal range until the 6-month follow-up. Moreover, platelet counts were independent of the infection. Thrombocytosis was probably attributable to imipenem–cilastatin with a Naranjo score of seven. This is a probable rare case in which the thrombocytosis was likely an adverse reaction induced by imipenem–cilastatin. We suggest that clinicians need to be vigilant concerning the impact of imipenem–cilastatin on platelet count in patients with thrombocytosis.

Introduction

Imipenem-cilastatin is a commonly used broad-spectrum carbapenem for the treatment of complicated infections. ¹ It has shown good safety and efficacy; however, rare adverse effects, induced by one or both components, have been discovered gradually as it becomes more widely used. Common adverse events reported with imipenem–cilastatin include irritation at the injection site, diarrhea, rash, nausea, and vomiting. ² A rare adverse event of imipenem–cilastatin is a hematologic reaction, including thrombocytopenia and thrombocytosis.^3,4 The rare effect of imipenem-cilastatin on platelets appears as thrombocytopenia at a rate of <1% in adults. ⁵ Thrombocytosis caused by imipenem–cilastatin is rarer than thrombocytopenia but may be related to a thromboembolism or a hemorrhagic event. ⁶ Thrombocytosis can be defined as the abnormal accumulation of platelets in the blood with a threshold of >450 × 10⁹ cells/L for adults and can be further categorized into primary (essential) and secondary (reactive) thrombocytosis.^7,8 Potential factors that can contribute to secondary thrombocytosis include acute blood loss, infection, inflammation, hemolytic anemia, and drug reaction.^9,10 Drugs may cause thrombocytosis, but this is rarely reported. ⁹ Although thrombocytosis was found in patients with infections receiving imipenem–cilastatin, this adverse event was not attributed to imipenem–cilastatin because of coexisting confounding factors, mainly infection. ³ Here, we report a rare case of thrombocytosis that was probably attributable to imipenem–cilastatin treatment.

Case presentation

A 51-year-old female outpatient presented at her doctor’s office with a suspected urinary tract infection. She reported hypogastrium pain for 7 days and fever for 4 days. Her body mass index was 22.0. She had a history of urinary calculi 6 months previously but no other comorbidity or surgical history. The patient reported no history of smoking, alcohol drinking, or medicine use, but reported a history of allergy to cephalosporins. Laboratory tests revealed the following results: white cell count 15.97 × 10⁹ cells/L, C-reactive protein (CRP) 112.1 mg/L, procalcitonin (PCT) 0.364 ng/mL, and platelets 358 × 10⁹ cells/L. She was hospitalized the next day with a suspicious urinary tract infection. Initial empiric anti-infection therapy was started using levofloxacin (0.5 g/day, i. v.) on admission. But the patient had no typical symptoms of a UTI such as frequent urination or painful urination. Ultrasound examination also found no abnormities in the kidney, ureter, or bladder. Subsequently, a full-body computed tomography (CT) scan identified a pelvic abscess and peritonitis on day 3 of admission. The abscess may have been of urinary tract origin because of her history of urinary calculi. Thus, imipenem–cilastatin (0.5 g/8 h, i. v.) therapy was initiated instead of levofloxacin because of its superior activity against common bacteria found in intra-abdominal infections. CRP and PCT levels decreased over the following days and the patient felt better, but physical examination revealed remaining tenderness and, to a lesser extent, rebound tenderness. A repeated CT scan on day 8 of admission revealed fluid accumulation around the abscess. The abscess was localized but seemed not able to resolve. Transvaginal pelvic abscess puncture and drainage guided by B ultrasound was then performed on day 10 and imipenem-cilastatin therapy was continued. Microculture of the drainage abscess revealed drug-sensitive Escherichia coli on day 12. A repeat CT scan was done on day 18, showing that source control was achieved. During imipenem–cilastatin therapy, the platelet count increased continuously, and no other cause related to the thrombocytosis was diagnosed. We used the Naranjo scale to evaluate the causality of drugs used and the thrombocytosis. The Naranjo score of imipenem–cilastatin was seven and the relationship was defined as “probable” Table 1 while the scores for other drugs were all below two. Severe infection is a common cause of thrombocytosis but the trend in CRP levels did not parallel the trend in platelet counts. No other condition associated with thrombocytosis was identified. Thus, thrombocytosis was probably attributable to imipenem–cilastatin administration. Antimicrobial therapy was changed to levofloxacin (0.5 g/day, i. v.) combined with amikacin (0.4 g/day, i. v.) on day 14. Aspirin (100 mg/day, po) and low-molecular-weight heparin (4100 IU/day, subcutaneous injection) were also administered because the patient had a Padua score of 6, and therefore there was a high risk of a thromboembolism event. CRP levels continued to decrease, and the symptoms related to the pelvic abscess were relieved. She was discharged on day 24 and continued an additional 4 days of oral levofloxacin treatment. Her renal and liver function remained normal during hospitalization, and no clinically significant coagulation function abnormality was found. Detailed platelet counts and pharmacological treatment history are shown in Figure 1. Other laboratory tests are listed in Table 2.

Table 1.

Naranjo score questionnaire for imipenem–cilastatin in a patient with thrombocytosis.

Question	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	+1
Did the adverse events appear after the suspected drug was given?	+2	-1	0	+2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	+1	0	0	+1
Did the adverse reaction appear when the drug was readministered?	+2	-1	0	0
Are there alternative causes (other than the drug) that could have caused the reaction?	-1	+2	0	+2
Did the reaction reappear when a placebo was given?	-1	+1	0	0
Was the drug detected in any body fluid in toxic concentrations?	+1	0	0	0
Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1

Figure 1.

Timeline showing the patient’s platelet counts and timing of specific drug administration. Dose of each drug: imipenem-cilastatin, 0.5 g every 8 h, intravenous infusion; levofloxacin, 0.5 g every 24 h, intravenous infusion; amikacin, 0.4 g every 24 h, intravenous infusion; aspirin, 100 mg every day, oral; low-molecular-weight heparin, and 4100 IU every day, subcutaneous injection.

Table 2.

Laboratory findings for a patient who developed thrombocytosis during imipenem–cilastatin treatment.

	Reference range	D0	D2	D3	D6	D9	D12	D13	D14	D17	D21	D22
T(°C)	36.0–37.0	—	38.4	37.9	37.4	37.4	37.4	37.3	37.3	36.8	36.8	36.7
WBC(×109/L)	3.5–9.5	15.97	14.42	19.16	13.47	11.38	7.55	5.71	4.92	4.72	5.84	7.32
NE%	0.4–0.75	0.828	0.822	0.949	0.833	0.824	0.706	0.573	0.662	0.447	0.539	0.586
ANC(×109/L)	1.8–6.3	13.22	11.85	18.18	11.22	9.38	5.33	3.27	3.26	2.11	3.15	4.29
PLT(×109/L)	125–350	358	406	416	512	690	993	1013	1058	941	656	504
RBC(×1012/L)	3.8–5.1	4.48	3.97	3.76	3.75	3.88	4.10	4.17	4.34	4.16	4.27	4.30
HGB (g/L)	115–150	135	120	111	110	119	120	124	128	123	125	130
CRP(mg/L)	<8	112.1	110.0	110.9	180.8	52.3	23.9	—	7.7	—	—	3.4
PCT(ng/ml)	<0.1	0.364	—	1.630	1.220	0.205	0.066	—	0.026	—	—	<0.020
Scr(μmoI/L)	35–80	43	33	—	36	—	—	—	37	—	38	43
PT(S)	11.7–15.4	—	15.6	—	—	—	—	—	15.0	15.6	—	13.0
APTT(S)	28–43.5	—	58.1	—	—	—	—	—	49.8	49.2	—	38.7
INR	0.8–1.25	—	1.25	—	—	—	—	—	1.19	1.25	—	1.00
ALT(U/L)	7–40	29	23	—	12	—	—	—	9	—	19	18
AST(U/L)	13–35	—	21	—	10	—	—	—	17	—	24	24
Albumin (g/L)	40–55	—	33.5	—	27.3	—	—	—	34.4	—	35.1	39.1
TB (μmoI/L)	<17.1	—	6.8	—	4.2	—	—	—	5.2	—	5.9	5.9

T: body temperature; WBC: white blood cell count; NE%: neutrophil granulocyte percentage; ANC: absolute neutrophil count; PLT: blood platelet; RBC: red blood cell; HGB: hemoglobin; CRP: C-reactive protein; PCT: procalcitonin; Scr: serum creatinine; PT: prothrombin time; APTT: activated partial thromboplastin time; INR: international normalized ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TB: total bilirubin.

The patient received blood tests at 5 days, 1 month, and 6 months after discharge, and platelet counts were all within the normal range. We therefore concluded that thrombocytosis was probably induced by imipenem–cilastatin treatment. Written informed consent was obtained from the patient for her anonymized information to be published in this article.

Discussion

We have reported a rare case of thrombocytosis probably induced by imipenem–cilastatin treatment. Thrombocytosis can be diagnosed on clinical evidence; however, the type of thrombocytosis and the cause of secondary thrombocytosis are always difficult to determine. ⁸ Patients with thrombocytosis always had multiple factors contributing to their condition. In the current case, platelet count was independent of infection progression and recovery. Pharmacological treatment was simple and so this adverse effect could be attributed to imipenem–cilastatin according to the Naranjo scale. Imipenem–cilastatin combination therapy is frequently used in patients with severe infections, and imipenem–cilastatin-induced thrombocytosis may be masked by other confounding factors. We suggest that imipenem–cilastatin should be considered as a possible cause in patients with thrombocytosis.

Current literature regarding drug-induced thrombocytosis covers a wide variety of drugs and no pattern is evident as of yet. ⁹ Some antibiotics have been implicated in the development of thrombocytosis,^11,12 and this was a rare case in which it was concluded that thrombocytosis was probably induced by imipenem-cilastatin. Thrombopoietin, interleukin-6, and interleukin-11 are considered key elements in the regulation of platelets and in the development of thrombocytosis. ¹³ However, the effect of imipenem–cilastatin on these factors has not been reported and the exact mechanism of drug-induced thrombocytosis should be investigated in future studies.

It has been reported that patients with secondary thrombocytosis did not need specific anti-platelet or platelet-lowering therapy. ⁸ Identifying the cause of secondary thrombocytosis and then treating the underlying disease is more important. In this case, thrombocytosis was probably attributed to imipenem–cilastatin treatment and then these drugs were discontinued. The patient had a high platelet count and was evaluated to be at risk of a thromboembolism; therefore, aspirin and low-molecular-weight heparin were also administered. The platelet count decreased progressively over several days and ultimately returned to the normal range. Imipenem–cilastatin-induced thrombocytosis did not cause any long-term effects in this case.

Conclusion

This was a probable rare case of thrombocytosis induced by imipenem–cilastatin treatment and suggests that clinicians need to be vigilant regarding the impact of imipenem–cilastatin on platelet count. Replacement with other antibiotic classes and evaluation of the risk of thromboembolism events should be performed when thrombocytosis is induced in patients by imipenem–cilastatin.