Case of the Month

February 2013

From Peshawar to Cape Town – Dr Trevor Mnguni and Dr Karen Keddy

A 21 year old male from Pakistan travelled to South Africa. He travelled from Peshawar to Maputo by air (10 days including stopovers); he then drove to Cape Town via Johannesburg.

He presented to hospital with a 3 week history of being unwell, fever, abdominal pain, diarrhoea, headaches and generalised myalgia. He had no respiratory complaints and no previous history of seizures.

On physical examination he appeared unwell. He had a coated tongue and was pale. There was no jaundiced nor adenopathy. There were no peripheral stigmata of retroviral disease His recorded oral temperature was 38°C; blood pressure of 100/68; and pulse rate 56 beats per minute.

On abdominal examination, discrete maculopapular lesions of 2-4mm were observed, with generalised abdominal tenderness and 2cm tender hepatomegaly, neither rebound nor splenomegaly. Cardiorespiratory findings were unremarkable, other than the relative bradycardia. The central nervous system examination revealed a patient who was alert and orientated. There was no meningism or other neurological findings.

Shortly thereafter the patient developed generalised tonic-clonic seizures and was loaded with diazepam 10mg intravenously. There was concern of intracranial pathology and blood cultures were taken, followed by empiric ceftriaxone 2g intravenously.

The initial blood results revealed that the full blood count and biochemistry were normal and liver functions tests were within normal range. Blood tests for Hepatitis a, B and C were all negative, as were malaria smears on tow occasions. Lumbar puncture was normal, including a negative cryptococcal latex agglutination test (CLAT) and fluorescent treponemal antibody absorbed (FTA-Abs). Abdominal ultrasound was non-contributory. Cat scan of the brain was normal with no intracranial pathology.

The blood culture was positive for Gram negative bacilli, which were identified as Salmonella enterica serotype Typhi (Salmonella Typhi), resistant to trimethoprim-sulfamethoxazole, ampicillin and nalidixic acid, intermediately resistant to ciprofloxacin and susceptible to cefotaxime and ceftriaxone.

Question 1: What is the aetiological agent of typhoid fever?

Answer to Q1

Typhoid Fever is a systemic infection with the bacterium Salmonella enterica serotype Typhi (Salmonella Typhi) which is a member of the family Enterobacteriaceae. The bacterium is serologically positive for lipopolysaccharide antigens O9 and O12, protein flagellar antigen Hd, and polysaccharide capsular antigen Vi. The Vi capsular antigen is largely restricted to Salmonella Typhi1-3. Typhoid is usually contracted by ingestion of food or water contaminated by faecal or urinary carriers excreting Salmonella Typhi. It is a sporadic disease in developed countries that occurs mainly in returning travellers, with occasional point-source epidemics1-3. Clinicians should have a high index of suspicion in patients with a positive travel history to highly endemic countries, where multidrug resistance is common4.

Question 2: How is typhoid fever contracted?

Answer to Q2

In endemic areas identified risk factors for disease include eating food prepared outside the home, drinking ontaminated water, having a close contact with a friend or relative with recent typhoid fever and poor housing with inadequate facilities for personal hygiene 1-5.

Question 3: What are the clinical manifestations of typhoid fever?

Answer to Q3

After a person ingests Salmonella Typhi, an asymptomatic period follows that usually lasts 7 to 14 days (range 3 - 60). The onset of bacteraemia is marked by fever and malaise. Patients typically present to the hospital toward the end of the first week after the onset of symptoms with fever, influenza-like symptoms with chills (although rigors are rare), a dull frontal headache, malaise, anorexia, nausea, poorly localized abdominal discomfort, a dry cough, and myalgia, but with few physical signs. A coated tongue tender abdomen, hepatomegaly, and splenomegaly are common. A relative bradycardia is considered common in typhoid, although in many geographic areas this has not been a consistent feature. A few rose spots, blanching erythematous maculopapular lesions approximately 2 to 4 mm in diameter, are reported in 5 – 30% of cases. They usually occur on the abdomen and chest and more rarely on the back, arms, and legs. These lesions are easily missed in dark-skinned patients. Salmonella Typhi must survive the gastric acid barrier to reach the small intestine, and a low gastric pH is an important defence mechanism. Achlorhydria as a result of aging, previous gastrectomy, or treatment with histamine (H2)-receptor antagonists, proton-pump inhibitors, or large amounts of antacids lowers the infective dose. In the small intestine, the bacteria adhere to mucosal cells and then invade the mucosa. The M cells, specialized epithelial cells overlying Peyer’s patches, are probably the site of the internalization of Salmonella Typhi and its transport to the underlying lymphoid tissue. After penetration, the invading microorganisms translocate to the intestinal lymphoid follicles and the draining mesenteric lymph nodes, and some pass on to the reticuloendothelial cells of the liver and spleen. Salmonella organisms are able to survive and multiply within the mononuclear phagocytic cells of the lymphoid follicles, liver, and spleen. At a critical point that is probably determined by the number of bacteria, their virulence, and the host response, bacteria are released from this sequestered intracellular habitat into the bloodstream2,3.

Question 4: What are the complications of typhoid fever?

Answer to Q4

Occur in 10-15% of patients and are particularly likely in patients who have been ill for more than 2 weeks2,3. Systems affected include:

  • Abdomen
    • Gastrointestinal Perforation
    • Gastrointestinal Haemorrhage
    • Hepatitis
    • Cholecystitis (usually subclinical)
  • Cardiovascular
    • Asymptomatic Electrocardiographic changes
    • Myocarditis
    • Shock
  • Neuropsychiatric
    • Encephalopathy
    • Delirium
    • Psychotic states
    • Meningitis
    • Impaired Co ordination
  • Respiratory
    • Bronchitis
    • Pneumonia
  • Haematologic
    • Anaemia
    • Disseminated intravascular coagulation(usually subclinical)
  • Other
    • Pharyngitis
    • Focal abscess
    • Miscarriage
    • Relapse
    • Chronic carriage

Question 5: What is the definition of a chronic carrier?

Answer to Q5

A chronic carrier is a patient who continues to excrete the organism for one year after adequate antimicrobial treatment. Chronic carrieage is more common among women and the elderly and in patients with cholelithiasis. Most chronic carriers are asymptomatic and treatment includes a cholecystectomy due to persistence of the infection in the gallbladder or the biliary tract2-3.

Question 6: What is the antimicrobial management of typhoid fever?

Answer to Q6

Effective antibiotics, good nursing care, adequate nutrition, careful attention to fluid and electrolyte balance, and prompt recognition and treatment of complications are necessary to avert death. Multi-drug resistance has long been a challenge and was first described in South Africa in the 1980s5. There is strong evidence that the fluoroquinolones are the most effective drugs for the treatment of typhoid fever (table 1 and table 2). In randomized, controlled trials involving patients infected by quinolone-susceptible Salmonella Typhi, these drugs have proved safe in all age groups and are rapidly effective even with short courses of treatment (3 -7days). The average fever-clearance time is less than four days, and the cure rates exceed 96 percent. Less than 2 percent of treated patients have persistent faecal carriage or relapse7-11. The published data also suggest that the fluoroquinolones are more rapidly effective and are associated with lower rates of stool carriage than the traditional first-line drugs (chloramphenicol and trimethoprim–sulfamethoxazole). Fluoroquinolones should be used at the maximal possible dose for a minimum of 5 - 7 days, and the patients should be carefully followed to determine whether they are excreting Salmonella Typhi in their faeces3.

The Clinical and Laboratory Standards Institute (CLSI) revised the breakpoints for testing the fluoroquinolones against Salmonella Typhi and invasive non-typhoidal Salmonella in 2012: this reinterpretation of clinical data has resulted in greater numbers of Salmonella Typhi being reported as intermediately resistant, and has implications for patient management9-11. Resistance to the fluoroquinolones is rapidly developing, necessitating the use of novel treatment strategies (table 2)8-10. Unfortunately, quinolone-resistant strains are often also multi-drug resistant, and therefore the choice of drugs is limited to azithromycin or the cephalosporins, which are expensive (table 2). Alternatively, prolonged treatment with high-dose fluoroquinolones (10 – 14 days), has been used (table 2), but experts are reviewing this recommendation, given the current lack of evidence for this treatment. Note that oral third generation cephalosporins should not be used, as these have been associated with the development of extended spectrum beta-lactamases

(ESBL) in Salmonella Typhi3,11.

Table 1. Treatment of uncomplicated typhoid fever7-11

*The widely available fluoroquinolones (ofloxocin, ciprofloxacin and perfloxacin) all highly active and equivalent in efficacy. Norfloxacin has inadequate oral bioavailability and should not be used to treat typhoid fever.

*Three-day courses are also effective, particularly for the containment of epidemics.

*The optimal treatment for quinolone-resistant typhoid fever has not been determined. Azithromycin, or a third-generation cephalosporin, or a 10-to-14-day course of high doses of a fluoroquinolone is effective. Combinations of these treatments are now being evaluated.

Table 2. Treatment of severe typhoid fever.7-11

*The widely available fluoroquinolones (ofloxacin, ciprofloxacin, and perfloxacin) are all highly active and equivalent in efficacy.


  1. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid Fever : Review article. N Engl J Med 2002; 347: 1770-1781.
  2. Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT, Snyder MJ. Typhoid Fever: pathogenesis and immunologic control. N Engl J Med 1970; 283: 686-91.
  3. (WHO) WHO. Background document: the diagnosis, treatment and prevention of typhoid fever. Available at: http://whqlibdoc.who.int/hq/2003/WHO_V&B_03.07.pdf. Last accessed 24 July 2012.
  4. Threlfall EJ, Ward LR, Rowe B, Raghupathi S, Chandrasekaran V, Vandepitte J, Lemmens P. (1992). Widespread occurence of multiple drug-resistant Salmonella typhi in India. Eur J Clin Microbiol Infect Dis: 11: 990-3.
  5. Mermin JH, Villar R, Carpenter J, et al. A massive epidemic of multidrug-resistant typhoid fever in Tajikistan associated with consumption of municipal water. J Infect Dis 1999; 179: 1416-22.
  6. Cohen SL, Wylie BA, Sooka A, Koornhof HJ. Bacteremia caused by a lactose-fermenting, multiply resistant Salmonella typhi strain in a patient recovering from typhoid fever. J Clin Microbiol. 1987 Aug;25(8):1516-8.
  7. Butler T. Treatment of typhoid fever in the 21st century: promises and shortcomings. Clin Microbiol Infect. 2011 Jul; 17(7):959-63.
  8. Zaki SA, Karande S. Multidrug-resistant typhoid fever: a review. J Infect Dev Ctries. 2011 May 28;5(5):324-37.
  9. Humphries RM, Fang FC, Aarestrup FM, Hindler JA. In vitro susceptibility testing of fluoroquinolone activity against Salmonella: recent changes to CLSI standards. Clin Infect Dis. 2012 Oct; 55(8): 1107-13.
  10. Group for Enteric, Respiratory and Meningeal disease Surveillance in South Africa. GERMS-SA Annual Report 2011. Available at: http://www.nicd.ac.za/assets/files/2011%20GERMS-SA%20Annual%20report%20Final.pdf.
  11. National Institute for Communicable Diseases. Communicable Diseases Communiqué September 2012. Available at: http://www.nicd.ac.za/assets/files/NICD-NHLS%20Communiqu%C3%A9_September%202012f.pdf.
Outcomes of the case

Patient was isolated and the Western Cape health authorities were notified. He received two weeks of intravenous ceftriaxone and was followed up at outpatients clinic. The patient was counselled on personal hygiene including hand washing and food preparation.

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