From treating UTI to agranulocytosis

ABSTRACT

The growing problem of antibacterial resistance has resulted in increased interest in fosfomycin, especially its parenteral formulation. It is a broad-spectrum antibiotic with both in vivo and in vitro activity against a wide range of bacteria, including MDR and XDR bacteria. Due to its high tissue penetration, fosfomycin may be used in a broad range of tissues and targets, including the CNS, soft tissue, bone, lungs, and abscess fluid. The most commonly reported adverse effects are hypokalemia and hypernatremia. We describe a case of agranulocytosis in a young patient with chronic kidney disease, a rarely described side effect that may be fatal. A 21-year-old woman was a freshly diagnosed case of end-stage renal disease during workup for complaints of generalized body weakness, reduced appetite, and hypertension. She was started on hemodialysis. During the course of her hospital stay, she developed features of urinary tract infection, urine routine and microscopy revealed leucocyte esterase 3+ and nitrites 3+ and microscopy showed numerous pus cells. The blood culture was sterile. The urine culture was positive for Klebsiella pneumoniae ssp pneumoniae (MDRO) and was sensitive to only fosfomycin. Oral fosfomycin was started; however, she developed multiple episodes of nausea and vomiting after taking the first oral dose. Therefore, she was started on 4 g of injectable fosfomycin, followed by 2 g of fosfomycin twice a day. She was found to have leukopenia, with her total leucocyte counts decreasing from 13500/cumm to 4100/cumm and then further to 2100 cells/cumm in two consecutive days of administration of injectable fosfomycin. On the third day, the counts further decreased to 1700/cumm, with an absolute neutrophil count of 493 cells/μ. In view of suspected fosfomycin-induced leukopenia, the injectable drug was stopped. The total leucocyte counts were repeated after two days of stopping fosfomycin. The repeated leucocyte counts were normal. To our knowledge, this is the first paper reporting on agranulocytosis induced by fosfomycin in chronic kidney disease patients and the fourth paper to date. This paper provides the second detailed description of a case. Cytotoxic chemotherapy can cause predictable and dose-related decreases in neutrophil counts. Neutropenia secondary to other medications tends to be an idiosyncratic reaction either as an immune-mediated reaction or because of direct myeloid cell line damage. This effect has been associated with a variety of medications. Literature data are scarce. A summary of product characteristics revealed that only a few cases of transient neutropenia and agranulocytosis have been reported. Parenteral fosfomycin is often used in patients receiving other medications, so it is rarely the only suspect. In our patient, there was a sudden decrease in the neutrophil count after two days of treatment with injectable fosfomycin, indicating that it is the causative agent. The counts normalized after stopping the drug.

Fosfomycin is a bactericidal antibiotic used against aerobic gram-positive and gram-negative bacteria. As discovered in 1969, it inhibits bacterial cell wall synthesis by acting on pyruvyl transferase, which is involved in one of the first steps of peptidoglycan synthesis.[1] The oral formulation of fosfomycin tromethamine is used as a single 3-gram dose in the treatment of uncomplicated cystitis. It is well tolerated and safe, with gastrointestinal disorders being the most frequent adverse effect.[2] The intravenous form of fosfomycin, available in Europe as a disodium salt, is seldom prescribed.[2] Its use is restricted to the treatment of multidrug-resistant bacterial infections. The important resistance mechanisms implicated in MDROs or ESBLs were class B metallo-β-lactamases, ceftazidime/avibactam-resistant class A β-lactamases, plasmid-mediated AmpC genes, porin loss, and plasmid-mediated colistin resistance. The recommended dose is 12–16 g/day (up to 24 g/day) divided into three to four doses. The most common adverse effects reported with parenteral fosfomycin are hypokalemia and hypernatremia.[2,3] Agranulocytosis is a rare adverse effect defined by a neutrophil count less than 500/cumm and may be fatal. Here, we describe a case of agranulocytosis associated with parenteral fosfomycin.

Case Summary

A 21-year-old woman with a known comorbidity of Retinitis pigmentosa presented with a history of burning epigastrium, generalized weakness, and loss of appetite. There was no history suggestive of connective tissue disorders, recurrent urinary tract infections, inherited kidney disease, childhood fever, childhood kidney disease, long-term medications, or the intake of complimentary or alternative medications. On evaluation at admission, she was afebrile with a BP of 160/100 mmHg and pallor and bilateral pedal edema. Her investigations revealed a hemoglobin of 8.0 g/dl, total leucocyte counts of 6500 cells/cumm, platelet count of 1.9 lakh/cumm, serum creatinine of 9 mg/dl, serum urea of 96 mg/dl, total protein of 5 g/dl, and serum albumin of 2.0 g/dl. The urine routine showed protein 2+. On etiological workup, ultrasonography of the kidneys revealed bilateral small kidneys with increased cortical echogenicity, multiple cortical and medullary cysts, and poor corticomedullary differentiation. Her 24-hour urinary protein level was 1.1 g/24 hr. In view of this, she was started on hemodialysis through a right-cuffed dialysis, a 19-cm Covidien catheter placed in the right internal jugular vein. She was also started on tablet amlodipine, tablet Metoprolol, tablet Furosemide, erythropoietin-stimulating agents, and other supportive measures.

During the course of her hospital stay, she developed high-grade fever, which was associated with lower urinary tract symptoms, such as dysuria, increased frequency, and urgency. Clinically, she was found to be sick looking with temperature of 103.7°F, heart rate of 110/min, and pain over bilateral flank region. Her urine routine examination showed leucocyte esterase 3+ and nitrites 3+ and microscopy showed numerous pus cells. Her hematological, serological evaluation showed neutrophilic leukocytosis (total count—13500 cells/cumm and polymorph count—90%) and serum creatinine of 11 mg/dl, serum urea of 109 mg/dl, total protein of 5.3 g/dl, serum albumin of 2.1 g/dl, and serum procalcitonin of 5.8 ng/ml. Blood cultures taken from the central and peripheral sites were sterile. Her CT abdomen revealed bilateral perinephric fat stranding, no cyst hemorrhage. Her urine culture was positive for Klebsiella pneumoniae ssp pneumoniae (MDRO) and was sensitive to only fosfomycin. She was managed as a case of acute Pyelonephritis and was started on injectable fosfomycin oral Fosfomyin, however she didn’t tolerate the same and developed multiple episodes of Nausea and vomiting. In view of these side effects, she was started on an injectable fosfomycin. She was initially given a loading dose of 4 g, which was followed by 4 g alternative day. After the second day of administration of injectable fosfomycin, her routine blood tests revealed leukopenia and neutropenia, with total leucocyte counts decreasing from 4500/cumm to 2000/cumm, and her neutrophil count decreased to 45% [Table 1]. On the third day of injectable fosfomycin use, the total leucocyte counts further decreased to 1700/cumm, with a polymorph count of 25%. In view of suspected fosfomycin-induced agranulocytosis, the injection of Fosfomycin was stopped and the total counts was repeated after two days of fosfomycin were stopped. The repeated leucocyte counts were normal. Filgrastim was not administered to this patient during the leukopenia phase.

Table 1.

The effects of injectable fosfomycin over the leucocyte panel as seen over a few days and the reversal of adverse effects on stopping the drug

	Injectable fosfomycin	TLC Count (cu/mm)	Neutrophil (%)	ANC
Day 1	Not given	13500	90	12555
Day 2	4 g	4100	47	1500
Day 3	4 g	2500	37	900
Day 4	Not given	1763	25	493
Day 5	Not given	4600	58	2760

Discussion

To our knowledge, this is the first paper reporting agranulocytosis induced by fosfomycin in an end-stage renal disease patient and the fourth paper reported overall. This paper is the second detailed description of a case. Cytotoxic chemotherapy can cause predictable and dose-related decreases in total leucocyte and neutrophil counts. However, neutropenia secondary to other medications tends to be an idiosyncratic reaction either as an immune-mediated reaction or because of direct myeloid cell line damage. However, no other markers of drug-induced neutropenia or allergy were tested. Although data on the side effects of parenteral fosfomycin are scarce, six cases of leucopenia and five cases of neutropenia were reported in the literature.[4,5,6,7] Similarly, the French summary of product characteristics mentions that cases of transient neutropenia and agranulocytosis have been described, without any further details on the reported cases. The transient aspect needs to be further studied. An analysis of the FDA Adverse Event Reporting System Database revealed that the frequency of agranulocytosis was greater than expected and several cases occurred after a single dose of the drug as well. The authors of the FDA analysis differentiated the profile of the reported adverse effects according to the route of administration with increased risk of neutropenia with parenteral usage. In the French National Pharmacovigilance Database, three patients with neutropenia in whom fosfomycin was the only suspected drug were registered. Among these patients, the time to onset was 8, 20, and 28 days, and the outcome was favorable after stopping the drug in two patients. In our case, the patient was dialysis dependent, and there was a sudden neutropenia after two days of initiation of treatment with injectable fosfomycin and in the absence of any other cytotoxic drugs. This normalized within two days after stopping fosfomycin.

Conclusion

Although few data are reported, awareness should be raised about agranulocytosis induced by fosfomycin. The mechanisms of this hematological toxicity remain to be clarified. Patients with chronic kidney disease may have a greater likelihood of developing early agranulocytosis with injectable fosfomycin.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.