June 1998, Volume 48, Issue 6

Original Article

Typhoid Fevers: Treatment with Lomefloxacin

Saleem Hafiz  ( Mid East Medical Center, Karachi. )
Farangis Habib  ( Clifton, National Innstitute of Child Health, Karachi. )
Naeem Ahrnad  ( Punjab Medical College, Faisalabad, Allied Hospital P.M.C. Faisalabad. )
Irshad-ul Haq  ( Punjab Medical College, Faisalabad, Allied Hospital P.M.C. Faisalabad. )
Rafaqat Husain  ( Punjab Medical College, Faisalabad, Allied Hospital P.M.C. Faisalabad. )

Abstract

Typhoid group of fevers pose a major threat and are a cause of high morbidity and mortality in the tropical countries. Over the last decade there has been a steady increase in the development of multiresistant strains of Salmonellae all over the world. Multiresistance ranges between 5% to 86%. In a recent study in Pakistan multidrug resistance in Salmonellae has increased to over 39%. Hence alternative therapy is needed. Fluroquinolones are an effective alternative requiring a shorter course of treatment than convenĀ­tional antimicrobial agents. Lomefloxacin because of its longerhaif life and convenient BD dose was used in a multicentre study to treat cases of typhoid group of fevers including cases due to multiresistant isolates. In order to overcome the challenge presented by the multiresistant salmoneallae, a dual purpose multicentre study was conducted in two stages. The first stage included a vitro study and the second in vivo study. Two hundred local salmonellae isolates were collected and their sensitivity and minimum inhibitory concentrations were determined by standard methods. Two hundred and fourteen patients clinically suspected of suffering from typhoid groups of fevers were given Lomefloxacin 200 mg. BD for 14 days. Forty percent of Salmonellae isolates were found to be multiresistant while only 2% were found to be resistant to Fluroqunilones. The mean MIC 90 was found to be 0.06 mg/L Lomefloxacin was found to be effective in over 97% cases for treating typhoid group fevers including the ones due to multiresistant isolates. The side effects were found to be minimal and transient (JPMA 48: 168, 1998).

Introduction

Typhoid is a very important disease in the developing countries where potable water which plays a major role in the spread of enteric diseases is still a rare commodity1. Typhoid fever is a severe, debilitating and potentially life threatening illness. Salmonella typhi, S. paratyphi A and B are important because of their frequent association with severn disease and bacteremia2-4. These serotypes are endemic in developing countries and results in high morbidity and mortality. The organisms invade the bowel mucosa and multiply in the submucosa and depending upon the virulence of the strain and the host response, they may invade the blood stream, lymphatic tissue or both5-7. The situation is more complicated by the fact that a high percentage of the isolates are resistant to the three commonly used antibiotics i.e. Cotrimoxazole, Ampicillin and Chloramphenicol8. As multiresistance is increasing, there is great room for the use of alternative therapy.
To overcome the challenge presented by the mulliresistant salmonellae, a dual purpose multicentre study was conducted in two stages. The first stage included in vitro study and the second stage was in vivo study.

Methods and Subjects

In Vitro Study
Two hundred local Salmonellae isolaates were obtained from Karachi, Lahore and Rawalpindi/Islamabad. These were consecutively collected routine isolated from the blood of patients with Typhoid group of fevers confirmed by API and Serological tests. Their sensitivity and minimum inhibitoiy concentration was determined by sensitivity discs and agar dilution method6 using Brain Heart infusion agar. The Discs were standard discs manufactured by DIFCO USA9. The in-vitro study was conducted at one centre. Isolates from the other centres were isolated, identified and transported to Karachi on agar slopes where they were reconfirmed and all tests performed for sensitivity and MIC. Fifty isolates of Salmonealla included Salmonella typhi 30, Salmonella paratyphi A 10 and Salmonella paratyphi B 10. There were taken randomly from the 200 isolates and minimum iithibitoxy concentration to Lomefloxacin was carried out at Karachi centre by incorporating the antibiotic in Brain Heart infusion agar and inoculating by multipoint inoculator (Denley).
In Vivo Study
An open multicentre trial was conducted to evaluate the safety and efficacy of Lomefloxacin (2x200 mg for 14 days). In all 214 patients clinically suspected of suffering from typhoid group of fevers were asked for their consent and detailed history was taken. Blood was collected for Haematology, Biochemistry and Microbiological tests including serological tests. Then the patients were given Lomefloxacin 200 rug BD for 14 days after which blood cultures were taken and after 21 days three consecutive stool samples were collected to evaluate the eradication of Salmonella species. The in-vivo study was conducted at Karachi, and Faisalabad.

Results



Table I gives the results of in vitro study. In all 140 salmonella isolates were tested with the antibiotic routinely used for treating Salmonellosis and compared with Lomefloxacin. It is interesting to note that 99% isolates were found to be sensitive to the drug with the MIC range being 0.03-4.0 ug/mI while MIC 90 was found to be 0.5 ug/mi (Table II).


The in vivo study was carried out in 214 patients including 139 males (65%) and 75 females (35%). The age range was 18- 80 years. The most susceptibe group was 20-30 years of age (Table III).


The clinical histoiy revealed that only 9.3% of the patients had not taken any medication, during the 2 weeks prior to investigations (Table IV).


The most common presenting symptom was Gastrointestinal which was seen in 56% of case (Table V).


Enteric fevers were diagnosed on the basis of Widal test which was positive in 137 cases (64.0) while culture was positive inonly 100 patients (46. 7). Twenty three patients with a positive culture showed a significant rise in antibodies level while inthe other 77 patients widal titre was insignificant. This ilisutrates the fact that culture for enteric pathogens specially blood culture should be carried out during the first seven days of onset of fever, otherwise it becomes negative as the antibodies levels rise.
The laboratoiy findings are listed in Table VI.

The TLC count either was within normal range or showed leucopenia ESR was raised while platelets were within normal range (Table VI).

Table VII records the side effects ofLomefloxacin therapy. No adverse symptoms were reported of 74% of patients, while 26% experienced some side effects the commonest being nausea in 19(9%) and Photosensitivity and confusion in two individuals each.
Of the 100 culture positive patients, 11 were lost to follow up after stopping of the therapy. Only 89 subjects could be evaluated of which 88 (98%) achieved complete eradication of the pathogens as confirmed by a negative stool culture. The pathogen persisted in one case. Of the 214 patients on Lomefloxacin, 209 (97.6%) responded satisfactorily. 5 (2.3%) failed to respond and were classed as treatment failure.

Discussion

Typhoid fever is a very common disease seen in the developing countries, the main promoting factor being contaminated water. Typhoid is endemic in Pakistan and usually a higher frequency is seen in the wanner months. There is a gradual increase in the multiresistant strains in the community6 thus causing tremendous difficulties in the treatment of typhoid fevers.
The in-vitro study suggested that 99% of the isolates are sensitive to Lomefloxacin hence a in-vivo study was conducted. It is interesting to note that of the 220 patients included in the study, only 9.5% had received no medication before presentation. This is quite common in countries where medicines ate available over the counter leading to self medication. The most vulnerable age group was found to be 20-29 years. This could be due to the fact that individuals in this age group are adventurous and consume food which is exposed to contamination. The most common clinical symptom was found to be gastrointestinal upset. The culture waspositiveonly in 100 (46.8%) cases this could be due to thefact that the Laboratory standards are not the same orbecause most of the patients had taken some medication prior to presentation. Widal test was positive in 137 patients and is probably the test which is relied onby most of the local physicians.
Lomefloxacin (2x200 mg) was found to be effective in treating Typhoid group of fevers in 97.6% of patients which inicuded patients who had multiresistant salmonella isolates. The mean MIC of Salmonella isolates was found to be 0.5 uG/ML, which is generally achievable at all body sites. The pathogen was eradicated in 98% cases hence the drug was found to be effective in eliminating the possibility of conversion of patients into the carrier state. This would help in the Epidemiological control of the disease.

References

1. Wolfe SM. Diseases of travellers, Clinical symposia. Medical education division. New Jersey. Ciba Pharmaceutical Company, 1984,36 2.3.
2. Askerkofe B, Bennett JV. Effect of antibiotic therapy in acute salmonellosis on the faccal excretion of Salmonellae. N. EngI. J. Med.. 1969;281 :636-640.
3. Baine WB, Gangarosa EJ, Bennett JV et el. institutional salmonellosis. J. Infect. Dis. 1973;128:357-360.
4. Bennett IL, Hook EW. Infectious diseases (some aspects of salmonellosis) Annu. Rev, Med., 1959; 10:1-20.
5. Black PH. Kunz LJ, Swartz MN. Salmoneilosis A review of some unusual aspects. N. EngI. 5. Med., 1960;262:813.817.
6. Saphra I, Winter JW Clinical manifestations of saimonellosis in man: An evaluation of 7779 human infections identified at the New York Salmonella-Centre. N. Engl. J. Med.. 1957;256:1 128-1134.
7. Hafiz S. Lyall N, Punjwani S et al. Reliable and realistic approach to sensitivity testing. J. Pak. Med. Assoc., 1989;39:94- 97.
8. Hafiz S. Khan SW, Shariff, R. et al. Epidemiology of Salmonellosis and its sensitivity in Karachi. S. Pak. Med. Assoc., 1993;43:178-l79.
9. Bauer AW, Kirby WMM, Sherris SC et al. Antibiotic susceptibility testing by a standardised single disc method. Am. J. Clin. Pathol.. 1966;45:493-496.

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