Ceftriaxone therapy in ciprofloxacin treatment failure typhoid fever in children
Background & objectives: The rapid spread of multidrug resistant (MDR) typhoid fever has posed a great challenge for the treatment of these cases the world over. After the emergence of chloramphenicol resistant Salmonella typhi strains, ciprofloxacin has become the drug of choice for the treatment of typhoid fever even in the paediatric age group. This study evaluated the role of ceftriaxone therapy in bacteriologically confirmed MDR typhoid cases who did not respond to 12-14 days of ciprofloxacin therapy. Attempts have also been made to investigate the in vitro susceptibility of isolated S. typhi strains to chloramphenicol, ciprofloxacin and ceftriaxone.
Methods: A total of 140 children, aged 3-10 yr, clinically diagnosed as having typhoid fever, without any clinical response after 12-14 days of ciprofloxacin therapy were screened for S. typhi by blood culture. In the bacteriologically positive children the treatment was changed to intravenous ceftriaxone for 14 days. The isolated strains of S. typhi were tested for in vitro antimicrobial susceptibility.
Results: Clinical and bacteriological cure was observed with intravenous ceftriaxone therapy in all the 32 bacteriologically positive patients. All isolated S. typhi strains were uniformly (100%) susceptible to ciprofloxacin and ceftriaxone but 50 per cent of the strains were resistant to chloramphenicol. The MIC values of chloramphenicol, ciprofloxacin and ceftriaxone ranged between 125-500, 0.0625-0.5 and
Interpretation & conclusion: The study indicates that although the S. typhi strains were susceptible to ciprofloxacin in vitro, the patients did not respond clinically and bacteriologically to ciprofloxacin therapy. Hence, ciprofloxacin may not represent a reliable and useful option for treating MDR typhoid fever; ceftriaxone may be an effective alternative for the treatment of such cases.
Key words Ceftriaxone – ciprofloxacin – Salmonella typhi – typhoid fever
Typhoid fever is traditionally treated with chloramphenicol, trimethoprim-sulphamethoxazole or ampicillin/amoxycillin with roughly equal efficacy despite minor differences in toxicity, duration of fever, carriage and relapse rate1,2. From the late 1980s, Salmonella tYphi resistant to these standard antimicrobial agents have been reported with alarming frequency from different parts of India 3-6. Subsequently, ciprofloxacin, a fluoroquinolone, became the drug of choice for the treatment of multidrug resistant (MDR) typhoid fever in children in India7 as it shortened the illness by 3 days7,8.
There are however, diverge opinions regarding the use of this drug in the paediatric age group9,10. After 1997 many children with typhoid fever did not respond to ciprofloxacin, which became a cause of concern for both parents and physicians. We reported here our experience with intravenous ceftriaxone for treating bacteriologically confirmed MDR typhoid fever patients who failed to respond to 12-14 days of ciprofloxacin therapy. At the same time in vitro susceptibility testing of the S. typhi isolates was done and attempts were made to correlate the in vitro test results with the patients’ response to the drug.
Material & Methods
Study population : Between January 1998 and March 2000, 140 children aged 3-10 yr who presented with sustained high temperature (>=39 deg C) with no signs and symptoms of respiratory tract infection, urinary tract infection, gastroenteritis, hepatitis or meningitis and no malarial parasite in the peripheral blood smear, were diagnosed as having typhoid fever and advised ciprofloxacin therapy at their residence by practicing physicians. These children were referred to the Dr B.C. Roy Memorial Hospital for Children, Kolkata, as there was continuation of fever (>=39 deg C) in spite of having ciprofloxacin orally in a dose of 10 mg/kg body weight/day in two divided doses for the previous 3-4 days. After admission detailed clinical history was obtained either from the parents or patients and a thorough physical examination was done. It was reconfirmed that these children did not have any other systemic illnesses. Patients were weighed to the nearest 100 g. Ciprofloxacin was continued orally at the same dose under direct medical supervision for another 8-10 days, but there was no response to the therapy as evident by lack of remission or decrease in fever and improvement of general condition. After receiving therapy at the hospital for 8-10 days, a blood sample (5 ml) was collected aspectically from each patient and inoculated into 50 ml of glucose broth at the bedside for isolation-bf S. typhi by standard techniques . In addition stool samples or rectal swabs in transport media were also collected and transported to the microbiology laboratory for further processing.
Routine examination of blood, urine and stool was carried out in all patients. Chest and abdominal X-rays were done in patients where it was indicated. Liver function tests, kidney function tests and examination of cerebrospinal fluid were performed as per indication.
After collection of the blood sample, the treatment was changed to intravenous ceftriaxone (80 mg/kg body weight/day in two divided doses) for 14 days in all these children. Children were followed up three times daily for assessment of general condition and remission of fever. Remission of fever was considered when the maximum body temperature (axillary) was
(i) Processing of blood samples – Selective agar media was used for subculture at least once during day 1 (12 h after collection) and thereafter at intervals. After incubation at 37 deg C for 24 h typical colonies of S. typhi were identified by biochemical tests and confirmed serologically by agglutination with group specific 0 and H factor sera (Denka Seiken Co., Japan).
(ii) Processing of stool samples – Enrichment selective media were used for processing stool samples. Selenite F broth was used for enrichment and Hoektoen Enteric Agar (HEA) or Xylose Lysine Dextrose (XLD) plate were used as selective media.
(iii) Antimicrobial susceptibility test-All S. typhi isolates were tested for antimicrobial susceptibility using the disc diffusion technique 12 and commercially available discs of antibiotics like chloramphenicol, ciprofloxacin and ceftriaxone commonly used to treat enteric fever. Escherichia coli ATCC 25922 was used as the quality reference strain. The minimal inhibitory concentrations (MICs) of these drugs were also determined by an agar dilution technique 13.
Results & Discussion
Of the 140 children, 32 (23%) were bacteriologically positive for S. typhi by blood and stool culture and these children became the subjects of this communication. They were aged between 3-10 yr (mean 6.6 yr) and had high fever for 14-44 days (mean 20.6 days) for which they received ciprofloxacin for a period of 8-10 days (mean 9.2 days) at the hospital under direct medical supervision and 3-4 days at the domiciliary level without any clinical improvement. However, the S. typhi strains isolated from these children were susceptible (100%) to ciprofloxacin in vitro, with MIC ranging between 0.0625-0.5 (mu)g/ml (MIC^sub 50^ = 0.0625; MIC^sub 90^ = 0.5).
Oral ciprofloxacin was changed to intravenous ceftriaxone which was continued for 14 days even after remission of fever. All the S. typhi isolates were also susceptible (100%) to ceftriaxone in vitro with an MIC of 125; MIC^sub 90^ > 500).
During the early part of the epidemic of typhoid fever in and around Kolkata in 1990, S. typhi isolates were moderately resistant to the antibiotics recommended for typhoid fever treatment like chloramphenicol (78.3%), ampicillin (49.1%) and trimethoprim-sulphamethoxazole (89.1%)4. However, during the later part of the epidemic all the S. typhi isolates became uniformly (100%) resistant to these drugs 3. During 1990-1993 ciprofloxacin became the preferable drug and finally the drug of choice in the treatment of MDR typhoid fever not only in adults but also in children’s7,14. However, it was observed that gradually longer periods (from 3 days to 5-6 days) were required for the fever to subside 15,16 though the susceptibility pattern of S. typhi strains remained unchanged 16,17.
The present study between 1998 and early 2000, showed that the patients did not respond to ciprofloxacin therapy even after 12 to 14 days of use. It was initially thought that the clinical failure of ciprofloxacin was due to the development and spread of ciprofloxacin resistant strains of S. typhi in this part of India as seen in other parts of the world18-20. However, in vitro tests revealed that the strains were uniformly susceptible to ciprofloxacin. Such decreasing clinical efficacy and treatment failure despite in vitro susceptibility to ciprofloxacin were also observed in other parts of world including India15.16. Though the MIC of this drug was within the normal range, treatment of these patients with a higher dose was avoided as it might cause dose dependent side effects9,10.
With institution of ceftriaxone therapy both clinical and bacteriological cure was observed in the patients within an average of 4.6 days. Relapse or any complication was not encountered in the study population during 3 months follow up period. In other studies ceftriaxone has also been regarded as the reasonable choice for treatment of MDR typhoid fever in children due to reported clinical success and low MIC value21-23.
Hence, it may be concluded that due to the increase in the number of treatment failures with ciprofloxacin, ceftriaxone is an effective and useful alternative treatment for clinical and bacteriological cure of MDR typhoid fever even though the strains isolated are susceptible to ciprofloxacin. The rapid spread of MDR typhoid fever over a large geographic area presents multiple challenges, specially in less developed countries where access to newer and more expensive antimicrobial agents may be limited. Therefore, research efforts must be continued to focus on oral agents with chances of high cure rate.
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P. Dutta. U. Mitra, S. Dutta, A. De, M.K. Chatterjee* & S.K. Bhatachara
Divisions of Clinical Medicine & Microbiology, National Institute of Cholera & Enteric Diseases (ICMR) & *Department of Pediatric Medicine. Dr B.C. Roy Memborial Hospital for children, Kolkata, Intdia
Received February 8, 2001
Reprint requests: Dr. P. Dutta, Deputy Director (Senior Grade) & Head Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases. P-33, C.I.T. Read Scheme XM. Belasghata, Kolkata 2000010. India
Copyright Indian Council of Medical Research Jun 2001
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