Netilmicin-induced carpopedal spasm.

Aminoglycoside-induced nephrotoxicity is not uncommon. Netilmicin being a member of gentamicin family has the advantage of being relatively free from ototoxicity and nephrotoxicity and is also prescribed for gentamicin resistant cases. In spite of these benefits with netilmicin, occasional development of symptomatic hypomagnesemia, hypocalcemia, and hypokalemia due to renal electrolyte wasting cannot be ruled out. Here we describe two cases of carpopedal spasm due to hypocalcemia following use of netilmicin.

INTRODUCTION

Netilmicin, a semi-synthetic aminoglycoside, is highly effective against gram negative infections of the urinary tract (UTI), skin and skin structure (SSTI), and lower respiratory tract (RTI), as well as in intraabdominal infections and septicemia.[1] It has similar pharmacokinetic properties and dosage to that of gentamicin. Its major advantages are comparable or superior efficacy over other aminoglycosides, good clinical efficacy against gentamicin-resistant strains with relatively reduced ototoxicity and nephrotoxicity.[234] Hypocalcemia manifesting as carpopedal spasm with this drug has not been reported till date. Here we report two cases of carpopedal spasm following use of netilmicin prescribed for genitourinary surgery.

CASE REPORTS

Case 1

A 12-year-old boy had to undergo operative procedure for epispadias and was on surgical prophylaxis with netilmicin 150 mg i.v. twice daily and ceftriaxone (500 mg) i.v twice daily. The boy received both the drugs for 3 days (six doses) following which he developed severe spasm of the feet and hands [Figures 1–3]. On observation the patient was irritable, there was flexion of the hands at the wrists and of the fingers at the metacarpophalangeal joints and extension of the fingers at the inter-phalangeal joints; the feet were dorsiflexed at the ankles and the toes plantar flexed. Immediate laboratory investigation revealed the following picture: Serum calcium 7.2 mg/dL (normal, 8.7-11 mg/dL), potassium 3.9 mmol/L (normal, 3.5-5.5 mmol/L), and sodium of 145 mmol/L (normal, 135-155 mmol/L), serum creatinine 3.0 mg/dL and serum albumin 3.4 g/dL (normal, 3.8-4.4 g/dL) with normal urine output. Total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic-pyruvic transaminase (SGPT) were also normal. Assuming that the patient developed drug-induced nonoliguric renal failure; both the drugs were withdrawn and the surgery postponed. The hypocalcemia was managed with i.v calcium gluconate. 24 h following this episode the laboratory investigations were repeated, which showed serum calcium 9.3 mg/dL, potassium, 3.9 mmol/L, sodium 144 mmol/L and serum albumin 4.2 g/dL [Table 1]. On recovery, the patient was discharged with oral calcium supplementation. After 4 weeks the surgery was planned. Netilmicin 300 mg once daily was given preoperatively for 1 day and continued postoperatively. But after 3 days (4 doses) postoperatively the patient developed the same features of carpopedal spasm with laboratory findings of hypocalcemia. On withdrawal of netilmicin and calcium supplementation the boy recovered.

Figure 1

Carpal spasm (left hand)

Figure 3

Flexed legs

Table 1

Laboratory findings of netilmicininduced carpopedal spasm

Carpal spasm (right hand)

Case 2

A 8-year-old boy diagnosed to be a case of hypospadias was given netilmicin 150 mg i.v. once daily as surgical prophylaxis for 2 days and was operated on the second day. Netilmicin in the same dose was continued postoperatively, but following the fifth dose, the child developed the characteristic features of tetany. Laboratory findings revealed low serum calcium (7.6 mg/dL), high serum creatinine (2.5 mg/dL) [Table 1]. Urine output was normal with serum electrolytes (Na+ and K+) within the normal range. Assuming that the reaction was due to hypocalcemia induced by netilmicin, it was withdrawn and supplemented with piperacillin + tazobactum. The child recovered following i.v. administration of calcium gluconate.

DISCUSSION

Carpopedal spasm (seen in tetany) is usually caused by low ionized serum calcium concentration, which causes increased excitability of peripheral nerves resulting in carpopedal spasm, convulsion, and stridor. The total serum calcium <8.5 mg/dL may be associated with tetany. We reported here two cases of carpopedal spasm caused by netilmicin.

A dose dependent nephrotoxicity occurs with aminoglycoside therapy despite adequate fluid volume control and drug level monitoring. Renal electrolyte wasting is occasionally caused by symptomatic hypomagnesemia, hypocalcemia, and hypokalemia when treated with these drugs[5] but tetany has not been frequently reported except for a single report on paramomycin.[6] Several risk factors, like volume depletion, sepsis, liver and renal dysfunction, hypokalemia, hypomagnesemia, advanced age, prolonged therapy, type of aminoglycoside, time and frequency of dosing, an elevated serum aminoglycoside concentration, and interactions with other nephrotoxic drugs such as vancomycin, amphotericin B, piperacillin, cephalosporins, foscarnet, allopurinol, NSAIDs, inhibitors of angiotensin converting enzyme, cyclosporine, and cisplatin have been identified.[78] Among all aminoglycosides, netilmicin stands out clear because of its least toxicity and superior clinical efficacy, even in some resistant microorganisms.[39] Though studies show a clear benefit of the ceftriaxone-netilmicin combination,[10] their potential for interaction cannot be overlooked. Therefore netilmicin and ceftriaxone being nephrotoxic, both may be the suspects in the case report one. But it was also observed that, netilmicin prescribed alone in once daily dose later on (in case report one) and even half the dose (in case report two) also resulted in hypocalcemia and carpopedal spasm (tetany). In both the cases, laboratory findings with regard to serum electrolytes, urea, creatinine, albumin prior to administration of netilmicin were within normal range. Other causes of hypocalcemia like vitamin D deficiency, chronic renal failure, hypoparathyroidism were ruled out in both the cases. Another important point to be noted here that, though majority of patients in this hospital setup are being given netilmicin alone/netilmicin + ceftriaxone in combination, this type of adverse effects are seldom reported. Therefore netilmicin is probably the drug responsible for this rare adverse effect in these two cases (causality assessment using Naranjo's Adverse Drug Reaction probability score = score 7 and WHO-UMC causality assessment scale).

CONCLUSION

Recent studies have emphasized the role of calcium in aminoglycoside-induced renal failure.[11] Netilmicin has long been used both alone and in combination with ceftriaxone in the adult and pediatric population for the treatment of severe gram negative infections in hospital settings. Judicious use of such drugs is required to prevent untoward side effects like tetany and its associated disability. Identifying high risk patients and quick recognition of drug-induced injury with prompt cessation of the offending drug is the key to managing such cases before the injury causes permanent damage to the renal tissue.