Relapse of typhoid fever following delayed response to meropenem: A case report and review of previously published cases indicating limited clinical efficacy of meropenem for the treatment of typhoid fever

 Christian G. Blumentrath ¹
Gernot Müller ²
Dieter Teichmann ²
Jens Tiesmeier ³
Jasmina Petridou <sup>4


1</sup> Clinic for Cardiology, Angiology and Intensive Care Medicine, Klinikum Lippe Detmold, Germany
² Department of Infectious Diseases and Tropical Medicine, Städtisches Klinikum Dresden, Germany
³ Institute of Anaesthesiology, Intensive Care and Emergency Medicine, General Hospital Lübbecke-Rahden, Germany
⁴ Institute of Medical Microbiology, University Hospital Minden, Germany

Abstract

In times of emerging multi-drug resistance among Gram-negative bacteria (including Salmonella enterica, Serovar Typhi), we observed relapse of typhoid fever following delayed response to treatment with meropenem, suggestive for limited clinical efficacy of the drug. Three previously published cases supported our suspicion. Within this context, we discuss the case details with a focus on potential explanations for insufficient clinical response to meropenem (e.g. limited intracellular penetration, phenomena of tolerance and persistence). Meropenem is a last-resort antimicrobial agent for the treatment of multi-drug resistant Gram-negative infections. Reliable clinical data evaluating the efficacy of meropenem for the treatment of typhoid fever are urgently needed. Future clinical studies evaluating typhoid fever outcome should also investigate the impact of (i) intracellular penetration of antibiotics, and (ii) tolerance and persistence on outcome.

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Introduction

While bacterial infections such as typhoid fever had formerly lost much of their terror due to improved sanitation, appropriate antibiotic therapy, consequent infection control, and surveillance measures of cases in industrialized countries [1], [2], the disease remains a major public health problem in resource-limited, endemic countries [2]. The Robert Koch Institute reports approximately 50 cases of typhoid fever in Germany annually, most of them acquired in India and other endemic areas [3]. Hence, in numerous medical institutions in non-endemic countries, experience concerning diagnosis and treatment of typhoid fever is limited. In Germany, suspicion or confirmation of disease, as well as death due to Salmonella enterica Serovar Typhi (S. Typhi) are notifiable [3].

Following exposure (faecal-oral transmission: contact to typhoid fever patients or chronic carriers, or ingestion of contaminated food or beverages), it takes 10–14 days (range: 3–60 days, depending on the number of bacteria ingested), until the first symptoms occur [2], [3], [4].

The initial symptoms are unspecific: general malaise, stepladder-fever (over 3–4 days), headache, sore throat, dry cough, muscle and joint pain, constipation, or diarrhoea (approximately 48% of the patients display diarrhoea on admission) [2].

Clinical examination may reveal: relative or absolute bradycardia, high-grade fever and rose spots (rather rare) [2], [4]. Laboratory examination may corroborate the initial suspicion: normal white blood count, mild thrombocytopenia, eosinopenia or aneosinophilia, moderately elevated C-reactive protein (CRP) and lactate-dehydrogenase (LDH) [2], [4]. During the second week of infection, alanine- (ALT) and aspartate-aminotransferase (AST) increase. A 2–3 fold elevation of liver enzyme levels (AST and ALT) is a common characteristic of the disease [2], [4], [5]. Blood cultures are the gold standard for the detection of S. Typhi [2], [3], [4]. Sensitivity declines over time: in the first week to 90%; in the second week to 75%; in the third week to 60%; in the fourth week to 25% [4]. Bone marrow culture may reveal bacteria in late disease if blood cultures remain negative [4]. Sensitivity of stool culture is poor (approximately 40%) – polymerase chain reaction (PCR) improves sensitivity of blood, stool, and urine examination [6]. Serology and Widal reaction are unspecific [4].

Early and appropriate antibiotic treatment significantly reduces complication rate, rate of chronic carriers, and mortality (up to 30% in the pre-antibiotic era versus virtually no deaths in returning travellers) [4], [7].

Multi-drug resistance among Gram-negative bacterial infections (including S. Typhi) is alarmingly increasing [8], [9]. Although multi-drug resistance rates vary largely among different geographic regions (e.g. up to 70% in some hospitals in India vs. less than 7% in European countries), infections due to these bacteria provide a challenge to modern medicine [8], [9]. Global warming, increased migration, tourism and international trading, as well as public impoverishment (of marginalised groups) inevitably result in the globalisation of infectious diseases, and facilitate their spreading [8], [10]. As observed in our case, ciprofloxacin-resistant S. Typhi strains are associated with a growing number of complications [11], [12]. Therefore, physicians should be aware of red flag features (Table 1 [Tab. 1]) and the following factors indicating complications:

• infections with multi-drug resistant strains [2], [4], [10], [13];
• state of immunosuppression, e.g. HIV, malnutrition [2], [4], [10], [13], [14];
• structural and functional abnormalities, e.g. malignant tumours [15], haemoglobinopathies (Sickle cell disease) [16], [17], cysts [18], neurologic disorders [19];
• infants/young children, elderly patients [2], [4], [10], [13];
• patients with limited access to proper health care, e.g. patients from remote areas or low-income countries, patients affected by poverty [2], [4], [13];
• delay in diagnosis and treatment [2], [4], [13];
• inappropriate antibiotic treatment, e.g. short-course therapy, not according to sensitivity testing [2], [4], [10], [13];
• inoculation of a huge number of bacteria [2], [4], [13];
• strain-related virulence factors [2], [4], [10], [13].

Rarely, patients may develop late onset and persisting complications:

• relapse (14 days up to 3 months following treatment) [4];
• psychiatric disorders [20];
• neurologic disorders [21], [22], [23];
• ophthalmologic disorders [24];
• intracranial abscess (47 years following typhoid fever) [25];
• atrophic rhinitis [26].

Here, we are analysing a case of relapse following treatment of typhoid fever using meropenem. The case illustrates the diagnostic and therapeutic difficulties which arise from the above-mentioned problems. Furthermore, it is the fourth case questioning the efficacy of meropenem for the treatment of typhoid fever.

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