Enteric fever, MDR and XDR typhoid

Overview

Enteric fever is a systemic febrile illness caused by Salmonella Typhi (typhoid fever) and Salmonella Paratyphi A, B and C (paratyphoid fever, usually milder). It is spread by food and water contaminated with human faeces and is very common in South Asia.

Pakistan faces a special problem: extensively drug-resistant (XDR) typhoid, first reported in Hyderabad, Sindh in 2016, which resists almost all routine oral antibiotics. This makes blood culture with sensitivity and correct antibiotic choice essential.

Aetiology and epidemiology

• Salmonella Typhi: Gram-negative, motile, flagellated bacillus. Antigens: O (somatic), H (flagellar) and Vi (capsular; resists phagocytosis).
• Humans are the only reservoir: acute cases and carriers.
• Spread: faeco-oral, through contaminated water, uncooked food, food handlers; the "5 Fs": food, fingers, flies, fluids, faeces.
• Incubation: usually 10–14 days (range about 1–3 weeks).
• Age: mostly school-age children and young adults in endemic areas.

Pathophysiology

1. Ingested bacilli survive stomach acid (risk rises with antacids and achlorhydria).
2. They cross the small bowel, mainly the Peyer's patches of the terminal ileum, via M cells.
3. Taken up by macrophages, they reach mesenteric lymph nodes, then the blood (primary bacteraemia).
4. They multiply in the liver, spleen, bone marrow and gall bladder (reticuloendothelial system).
5. A secondary bacteraemia produces the clinical illness.
6. Bacilli re-enter the gut through bile; inflammation and necrosis of Peyer's patches cause ulcers along the long axis of the ileum. These ulcers can bleed or perforate.

Clinical features (classic untreated course)

• Relative bradycardia: the pulse is slower than expected for the fever.
• Paratyphoid is usually shorter and milder.

Complications

• Gut: ileal perforation (peritonitis), haemorrhage (melaena), hepatitis, cholecystitis, pancreatitis.
• Neurological: encephalopathy, meningitis, psychosis.
• Cardiac: myocarditis.
• Other: pneumonia, osteomyelitis (especially in sickle cell disease), abscesses, nephritis, DIC.
• Relapse: in some patients after apparent cure.
• Chronic carrier state: excretion for more than 1 year; the organism lives in the gall bladder, especially with gallstones (urinary bladder carriage with schistosomiasis). Carriers are often food handlers spreading infection; associated with gall bladder cancer.

Investigations

Which test, when

Other blood tests

• Leucopenia (or normal WBC) with relative lymphocytosis; absent eosinophils; anaemia, thrombocytopenia.
• Raised liver enzymes.

Widal test

• Measures agglutinating antibodies against O and H antigens.
• Unreliable: false positives from past infection, vaccination, other salmonellae and cross-reaction (malaria, other infections); false negatives early and after antibiotics. A single titre means little in endemic areas.
• Rapid antibody tests (for example Typhidot) are also of limited accuracy.

Imaging

• Erect chest X-ray: gas under the diaphragm (pneumoperitoneum) after perforation; it is not always seen, so use CT if perforation is suspected.
• Ultrasound: thickened terminal ileum, mesenteric nodes, gall bladder changes.

Differential diagnosis

Resistance patterns

• XDR strains in Pakistan belong to the H58 lineage and carry a plasmid with an extended-spectrum beta-lactamase gene, plus chromosomal gyrA mutations that cause quinolone resistance.
• Quinolone resistance is now widespread across South Asia, so ciprofloxacin is no longer a reliable empirical drug.

Treatment

Principles

• Send blood culture before antibiotics; adjust to sensitivity.
• Fever may take 4–7 days to settle even with the right drug; this alone is not treatment failure.
• Supportive care: fluids, nutrition, paracetamol; avoid NSAIDs.

Antibiotic choice

• Dexamethasone may be given in severe typhoid with encephalopathy or shock (reduces deaths).
• Ileal perforation needs urgent surgery (repair or resection) plus antibiotics covering bowel anaerobes and Gram-negatives.

Chronic carriers

• Prolonged antibiotics (for example a fluoroquinolone if sensitive) can clear carriage if there are no gallstones.
• With gallstones, cholecystectomy may be needed.
• Exclude carriers from food handling until clear.

Pakistan note: national (NIH Pakistan) and provincial guidance sets empirical antibiotics for typhoid according to current resistance. Patterns are changing, including reports of reduced azithromycin sensitivity, so always check the latest national guideline and local culture data.

Prevention

• Safe water (boiling, chlorination), sanitation, hand washing, safe food.
• Screening and exclusion of carrier food handlers.
• Vaccines:
  • Typhoid conjugate vaccine (TCV): Vi polysaccharide joined to a protein carrier; works in infants from 6 months; longer protection. Pakistan was the first country to add TCV to its routine EPI (at 9 months) after the XDR outbreak.
  • Vi polysaccharide injectable vaccine (from 2 years).
  • Oral live Ty21a vaccine (capsules, older children and adults).

Quick revision

• S. Typhi: human-only, faeco-oral, incubation 10–14 days.
• Peyer's patches → nodes → blood → liver, spleen, marrow, gall bladder.
• Step-ladder fever, relative bradycardia, rose spots, splenomegaly.
• Week 3: perforation and haemorrhage (terminal ileum, longitudinal ulcers).
• Blood culture (week 1); bone marrow culture is most sensitive.
• Widal unreliable.
• MDR: chloramphenicol, ampicillin, co-trimoxazole resistant.
• XDR: plus quinolones and ceftriaxone → azithromycin (oral) or meropenem (severe).

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Park's Textbook of Preventive and Social Medicine; Levinson's Review of Medical Microbiology and Immunology).

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