PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL 1: 351-352 (1992)

LETTER TO THE EDITOR

Safe Administration of Metronidazole in a Patient with GGPD Deficiency

Sir, Glucose-6-phosphate-dehydrogenase (G6PD)

deficiency is associated with increased vulnerability of erythrocytes to oxidative stress. In patients suf- fering from G6PD deficiency many drugs, including several antimicrobial and antiparasitic drugs as well as antihypertensive and analgesic drugs, can cause hemolysis.' For even a larger number of drugs, it is unknown whether they can cause hemo- lysis in patients with decreased resistance to oxida- tive stress. Since a metabolite rather than the parent drug may be the oxidative compound, it is difficult to predict whether hemolysis will occur.

Metronidazole has never been reported to cause hemolysis,'-4 but neither has its safety in G6PD deficient patients been established. Hydroxyla- mines generated during metabolization of metroni- dazole might react with glutathione and increase hemolysis.

Recently we treated a patient with known G6PD deficiency with metronidazole for a diabetic ulcer.

A 51-year-old Haitian man was known since 10 years with G6PD deficiency and diabetes mellitus. Laboratory tests, performed 10 years before admis- sion, showed a haemoglobin of 8.3 mmol/l (normal) and a slightly increased number of reticulocytes (0.024), a slightly decreased osmotic fragility of erythrocytes, a decreased G6PD of 0.39 IU/gHb (normal 12.1 f 2.1 IU/gHb) a subnormal 6- phospho-gluconate-dehydrogenase of 7.86 IU/gHb (normal 8.78 _+ 0.78 IU/gHb), an elevated phos- phofructo-kinase of 19.15 IU/gHb (normal 10.4 1.5 IUigHb). Acute intravascular haemolysis was never detected. He was admitted for an ulcer at the right heel, which existed for 5 years but had increased in size for the past 4 months. Physical examination revealed a 5 X 5 x 0.5 cm non-granu- lating ulcer at the right heel, distal symmetrical

Addressee for correspondence: Dr R H. B. Meyboom, LAREB Foundation, Ringhaan West 273, 5037 PD, Tilburg, Nether- lands.

polyneuropathy and absent peripheral arterial pul- sations at the lower limbs. An X-ray examination of the right calcaneaus showed no signs of osteo- myelitis.

Cultures taken from the ulcer grew Enterobacter cloacae, susceptible to cefamandole, and Bacter- oides distasonis, resistant to penicillin and clinda- mycin, susceptible to metronidazole.

Initial treatment was supportive with bed rest, repeated warm soap foot soaks, repeated debride- ment, and cefamandole 4 X 1 g intravenously. In addition the at-admission badly regulated diabetes mellitus was treated by administration of insulin subcutaneously. In spite of this treatment the nec- rosis at the right heel proceeded.

Considering the multiple stenoses in the right femoral artery with relatively wide more distal arteries, seen on angiography, and considering the progression of the necrosis of the right heel during supportive therapy, an aorto-bifemoral reconstruc- tion was urgently indicated. To ensure maximum antibiotic therapy metronidazole was administered in a low dose of 3 x 250 mg daily orally, while laboratory tests for hemolysis were closely moni- tored; after three days the dosage was increased to 3 x 500 mg daily orally. There were no signs of hemolysis (no decrease of haemoglobin, numbers of erythrocytes, haptoglobin, no increase of biliru- bin and lactate dehydrogenase, no haemoglobi- nuria), neither during the 16 days metronidazole was given, nor in the following period.

After 6 days of maximum antibiotic therapy by cefamandole and metronidazole an aorto-bife- moral reconstruction was performed, after which the large ulcer at the right heel granulated.

Cefamandole is known to be safe in patients with G6PD deficiency, i.e. cefamandole does not cause haemolysis in these patients. Since we did not find evidence of increased hemolysis throughout the metronidazole treatment period, we conclude that metronidazole was safe in this patient with G6PD deficiency.

1053-8569/92/06035 1-02$06.00 0 1992 by John Wiley & Sons, Ltd.

352 LETTER TO THE EDITOR

The observation that none of the parameters revealed evidence of increased hemolysis suggests that metronidazole might be safe in other patients with G6PD deficiency.

C . M. P. W. MANDIGERS and J . DERKSEN Department of Internal Medicine, University

Hospital, Leiden, The Netherlands F . P. KROON

Department of Infectious Diseases, University Hospital, Leiden, The Netherlands

R. H. B. MEYBOOM Netherlands Pharmacovigilance Foundation

LAREB

REFERENCES

1. Gordon-Smith, E. C. Drug-induced oxidative haemo- lysis. Clinical Huematology 1980; 9: 557-586.

2. Dukes, M. N. G. (Ed.) Meyler’s Side EfSects of Drugs, vol. 1 1. Elsevier Science Publishers, Amsterdam, 1988.

3. Groupe de Travail de I’OMS. Deficit en glucose 6 phosphate deshydrogenase. WHO Bulletin, 1990; 68: 13-24.

4. Desforges, J. F. Glucose-Qphosphate dehydrogenase deficiency. New England Journal of Medicine 199 1 ; 324: 169-1 74.

0 1992 by John Wiley & Sons, Ltd. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 1: 351-352 (1992)