August 1990, Volume 40, Issue 8

Original Article

THERAPEUTIC IMPLICATIONS OF OFLOXACIN IN THE TREATMENT OF TYPHOID FEVER CAUSED BY MULTIPLY RESISTANT SALMONELLA TYPHI

Mohammad Ishaq  ( Department of Medicine, The Aga Khan University/Hospital, Karachi. )
Bader J. Farooqui  ( Department of Microbiology, The Aga Khan University/Hospital, Karachi. )
M. Khalid Ashfaq  ( Department of Microbiology, The Aga Khan University/Hospital, Karachi. )
M. Ata Khan  ( Department of Medicine, The Aga Khan University/Hospital, Karachi. )

ABSTRACT

The antibiotics of choice for the treatment of typhoid fever in most parts of the world is still chloramphenicol. Ampicillin and cotrimoxazole have been used in recent years. Selection of antimicrobials for therapy has been complicated by the emergence of Salmonella typhi strains resistant to the above mentioned antibiotics. Blood and/or bone marrow cultures of 30 adult patients grew S. typhi that was resistant to chloramphenicol, ampicillin and cotrimoxazole. However, these strains were sensitive to cefotaxime, ceftrioxone, aztreonam and ofloxacin. Ofloxacin 400mg twice a day was given orally to these patients for 14 days. All patients recovered with no untoward side effect. We concluded that ofloxacin can be used as a drug of choice for typhoid fever, in those adult patients who are infected with S. typhi resistant to chioramphenicol, ampicillin and cotrimoxazole (JPMA 40: 176, 1990).

INTRODUCTION

Typhoid fever is an acute and systemic illness. Although the incidence has decreased in the West, typhoid fever is still endemic in Karachi, as it is in other parts of the world with poor sanitation1-3. The commonest organism which causes typhoid fever is Salmonella typizi and less so are Salmonella paratyphi A, Salmonella paratyphi B, and Salmonella paratyphi C4. The diagnosis of typhoid fever is usually suspected on clinical ground and confirmed on the basis of isolation of the organism from blood5. In the absence of an­timicrobial therapy, blood cultures are positive in over 80% of patients seen in the first week of illness6. An­timicrobial therapy diminishes possibility of recovery of the causative agents from blood. In these patients cultures of supplementary site such as bone marrow is a better source of organism than blood7. The antimicrobial of choice for typhoid fever in most areas of the world is still chloramphenicol8,9. Ampicillin is also effective in the treatment of typhoid fever10 . Several studies have demonstrated a slower response rate to ampicillin than chloramphenicol10,11. Trimethoprim-sul­famcthoxazole has been used in recent years in the treatment of typhoid fever12. Strains of Salmonella typhi resistant to chloram­phenicol have been reported in recent years from Mexico, Vietnam and India13. Ampicillin is recommended as an alternative to chloramphenicol as antibiotic therapy for typhoid fever caused by chloramphenicol resistant strains of Salm onella typhi14. Only occasional strains of Salmonel­la typlii are known to be resistant to both chloramphenicol and ampicillin15. Trimethoprim-sulfamethoxazole is the drug of choice for typhoid fever caused by chloram­phenicol or ampicillin resistant strains of Salmonella typhi16. Over a period of three years 3224 patients attended emergency room and consulting clinic of the Aga Khan University Hospital Karachi, for pyrexia of unknown origin. Blood cultures from all of these patients and bone marrow from selective patients were collected and sent to Microbiology laboratory of The Aga Khan University Hospital for culture. Total positive isolated were 13% out of which 3 1.5% were Salmonella species. Further sub typ­ing of species showed Salmonella typhi in 83%. Antibiotic sensitivities result of these strains showed that ap­proximately 30% were resistant to ampicillin, chloram­phenicol and cotrimoxazole. We report management of 30 such patients suffering from typhoid fever caused by Salmonella typhi resistant to the first line antibiotics (chioramphenicol, ampicillin and cotrimoxazole). The aim of this study was to determine the effectiveness of ofloxacinin the treatment of such patients.

MATERIALS AND METHODS

Samples of blood and/or bone marrow were col­lected from 30 patients suspected for typhoid fever. Each blood sample (4-5 mls) or bone marrow sample (0.5 — 1.Oml) was collected in each of the 2 blood culture bottles containing 45ml of aerobic medium (brain heart infusion brOth) and anaerobic medium (thioglycolate broth). Bot­tles were immediately transported to the laboratory and incubated at 37°C for 7 days. Gram stain film was made from each bottle daily for 7 days. All bottles were sub cultured after 24,48,72 hours and 7th day of incubation on to blood agar and MacConkey\'s media. Non lactose fermenting colonies from MacConkey’s plate were biochemically speciated using API 20E* strips. Serologi­cal confirmation was done by type specific sera. Antibiotic sensitivity testing of all isolates was performed by the method described earlier17. The antibiotic discs used were anipicillin (10mcg), cotrimoxazole (25mcg), chloram­phenicol (30mcg), cefotaxime (3Omcg), aztreonam (30mcg), ceftrioxone(3Omcg) and ofloxacin (5mg).

RESULTS

A wide variety of clinical presentations were ob­served in these 30 patients (Table 1).

The blood and/or bone marro* cultures from all the 30 patients grew S. typhi at varied times after incubation (Table II).

Approximately 7% of the samples grew typhi on either day 1, 4 or S post incubation. However, 53.3% and 26.7% of the samples grew S. thphi on day 2 and 3 post incubation, respectiyely. The antibiotic sensitivity test showed all the isolates of S. typhi were resistant to ampicillin, cotrimox4zole and chloramphenicol, however they were sensitive to cefotaxime, aztreonam, ceftrioxone and ofloxacin. All patients were initially treated with the first line antibiotic therapy (ampicillin, cotrinioxazole or chloram­phenicol), Eleven patients were prescribed ampicillin 1gm 8 hourly,? patients’received cotrimoxazole D.S. 12 hourly and 12 patients were given chloramphenicol 1gm 6 hourly. Treatment was reviewed after the antibiotic sensitivity results were obtained. All patients were then given ofloxacin, 400mg twice a day, orally for 10 to 14 days. Temperature of all these patients) settled within 48 to 72 hours after the ofloxacin therapy.

DISCUSSION

This study clearly shows that most common cause of typhoid fever in Karachi is S. typhi as all the blood and/or bone marrow cultures grew this organism within 5 days of incubation, with over 50% showing growth of the organism 4t5 hours of incubation. The drugs of choice in typhoid fever are chloram­phenicol, ampicillin and cotrimoxazole5,13,15. All patients were initially treated with these antibiotics, but did not respond within 48 hours and in some cases even after 5 days of treatment. This observation indicated the infection with resistant S. typhi which was confirmed by microbiological results. At this point ofloxacin was administered to these patients. !n the recent past ofloxacin had been tested in vitro for its efficacy against S. typhi. The minimum in­hibitory concentration (M!C) ranged from 0.03 to 0.12 mcg16,17.. Similarly the mean MICs of cefotaxime, aztreonam, ceftrioxone for S. typhi has been shown to be less than 0.97 mcg18. The selection of ofloxacin for our patients was done because the drug is effective in vitro16, can be administered orally therefore eliminates the cost of hospitalization and is relatively less expensive than the other newer antibiotics. The recommended dose of ofloxacin in gram nega­tive systemic infections is 200mg twice a day. As these patients are seriously ill, theywere given 400mg twice a day. Fever subsided within 72 hours after administration of this therapy. The treatment was continued for 14 days. No untoward effects were observed. Ofloxacin is a good drug in S. typhi infection resistant to the first line antibiotics. However this drug should riot be used in children under 14 years of age and in pregnant women. Further studies with a larger group of patients are recommended to evaluate the dose and effectiveness of this drug to substantiate our conclusions.

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