Case Studies

Levofloxacin: Todays Choice for the Treatment of Typhoid Fever? An Illustrative Case Report from Indonesia
R. H. H. nelwan, MD, DtMH
Professor, Department of Internal Medicine, Consultant for Tropical and Infectious Diseases, Faculty of Medicine University of Indonesia / National Top Referral Hospital Dr. Cipto Mangunkusumo, Ministry of Health, Jakarta

Introduction Typhoid fever is still endemic in many parts of the developing world and can be transferred to the developed world by returning visitors to these endemic regions (1, 2). It is a potential life-threatening disease and may produce severe complications if not treated in its early stages. Ciprofloxacin is accepted as a drug of choice for typhoid fever and has been used for almost two decades (3). In recent years, the emergence of a decline in sensitivity of Salmonella typhi to ciprofloxacin has been reported by Threlfall et al (4). Also several individual cases of the failure of ciprofloxacin to treat typhoid fever have been reported (, 6). More important is the fact that laboratory reports of increased resistance to ciprofloxacin are on the increase, especially in the South Asian subcontinent (79). At the present time, serious thought is being given about the wisdom of treating future typhoid fever cases with ciprofloxacin (10). The latest Indonesian experience clearly highlights some clinical aspects of this issue where patients on ciprofloxacin needed, on average, a longer time to become free from fever compared with earlier studies in this region using the same antibiotic regimen (11). A case will now be described where gastrointestinal intolerance to oral ciprofloxacin was observed with possible hepatic adverse reactions and subsequent clinical failure of typhoid fever treatment. Levofloxacin was substituted as it has already been shown to be better tolerated when treating this kind of gastrointestinal
Address for correspondence R. H. H. Nelwan, MD, DTMH Department of Internal Medicine, Faculty of Medicine University of Indonesia Jl. Salemba Raya No.6, Jakarta, Indonesia

infection. In this case, levofloxacin successfully cured the patients typhoid infection without causing any adverse gastrointestinal reactions. Case presentation An Indonesian male, aged 40 years, was admitted complaining of fever for  days. The fever was monitored daily and it was more pronounced in the early evening. He also initially suffered from loose motions for one day before becoming constipated. He also had headache and muscular pain. However, he had no nausea, vomiting or epigastric discomfort. His physical examination showed that he was fully alert, with a body temperature of 37.9C, blood pressure of 110/70 mmHg, pulse 88/min and a respiration rate of 16/min. His height was 16 cm and his body weight was 77. kg. No abnormal findings were noted following examination of his chest and abdomen. His extremities were also normal while his laboratory findings were as follows: Hb 1.2 g, leucocyte count ,400/ml, thrombocyte count 199.000/ml, and BSR 34 mm/hr. Urine and stool examinations were normal. As far as liver enzymes were concerned his SGOT was 112 U/l and his SGPT was 144 U/l while his CRP was 16.68 mg/L. Widal agglutination titers were 1/80 for S. typhi O and 1/1,280 for S. typhi H. His Tubex S. typhi IgM test was positive. A chest X-ray revealed old fibrotic scar tissue at the apex of the left lung. His ECG was normal. The patient was initially treated with ciprofloxacin 2 5400 mg IV for 4 days and then an IV-oral sequential switch was made after the patient had been afebrile for 24 hours. The oral ciprofloxacin 2 500 mg was continued and the patient was allowed to leave the hospital on the sixth day after hospitalization. All abnormal laboratory values had im-

proved except for the SGPT which was slightly raised when the patient was discharged. The patient was readmitted to hospital sometime during the afternoon of the next day with sudden epigastric distress after taking oral ciprofloxacin early in the morning. He also experienced cold sweats and his most significant complaint was that he felt as if his stomach was being compressed from all sides. He was slightly icteric but had no abnormal vital signs and, on physical examination, there was pain on palpation of the epigastric region and some distention of the abdomen. This episode was diagnosed as most probably an adverse gastrointestinal reaction to oral ciprofloxacin. To ease his abdominal discomfort, he was prescribed dimethicone, lansoprazole and ketorolac tromethamine. A test for anti Helicobacter pylori IgM and IgG were both negative. On readmission, his CRP was near normal and antimicrobial treatment was discontinued as ciprofloxacin had already been administered for a total of one week. Unfortunately, the next day his temperature had increased slightly and his CRP had risen markedly to 28.841 mg/L signaling a probable relapse as far as his typhoid fever was concerned. The S. typhi IgM was positive and the SGPT had increased to 413 U/L, while the SGOT was 130 U/L and there was also an increase in total bilirubin to .47 mg/dl. Levofloxacin was initially administered IV, 00 mg daily for 2 days, and then continued orally as 00 mg daily. His PCR for S. typhi became negative. All markers of acute viral hepatitis infection (A, B and C) were negative. The patients also had blood in his stools on his second admission that cleared after levofloxacin was administered. His CRP returned to normal within a few days and no adverse gastrointestinal reactions were noted. His

41

Case Studies 2

Widal agglutination test was reactive only to S. typhi H with a titre of 1/160 on

discharge. A follow-up stool culture one month later failed to grow any Salmo-

nella microorganisms.

Commentary As far as this case is concerned, several aspects of typhoid fever treatment with ciprofloxacin require comment. The first point is the treatment failure causing an early relapse. After finishing one week of treatment this patient, who was initially only readmitted to the hospital for upper gastrointestinal pain after switching from IV to oral ciprofloxacin, began experiencing chills at night and had a slightly increased body temperature. Although, on readmission, his CRP was near normal and no antimicrobial was administered due to the adverse gastrointestinal reaction, the next day his CRP was markedly elevated indicating a possible clinical relapse of typhoid fever. The S. typhi IgM test was positive and the antimicrobial treatment was switched from ciprofloxacin to levofloxacin. Intravenous levofloxacin was administered since from previous experience IV ciprofloxacin did not cause any adverse gastrointestinal effects. His blood biochemistry results also showed increased transaminases and an increased total bilirubin. A comment will be made on this finding after discussing the clinical failure of treating typhoid fever with ciprofloxacin. Two points need to be taken into consideration. Firstly, the relapse occurred because of the interrupted administration of ciprofloxacin due to the severe gastrointestinal problems that the patient experienced and, secondly, this relapse occurred early and probably was due to reduced sensitivity of S. typhi to ciprofloxacin. Following many years of ciprofloxacin use, it is well known that the sensitivity of S. typhi to ciprofloxacin gradually declined. Also, in our randomized multicenter study comparing the clinical efficacy of levofloxacin with ciprofloxacin (11), it was found that in the cases that were finally diagnosed as typhoid fever, in the ciprofloxacin group it took on average five days until normalization of body temperature while in the levofloxacin group, it took only 3 days (Table 1). After initial administration of IV levofloxacin, 00 mg, and following resolution of his gastrointestinal complaints by the third day, a switch was made to oral administration. Following this treatment, the patient made an excellent recovery. There were no aggravating gastrointesti-

nal complaints during his course of treatment with oral levofloxacin. The S. typhi IgM that became negative was reconfirmed by a PCR test for S. typhi which showed that his typhoid infection had been completely cured. Levofloxacin is also very effective against the whole spectrum of Gram-negative microorganisms and it also exhibits excellent pharmacokinetic and pharmacodynamic properties (12, 13). The second aspect for discussion is the adverse reaction the patient experienced during ciprofloxacin treatment which was the main cause of his readmission to hospital. The patient described his epigastric distress as a feeling of compression from all sides of his stomach preventing him eating properly because he readily vomited any food he managed to swallow. The possibility of a H. pylori infection was ruled out because of negative results for both H. pylori IgG and IgM. Previously, he had never had any stomach problems. The ciprofloxacin was discontinued on his readmission and, as his CRP was nearly normal, no other antimicrobials were given. This gastrointesti-

nal type of adverse reaction to ciprofloxacin has been recorded ever since its first clinical use and has occasionally prompted its discontinuation. The results of a randomized single-blind multicenter study (11) comparing safety and efficacy in patients with uncomplicated typhoid fever in Indonesia showed that there was a significantly lower number of gastrointestinal reactions in the levofloxacintreated patients compared to those receiving ciprofloxacin. There were also cases where ciprofloxacin treatment needed to be stopped suddenly compared with no cases in the levofloxacin group where treatment for this kind of condition was surprisingly well tolerated. As typhoid fever is a gastrointestinal infection, drugs causing adverse reactions in the gastrointestinal tract may result in the interruption of treatment because of aggravation of intestinal complaints. This is actually what happened to cases in this large study comparing ciprofloxacin with levofloxacin for uncomplicated typhoid fever (Table 2). From the findings already described regarding the treatment of typhoid fever, levofloxacin may be a bet-

Table 1. A randomized single-blind multicenter study comparing the clinical efficacy of levofloxacin with ciprofloxacin for the treatment of typhoid fever
Clinical efficacy Average defervescence (days) Fever-free at day 7 (%) Clinical relapse Others (relapse) 3 100 1 0 No. of patients Levofloxacin (n = 53) Ciprofloxacin (n = 54) 5 77.8 1 1

Presented at the 55th Annual Meeting of the ASTMH, Atlanta, USA, November 2006. Adapted from reference (11).

Table 2. Comparison of adverse reactions in a randomized multicenter study comparing levofloxacin with ciprofloxacin for the treatment of typhoid fever
Adverse reaction Nausea Vomiting Nausea + vomiting Epigastric pain Insomnia Cephalgia 5 1 0 0 4 0 No. of patients Levofloxacin (n = 54) Ciprofloxacin (n = 56) 4 2 4 2 2 1

Presented at the 55th Annual Meeting the ASTMH, Atlanta, USA, November 2006. Adapted from reference (11).

42

Case Studies 2

ter choice than ciprofloxacin because of its excellent proven clinical efficacy and lower incidence of adverse gastrointestinal reactions in this kind of infection. An analysis of the toxicity profile of fluoroquinolones supports this finding (14). The third aspect of interest this case was the fact that although the patient became afebrile the increased liver transaminase SGPT on admission did not return to normal but increased slightly after his temperature returned to normal. Subsequently, when the patient was readmitted, his SGPT increased to over 10 times the upper limit of normal and his bilirubin also increased. This event may be a possible dual reaction that caused hepatic insufficiency due to both an adverse reaction to ciprofloxacin and a possible complication involving the hepato-biliary system due to typhoid fever. However, as has been reported by Aggarwal et al, the possibility of cholestasis caused by ciprofloxacin should be connsidered (1). This third aspect of hepatic problems is very interesting and it would be useful to discuss it more in depth. However, no hard evidence is currently available on the performance of ciprofloxacin in cases where hepatic problems are present. As reported by Parry et al, the levels of liver enzymes in typhoid fever are usually two to three times the upper limit of normal (16). This was exactly what happened in the case of our patient when he was admitted. Although his condition improved, his SGPT was still slightly elevated on his discharge on day 6. In addition, a very interesting result emerged from the study comparing the treatment of uncomplicated typhoid fever with either ciprofloxacin or levofloxacin. In the group of typhoid fever patients treated with ciprofloxacin there was a significantly higher number of patients with increased liver transaminases compared with those treat-

Table 3. Laboratory reactions in a comparative study of levofloxacin vs. ciprofloxacin for the treatment of uncomplicated typhoid fever
Laboratory reaction Hematologic Renal Hepatic (> 3 fold increase in SGPT) None None 2 No. of patients Levofloxacin (n = 54) Ciprofloxacin (n = 56) None None 6

Presented at the 55th Annual Meeting the ASTMH, Atlanta, USA, November 2006. Adapted from reference (11).

ed with levofloxacin (6 vs. 2, Table 3). Typhoid fever itself may cause hepatic complications that will be marked by an increase in bilirubin with liver transaminases that are only slightly increased. In 10 cases of typhoid hepatitis reported by Khosla SN, the total serum bilirubin ranged from 2.0 to 7.2 mg while the SGPT was between 80 186 IU (17). In the present case, a complication of typhoid fever may have occurred after the failure of ciprofloxacin to completely eradicate S. typhi. However, looking at the very high SGPT, it seems more likely that an adverse hepatic reaction occurred. After the infection was neutralized by levofloxacin, the bilirubin values slowly returned to normal as did the liver transaminases which prolonged the hospitalization of the patient. Whether this could have been avoided by initial immediate institution of levofloxacin treatment is a very good point for discussion. The findings of Harding and Simpson regarding the low potential of levofloxacin to cause adverse hepatobiliary reactions should be stressed in this kind of situation (18). As already reported, the efficacy of levofloxacin for the treatment of typhoid fever is excellent, and in 2 trials involving an open study and a comparative study with ciprofloxacin, it was found that all the patients in the levofloxacin group were free of fever by day 6, averaging 3 days without any

post-treatment carrier state, and the relapse rate was no different from that in the ciprofloxacin group (11, 19). Also, no severe adverse gastrointestinal reactions were noted during the use of levofloxacin while, in the ciprofloxacin group, the number of adverse gastrointestinal reactions was significantly higher resulting in more withdrawals of treatment. Also, in the cases of liver insufficiency, there seems to be less chance of such problems in the levofloxacin group compared with the ciprofloxacin group. We have to remember that the typhoid fever cases may already have had liver function impairment when admitted to hospital. In the case presented above, all sero markers for hepatitis A, B and C were negative proving that the deterioration in liver function may not have been caused by a co-infection of hepatitis viruses but could possibly be attributed to the drug that was used together will possible late hepatic complications of typhoid fever. It looks as if there is a bright future for the early use of levofloxacin in typhoid fever patients in general and, especially, in patients with impaired liver function. The chance of levofloxacin exacerbating this condition is significantly smaller compared with the use of ciprofloxacin while, at the same time, levofloxacin offers a very high level of clinical efficacy with a minimal number of adverse gastrointestinal reactions.

Summary A case was presented describing the treatment failure of typhoid fever with ciprofloxacin, along with gastrointestinal and hepatic adverse reactions resulting in

prolonged morbidity and hospitalization. The case was finally treated with levofloxacin producing excellent results and rapid hospital discharge. It appears that typhoid fever can be better treated with

levofloxacin because of its dual features of high efficacy and lower rate of adverse reactions compared with ciprofloxacin especially in infections due to S. typhi.

43

Case Studies 2

ReFeRenCeS
1 Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004; 82: 34653. 2 Jelinek T, Nothdurft HD, von Sonnenburg F, Lscher T. Risk factors for typhoid fever in travelers. J Travel Med 1996; 3: 2003. 3 Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. Typhoid fever in Harrisons Manual of Medicine. 15th ed 2002 McGraw-Hill (Asia); 3601. 4 Threlfall EJ, Ward LR. Decreased susceptibility of ciprofloxacin in Salmonella enterica serotype typhi, United Kingdom. Emerg Infect Dis 2001; 7: 44850. 5 Nelwan RHH. Clinical and bacteriologial failure of ciprofloxacin in typhoid fever. Presented at the XIVth International Congress for Tropical Medicine and Malaria; 1996 Nov 1722; Nagasaki, Japan. 6 Threlfall EJ, Ward LR, Skinner JA, Smith HR, Lacey S. Ciprofloxacin resistant Salmonella typhi and treatment failure. Lancet 1999; 353: 15901. 7 Renuka K, Sood S, Das BK, Kapil A. High-level ciprofloxacin resistance in Salmonella enterica serotype Typhi in India. J Med Microbiol 2005; 54: 9991000. 8 Mushtaq MA. What after ciprofloxacin and ceftriaxone in treatment of Salmonella typhi. Pak J Med Sci 2006; 22: 514. 9 Parry CM, Karunanayake L, Coulter JBS, Beeching NJ. Test for quinolone resistance in typhoid fever. BMJ 2006; 333: 260 1. 10 Chitnis S, Chitnis V, Hemvani N, Chitnis DS. Ciprofloxacin therapy for typhoid fever needs reconsideration. J Infect Chemother 2006; 12: 4024. 11 Nelwan RHH, Lie KC, Hadisaputro S, Suwandoyo E, Suharto, Nasronudin, Yusuf H, Sudjana P, Ismanu G, Djunaedi D, Mubin H, Said M, Paramita D. A single-blind randomized multicentre comparative study of efficacy and safety of levofloxacin vs ciprofloxacin in the treatment of uncomplicated typhoid fever (Abstract 2517). 55th Annual Meeting ASTMH, Atlanta, USA, Nov 2006. 12 Davis R, Bryson HM. Levofloxacin: a review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 1994; 47: 677700. 13 Croom KF, Goa KL. Levofloxacin: a review of its use in the treatment of bacterial infections in the United States. Drugs 2003; 64: 2769802. 14 Lipsky BA, Baker CA. Fluoroquinolones toxicity profile: a review focusing on newer agents. Clin Infect Dis 1999; 28: 35264. 15 Aggarwal A, Gurka J. Probable ciprofloxacin induced cholestasis. Aust N Z J Med 1995; 25: 3412. 16 Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Eng J Med 2002; 347: 177082. 17 Khosla, SN. Severe typhoid fever, an appraisal of its profile. Proceeding 1st ISAC Internat Symp. (Ed. Nelwan RHH) Sanur Bali 1990; 5182. 18 Harding I, Simpson I. Levofloxacin: low potential for hepatobiliary adverse reactions, Abstract P851. Clin Bacterial Infect 2001; 7 (Suppl S1): 164. 19 Nelwan RHH, Chen K, Nafrialdi, Paramita D. Open study on efficacy and safety of levofloxacin in treatment of uncomplicated typhoid fever. Southeast Asian J Trop Med Public Health 2006; 37: 12630.

44