MADIAJAGANE et al. : ANTIBIOTICS IN FEBRILE NEUTROPENIA 67

single course. However, some probable TPE cases did not REFERENCES show a fall in eosinophil counts after receiving the drug; a Udwadia FE. Tropical eosinophilia. In: Hertzog H (ed). Progress in respira- phenomenon reported by others. 18,19 These patients require tion research:Pulmonary eosinophilia. Volume 7. Basel:S. Kargar, 1975:35-155. a repeat course of diethylcarbamazine and the cause of their 2 Viswanathan R, Jaggi OP. Tropical eosinophilia. In: Ahuja MMS (ed). Progress in clinical medicine in India. First series. New Delhi:Arnold- eosinophilia is probably related to a parasite other than Heinemann Publishers, 1976:75-91. microfilaria. 3 Neva FA, Ottesen EA. Tropical (filarial) eosinophilia. N Engl J Med 1978; The prevalence of TPE in our community was high. Since 298:1129-31. 4 Spry CJF, Kumaraswami V. Tropical eosinophilia. Semin Hematol 1982; TPE is commonly caused by human lymphatic filarial infec- 19:107-15. tion, its prevalence is expected to be higher in endemic areas. 5 Ottesen EA, Neva FA, Paranjape RS, Tripathy SP, Thiruvengadam KV, However, only few susceptible individuals who had lymphatic Beaven MA. Specific allergic sensitisation to filarial antigens in tropical filarial infection had features ofTPE. The high prevalence of eosinophilia syndrome. Lancet 1979;1:1158-61. 6 World Health Organization. Fourth report of the Expert Committee on TPE that we observed was probably related to the high level Filariasis. Lymphatic filariasis. WHO Tech Rep Ser 1984;702:3--112. of filarial infection present in the community. Moreover, 7 Joshi VV, Udwadia FE, Gadgil RK. Etiology of tropical eosinophilia. A study during the survey, we probably encountered a few cases of lung biopsies and review of published reports. Am J Trop Med Hyg 1969; 18:231-40. of TPE in the course of the disease without its full blown 8 Kar SK. Atypical features in lymphatic filariasis. Indian J Med Res 1986; features. Hence, by using the standard diagnostic criteria 84:270-4. • many early cases might have been missed. 9 Voller A, Bidwell DE, Bartlett A. The enzyme linked immunosorbent assay Our study of TPE in a stable endemic community, (ELISA): A guide with abstract of microplate application. Alexandria, Virginia, USA:Dynatech Laboratories, 1979. although difficult, has given us a fair idea of the prevalence 10 Dhanaraj TJ, da Silva LS, Schacher JF. The serological diagnosis of of the condition and the varieties of its manifestations. How- eosinophilic lung (tropical eosinophilia) and its etiological implications. Am J ever, these cases should be followed up carefully so that we Trop Med Hyg 1959;8:151-9. 11 Udwadia FE, Joshi VV. A study oftropical eosinophilia. Thorax 1964;19:54&--54. can better understand the causes of recurrence of the disease 12 King BG. Early filariasis diagnosis and clinical findings: A report of 286 cases and the pattern of its response to diethylcarbamazine. in American troops. Am J Trop Med Hyg 1974;24:285-98. 13 Ezeoke A, Perera ABV, Hobbs JR. Serum IgE elevation with tropical ACKNOWLEDGEMENTS eosinophilia. C/in Allergy 1973;3:33--5. 14 Kumaraswami V, Narayanan PRo Eosinophils and the lung in tropical We thank Dr S. P. Tripathy, Director General, Indian Council of pulmonary eosinophilia: A brief communication. Lung India 1985;1l1:25~. Medical Research, New Delhi and Dr K. A. V. R. Krishnamachari, 15 Udwadia FE. Pulmonary eosinophilia. J Assoc Physicians India 1978;26: Director, Regional Medical Research Centre (ICMR), Bhubaneswar 283--93,429-37. for their guidance and encouragement during this study. We acknow- 16 Shankar PS, Muralidhar SR. Haematological studies in tropical eosinophilia. Indian J Chest Dis 1971;13:148-54. ledge the active support and valuable cooperation of Mr K. Dhal, 17 Ambroise-Thomas P. Filariasis. In: Houba V (ed). Immunological investiga- Mr T. Moharana, Mr S. C. Rout and Mr R. N. Nayak, the staff of the tion of tropical parasitie diseases. London :Churchill Livingstone, 1980:84-103. Clinical Division in this work. We also thank Mr S. C. Muduli for typing 18 Ganatra RD, Lewis RA. Hetrazan in tropical eosinophilia. Indian J Med Sci the manuscript. 1955;9:672-81. 19 Udwadia FE. Tropical eosinophilia-a correlation of clinical, histopathologic and lung function studies. Dis ChestI967;S2:531-8.

Antibiotics in febrile neutropenia: A randomized prospective comparison of two combinations

R. MADIAJAGANE, V. MAITREYAN, T. G. SAGAR, V. SHANTA

ABSTRACT sets of antibiotics which differed in their spectrum of action, Background. Problems of initial empirical antibiotic availability and price. therapy in febrile neutropenia are further complicated by Methods. Sixty episodes of febrile neutropenia in other factors such as cost and the pattern of infective 40 patients who were not on any prophylactic antibiotics organisms in a particular institution. We, therefore, con- were randomized into one of two arms-cefotaxime and ducted a randomized study comparing the efficacy of two gentamicin or ciprofloxacin and gentamicin. Depending upon the response by 72 hours, they were crossed over to Cancer Institute (WIA), Adyar, Madras 600020, Tamil Nadu, India the other arm or continued with the same combination. R. MADIAJAGANE, V. MAITREYAN, T. G. SAGAR, Empirical antifungal therapy was added in those who did V. SHANTA Department of Medical Oncology not become afebrile. Correspondence to R. MADIAJAGANE, Results. Infection was documented either clinically, Department of Medical Oncology, Meenakshi Mission Hospital and bacteriologically or radiologically in 42% of the febrile Research Centre, Lake Area, Melur Road, Madurai 625107, episodes. The commonest organism isolated was Klebsiella Tamil Nadu, India © The National Medical Journal of India 1993 68 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 6, NO.2 and the commonest organism producing bacteraemia RESULTS was the Staphylococcus. The temperature was reduced to Out of the 60 episodes in this study, fever occurred after normal without cross-over in 53% of the febrile episodes grade IV myelosuppression in 52 episodes within 3 days, in with cefotaxime and gentamicin and in 60% with cipro- 6 episodes between 4 and 6 days and in 2 episodes after 7 days. floxacin and gentamicin (p>0.05). After cross-over the Infection based on either clinical, bacteriological or radio- temperature came down in 30% of the episodes with logical evidence was demonstrated in 13 (43%) episodes in cefotaxime and gentamicin (initial combination) and 40% arm A; in 12 (40%) episodes in arm a with an overall occur- with ciprofloxacin and gentamicin (initial combination; rence in 25 (42%). Unexplained fever was found in 17 (57%) p>0.05). The overall response rate without empirical episodes of arm A and 18 (60%) in arm B with an overall rate antifungal therapy was 83% in the patients on cefotaxime of 35 (58%; Table I). and gentamicin (initial combination; p>0.05). While both the The documented infections and their patterns are shown in arms of the study had a 100% response rate, there was no Table II. Fourteen (23%) episodes had clinical evidence of significant difference between the efficacy of the antibiotic infection, 21 (35%) had bacteria isolated and 3 (5%) had combinations. The ciprofloxacin-gentamicin combination radiological changes. Positive cultures were obtained from a is one-third as expensive as cefotaxime-gentamicin and is throat swab in 7 (12%), blood in 6 (10%), urine in 5 (8.3%) more readily available. . and pus, stool and sputum in 1 (1.7%) each. Conclusion. We recommend the use of ciprofloxacin and The effectiveness of the antibiotic regimen is shown in gentamicin as the initial drug combination and cefotaxime Table III. In the unexplained fever group, arm A and gentamicin only when the former is not effective. (cefotaxime and gentamicin) was successful without cross- Natl Med J India 1993;6:67-70 over in 12 (70% ). Of the 5 episodes which were crossed-over from arm A to arm B, only 2 (12%) responded and the other 3 (18%) needed empirical antifungal therapy. In arm B the INTRODUCTION success rate without cross-over was 10 (56%) and of the 8 Febrile neutropenia is a common cause of morbidity in patients with neoplasms, especially during the treatment of leukaemias and non-Hodgkin's lymphomas. Early and TABLEI. Clinical characteristics rational institution of antibiotics in these patients is Character Arm A ArmB mandatory. The cost of antibiotic therapy varies widely and we, therefore, conducted a randomized prospective trial to Mean age in years 23.0 (4-55) 32.4 (5-55) compare two sets of antibiotics, a cheaper easily available pair against a more expensive one, in neutropenic patients Sex (M:F) 21:9 25:5 who were febrile. Underlying neoplasm Lymphoma 19 22 Leukaemia 11 8 PATIENTS AND METHODS Mean granulocyte count on Febrile neutropenia was defined as a total granulocyte count randomization 311 (70-500) 236(20-500) less than 500 per cmm and a temperature of 99.6 of on two Mean duration of granulocytopenia successive readings or a single reading of above 100.5 of. in days 20 (15-27) 19.2 (15-31) Patients with acute lymphatic leukaemia (ALL) or non- Infection Hodgkin's lymphoma (NHL) fulfilling these criteria and Documented 13 12 those who were not on prophylactic antibiotics were Unexplained 17 18 randomized to receive either of the following antibiotic Arm A Cefotaxime and gentamicin Arm B Ciprofloxacin and gentamicin combinations: Figures in parentheses indicate the range A: Cefotaxime in a dose of 100 mg/kg/day and gentamicin in a dose of 5 mg/kg/day, both intravenously in three TABLEII. Documented infection divided doses Characteristics Arm A ArmB Total(%) B: Ciprofloxacin in a dose of 200 mg for adults and 100 mg for children every 12 hours by intravenous infusion given Clinical over 20 minutes, and gentamicin in the same dose as in Respiratory 5 1 6(10) armA. Gastrointestinal 2 3 5 (8) Central nervous system 1 0 1 (1.7) The antibiotics were started after specimens for cultures had Skin 1 1 2 (3.3) been obtained from the blood, urine, throat swabs and other Bacteriological body fluids and a chest X-ray performed. The patients were Blood 2 4 6(10) re-evaluated after 72 hours. If the fever persisted with nega- Urine 2 3 5 (8.3) tive cultures, the patient was crossed over to the other arm. Pus 1 0 1 (1.7) In culture-positive patients, appropriate antibiotics were Stool 1 0 1 (1.7) given. If the patient continued to have fever on the sixth Sputum 1 0 1 (1.7) day then empirical antifungal therapy was started with Throat swab 3 4 7 (12) amphotericin B in a dose of 1 mg/kg/day. All antibiotics were Radiological 2 1 3 (5) continued until the patient became afebrile and the counts returned to normal levels. Arm A Cefotaxime and gentamicin ArmB Ciprofloxacin and gentamicin MADIAJAGANE et al. : ANTIBIOTICS IN FEBRILE NEUTROPENIA ,69

TABLEIII. Response to therapy

Status Unexplainedfever Documentedinfection Total Arm A ArmB Arm A ArmB

Numberofepisodes 17 18 13 12 60 Successwithoutcross-over 12 10 4 8 Arm A 16;Arm B 18 Successwithcross-over 2 8 8 4 Arm A 10;Arm B 12 Successwithantibiotics 14 18 12 12 ArmA 26;Arm B 30 Failurewithantibiotics 3 o 1 0 ArmA4;ArmBO Additionof amphotericinB 3 o 1 0 4 SuccesswithamphotericinB 3 o 1 0 4 Overallsuccess 17 18 13 12 60

Arm A Cefotaxime and gentamicin Arm B Ciprofloxacin and gentamicin

TABLEIV. Microbial agents responsible for infection

Organism Blood Urine Throat swab Stool Sputum Discharge Total

Staphylococcus 4 0 0 0 0 0 4 Streptococcus 0 0 1 0 0 0 1 Pseudomonas 0 0 2 0 1 1 4 Klebsiella 1 4 3 0 0 0 8 Citrobacter 0 0 1 1 0 0 2 Enterobacter 0 1 0 0 0 0 1 Acinetobacter 1 0 0 0 0 0 1 Candida 0 0 2 0 0 0 2 ------Total 6 5 9 1 1 1 23 episodes (44%) crossed over to arm A, all responded and as infection, malignancy, administration of blood and blood required no antifungal therapy. In the documented infection products or drugs. Fifty-five to seventy per cent of these groups, arm A was successful in 4 episodes (31 %) and arm B fevers are due to infection, especially when the granulocyte in 8 (67%) without cross-over. Of the 9 episodes which count is less than 500 per crnm.? crossed-over from arm A to B, 8 (61 %) were controlled with In our study we identified the focus of infection in 42% of antibiotics alone and 1 (8%) required empirical antifungal episodes which is similar to the reported range of 30% to therapy. All the 4 episodes (33 %) which were crossed-over 50% in such patients.v' Ninety-one per cent of the infections from arm B to A were successfully treated. These differences were due to bacteria. In other studies the corresponding were not statistically significant. figure is 85% to 90%.5,6 The blood culture was positive in Overall, 16 episodes (53%) in arm A and 18 episodes 10% to 20% of patients with febrile neutropenia. Previously, (60%) in arm B were controlled without any cross-over. the organisms grown on blood culture were usually gram- Ten episodes (30%) in arm A and 12 (40%) in arm B were negative bacteria but recent studies have shown that the controlled with cross-over to the other arm. Antifungal treat- Staphylococcus is the commonest organism.' We also found ment was required in 4 episodes (17%) of arm A and in none similar results with staphylococci being responsible for 66% of arm B. The overall success rate in our trial was 100%, with of the bacteraemia in our patients. antibiotics in 93% and with antifungal therapy in 7%. The antibiotics given empirically to patients with febrile The average duration of antibiotic requirement in arm A neutropenia depend on their cost as well as local epidemio- was 8.6 days (median 7 days; SD ±3.41 days) and in arm logical factors." The National Cancer Institute, USA, B 8.3 days.(median 9 days; SD ±2.21 days). study showed that third generation cephalosporins (e.g. The microbial agents responsible for infection are listed in ceftazidime) used as single agents, were as effective as Table IV. Multiple organisms were identified in 8 episodes combination therapy with cephalothin, gentamicin and and a single organism in 15. On the antibiogram we found carbenicillin. Recent reports on antibiotic therapy have only one Klebsiella spp. which was resistant to ciprofloxacin compared a third generation cephalosporin either alone or and one Staphylococcus aureus and two Klebsiella spp. resis- with an aminoglycoside. 8 We therefore compared a combina- tant to cefotaxime. In no episode was there resistance to both tion of a third generation cephalosporin (cefotaxime) and ciprofloxacin and cefotaxime. Thirty per cent of the episodes gentamicin with ciprofloxacin and gentamicin. Both these were resistant to gentamicin and 10% to amikacin. drugs are fairly new to India=cefotaxime has been available for 3 years and ciprofloxacin for 2 years-hence exposure DISCUSSION and resistance were expected to be rare. While the role of Fever in neutropenic patients is rapidly fatal if not treated ciprofloxacin in neutropenic patients is not well established, with proper antibiotics.' It may be due to many factors such there are some trials which suggest that it is beneficial for 70 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 6, NO.2 prophylaxis against infection in neutropenic patients as it REFERENCES has a broad spectrum of coverage. Sickles EA, Green WH, Wiernik DH. Clinical presentation of infection in We found that both our drug combinations were equally granulocytopenic patients. Arch Intern Med 1975;135:715-19. effective. Infection was controlled in about 55% of cases and 2 Browder AA, Hoff JA, Petersdorf RG. The significance of fever in neoplastic disease. Ann Intern Med 1961;55:932-42. the duration of treatment required was similar. Cefotaxime 3 The EORTC International Antimicrobial Therapy Project Group. Three and gentamicin cost three times as much as ciprofloxacin and antibiotic regimes in the treatment of infection in febrile granulocytopenic gentamicin. In four episodes, the organisms isolated were patients with cancer. J Infect Dis 1978;137:14-29. resistant to cefotaxime but in only one were they resistant to 4 Pizzo PA, Hathorn JW, Hiemenz J, et al. A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with ciprofloxacin.? fever and neutropenia. N Engl J Med 1986;315:552-8. Empirical antifungal therapy was successfully used in 4 5 Pizzo PA, Robichand KJ, Wesly R, et al. Fever in the pediatric and young adult other episodes where cefotaxime and gentamicin had been patient with cancer. A prospective study.of 1001episodes. Medicine (Baltimore) 1982;61:153~5. administered. None of the episodes in the ciprofloxacin and 6 Schimpff Sc. Overview of empiric antibiotic therapy for the febrile netropenic gentamicin group required any antifungal therapy. patient. Rev Infect Dis 1985;7 (suppI4):5734-40. We suggest therefore that a combination of ciprofloxacin 7 Devita Jr VT, Hellman S, Rosenberg SA. Cancer. Principles and practice of oncology. New York:l.B. Lippincott, 1989:2094. and gentamicin is a safe, effective and low cost regime for 8 The EORTC International Antimicrobial Therapy Cooperative Group. treating febrile patients with neutropenia. If this combina- Ceftazidime combined with a short or long course of amikacin for empirical tion fails then cefotaxime and gentamicin should be used therapy of gram-negative bacteremia in cancer patients with granulocytopenia. followed if necessary by antifungal therapy. N Engl J Med 1987;317:1692-8. 9 Pizzo PA, Hathorn JW, Hiemenz J, et al. Correspondence. N Engl J Med lQR7·~16·dl1

Obituaries Many doctors in India practise medicine in difficult areas under trying cir- cumstances and resist the attractions of better prospects in western countries and in the Middle East. They die without their contributions to our country being acknowledged. The National Medical Journal of India wishes to recognize the efforts of these doctors in a new section 'Obituaries'. We invite short accounts of the life and work of a recently deceased colleague by a friend, student or relative. The account in about 500 to 1000 words should describe his education and training and highlight the achievements as well as the disappointments. A photograph should accompany this article. -Editor