a Adult Cystic Fibrosis Unit and b Department of Haematology, Birmingham Heartlands Hospital, Bordesley Green East,Birmingham B9 5SS, UK
Sir,
We describe a patient who developed severe haemolytic anaemia following treatment withpiperacillin. Although haemolysis is a widely recognized complication of penicillintherapy, 1,2 we believe this to be the first published report in the UK of piperacillin-inducedhaemolysis.
A 34 year old female patient with cystic fibrosis was admitted complaining of increasedshortness of breath and production of purulent sputum. She had no known allergies, although shehad previously experienced pruritis while receiving ceftazidime, and tingling in her hands withazlocillin. She had also completed courses of amoxycillin and flucloxacillin and, 2 yearspreviously, had been given piperacillin for 12 days, in all cases without adverse effects. Cultureof a recent sputum specimen yielded a strain of Pseudomonas aeruginosa that was susceptible only to imipenem and colistin and the patient was, therefore, treated withmeropenem and colistin, both by the iv route, for 16 days. However, as she was still producinglarge amounts of purulent sputum, the meropenem, to which the strain of P. aeruginosa had become resistant, was discontinued and treatment with iv piperacillin, to which it hadbecome susceptible, in a dosage of 6 g tds, was initiated; the patient continued to receivecolistin. After 12 days, piperacillin/tazobactam was substituted for the piperacillin because thepatient had failed to improve further and because the pathogen had become resistant to the latterdrug, although it was susceptible to the combination. On the following day, the patientcomplained of headache and nausea and noticed that she was passing pink urine. She was febrile (38.8°C) and clinically anaemic. Her haemoglobin concentration had fallen from 10.9 g/dLon admission to 5.5 g/dL, with spherocytes, polychromasia, anisocytosis and nucleated red cells.A positive direct Coombs' test, a serum bilirubin concentration of 28 mmol/L, a lowserum haptoglobin concentration (0.3 g/L) and the presence of haemoglobin in the urine wereconsistent with an immune-mediated haemolytic crisis. The piperacillin/tazobactam wasdiscontinued, prednisolone and folic acid were administered and the patient was transfused. Herhaemoglobin concentration subsequently remained stable at 14 g/dL and she was well whenreviewed in the outpatients' clinic 2 weeks later.
A panel of antibiotics that might be given to this patient in the future as treatment ofinfections caused by P. aeruginosa and/or other pathogens, including piperacillin, piperacillin/tazobactam, azlocillin, ticarcillin,temocillin, flucloxacillin, imipenem, meropenem, aztreonam, chloramphenicol, gentamicin, colistin, cefuroxime and ceftazidime, were incubated with her serum.Of these drugs, only piperacillin and piperacillin/tazobactam caused agglutination in an indirectagglutination test; sera from other patients (controls) did not react in this way. We concluded,therefore, that this patient's acute haemolytic anaemia had been induced by the piperacillin.
Piperacillin is frequently used to treat infections caused by P. aeruginosa in cystic fibrosis patients, in whom adverse reactions to this drug tend to be more common thanin non-cystic fibrosis patients. 3 ,4 ,5 In one study, nine of 38 patients who were given piperacillin developed swinging pyrexias aftertreatment for a mean of 13.5 days, 3 while, in another, 11 of 31 patients developed fever and rash after a mean of 9.1 days. 4 In a third study, 14 of 46 patients developed serum sickness-like illnesses which appeared to bedosage-related. 5
The patient described here developed brisk severe intravascular haemolysis after 12 daysof treatment with piperacillin. The mechanism of this reaction is an antibody/ hapten immuneresponse. The hapten/protein complex is formed when piperacillin combines with protein on redcell membranes. Haemolysis, which is usually extravascular, classically occurs afterapproximately 10 days in patients with penicillin-induced haemolysis. 1,2 Our patient did not experience haemolysis with either amoxycillin or flucloxacillin, presumablybecause they form different hapten complexes. Haemolysis in this case was highly specific topiperacillin, no agglutination having been observed in vitro with the closely related drugs azlocillin and ticarcillin which, therefore, remain therapeuticoptions for the future.
This is the first documented report from the UK of piperacillin-induced haemolysis (Wyeth,personal communication). The case is unusual because there was evidence of intravascularhaemolysis. Patients with cystic fibrosis have a greater predisposition than non-cystic fibrosispatients to develop allergic reactions to piperacillin, which occur 915 days aftertreatment has been initiated. It is important, therefore, to monitor the full blood counts of thesepatients during the second week of treatment with piperacillin and to be aware of the potential forthis serious complication to develop.
Notes
* Corresponding author. Tel: +44-121-766-6611; Fax: +44-121-772-0292.
References
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2 . Petz, L. D. & Fudenberg, H. H. (1966). Coombs-positive hemolytic anemia caused bypenicillin administration. New England Journal of Medicine 274, 1728.
3 . Stead, R. J., Kennedy, H. G., Hodson, M. E. & Batten, J. C. (1985). Adverse reactions topiperacillin in adults with cystic fibrosis. Thorax 40, 1846.[Abstract]
4 . Pleasants, R. A., Walker, T. R. & Samuelson, W. M. (1994). Allergic reactions to parenteralbeta-lactam antibiotics in patients with cystic fibrosis. Chest106 , 11248.[Abstract]
5 . Reed, M. D., Stern, R. C., Myers, C. M., Klinger, J. D., Yamashita, T. S. & Blumer, J. L.(1987). Therapeutic evaluation of piperacillin for acute pulmonary exacerbations in cysticfibrosis. Pediatric Pulmonology 3, 1019.[ISI][Medline]