000267
10.3205/000267
urn:nbn:de:0183-0002677
Case Report
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
Typhus-abdominalis-Rückfall nach verzögertem Ansprechen auf Meropenem: Eine Fallanalyse unter Einbeziehung der bisher veröffentlichten Fälle, die über eine eingeschränkte Wirksamkeit von Meropenem bei Typhus berichten
Blumentrath
Blumentrath
Christian G.
CG
DTM&H
Clinic for Cardiology, Angiology and Intensive Care Medicine, Klinikum Lippe Detmold, Röntgenstraße 18, 32756 Detmold, GermanyClinic for Cardiology, Angiology and Intensive Care Medicine, Klinikum Lippe Detmold, Germany
ChristianGeorg.Blumentrath@klinikum-lippe.de
author
Müller
Müller
Gernot
G
Department of Infectious Diseases and Tropical Medicine, Städtisches Klinikum Dresden, Germany
author
Teichmann
Teichmann
Dieter
D
PD Dr. med.
Department of Infectious Diseases and Tropical Medicine, Städtisches Klinikum Dresden, Germany
author
Tiesmeier
Tiesmeier
Jens
J
Institute of Anaesthesiology, Intensive Care and Emergency Medicine, General Hospital Lübbecke-Rahden, Germany
author
Petridou
Petridou
Jasmina
J
Institute of Medical Microbiology, University Hospital Minden, Germany
author
German Medical Science GMS Publishing House
Düsseldorf
610
tolerance
persistence
salmonella
treatment failure
resistance
Toleranz
Persistenz
Salmonella
Therapieversagen
Resistenz
Infectious Diseases
20180113
20181221
20190107
engl
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung).
1612-3174
17
GMS German Medical Science
GMS Ger Med Sci
01
In Zeiten zunehmender Multiresistenzen bei Gramnegativen Erregern (Salmonella enterica, Serovar Typhi eingeschlossen) beobachteten wir einen Rückfall nach verzögertem Ansprechen eines Typhus-Patienten auf die Behandlung mit Meropenem. Diese Beobachtung legte den Verdacht nahe, die Wirksamkeit des Antibiotikums könne bei Typhus-Patienten eingeschränkt sein. Drei bereits veröffentlichte Fälle bestätigten diesen Verdacht. Wir diskutieren die Details des Falles, legen den Schwerpunkt der Diskussion aber auf mögliche Erklärungen für ein vermindertes Ansprechen der vier Typhus-Patienten auf Meropenem. Meropenem ist ein Reserve-Antibiotikum zur Behandlung multiresistenter, Gramnegativer Infektionen. Verlässliche Daten zur Wirksamkeit von Meropenem bei Typhus-Patienten werden dringend benötigt. Zukünftige Studien zur Wirksamkeit von Antibiotika zur Behandlung des Typhus sollten auch (i) die Bedeutung des intrazellulären Eindringens der Medikamente und (ii) den Einfluss von Toleranz und Persistenz auf die Wirksamkeit der Therapie untersuchen.
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.
IntroductionWhile 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 , , the disease remains a major public health problem in resource-limited, endemic countries . The Robert Koch Institute reports approximately 5<![CDATA[0 cases</PlainText></TextGroup> of typhoid fever in Germany annually, most of them acquired in India and other endemic areas <TextLink reference="3"></TextLink>. 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 <Mark2>Salmonella enterica</Mark2> Serovar Typhi (S. Typhi) are notifiable <TextLink reference="3"></TextLink>.</Pgraph><Pgraph>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 <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>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) <TextLink reference="2"></TextLink>.</Pgraph><Pgraph>Clinical examination may reveal: relative or absolute bradycardia, high-grade fever and rose spots (rather rare) <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>. 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) <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>. 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 <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="5"></TextLink>. Blood cultures are the gold standard for the detection of S. Typhi <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>. 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% <TextLink reference="4"></TextLink>. Bone marrow culture may reveal bacteria in late disease if blood cultures remain negative <TextLink reference="4"></TextLink>. Sensitivity of stool culture is poor (approximately 40%) – polymerase chain reaction (PCR) improves sensitivity of blood, stool, and urine examination <TextLink reference="6"></TextLink>. Serology and Widal reaction are unspecific <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>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) <TextLink reference="4"></TextLink>, <TextLink reference="7"></TextLink>.</Pgraph><Pgraph>Multi-drug resistance among Gram-negative bacterial infections (including S. Typhi) is alarmingly increasing <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>. 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 <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>. 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 <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. As observed in our case, ciprofloxacin-resistant S. Typhi strains are associated with a growing number of complications <TextLink reference="11"></TextLink>, <TextLink reference="12"></TextLink>. Therefore, physicians should be aware of red flag features (Table 1 <ImgLink imgNo="1" imgType="table"/>) and the following factors indicating complications:</Pgraph><Pgraph><UnorderedList><ListItem level="1">infections with multi-drug resistant strains <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="13"></TextLink>;</ListItem><ListItem level="1">state of immunosuppression, e.g. HIV, malnutrition <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>;</ListItem><ListItem level="1">structural and functional abnormalities, e.g. malignant tumours <TextLink reference="15"></TextLink>, haemoglobinopathies (Sickle cell disease) <TextLink reference="16"></TextLink>, <TextLink reference="17"></TextLink>, cysts <TextLink reference="18"></TextLink>, neurologic disorders <TextLink reference="19"></TextLink>;</ListItem><ListItem level="1">infants/young children, elderly patients <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="13"></TextLink>;</ListItem><ListItem level="1">patients with limited access to proper health care, e.g. patients from remote areas or low-income countries, patients affected by poverty <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="13"></TextLink>;</ListItem><ListItem level="1">delay in diagnosis and treatment <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="13"></TextLink>;</ListItem><ListItem level="1">inappropriate antibiotic treatment, e.g. short-course therapy, not according to sensitivity testing <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="13"></TextLink>;</ListItem><ListItem level="1">inoculation of a huge number of bacteria <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="13"></TextLink>;</ListItem><ListItem level="1">strain-related virulence factors <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="13"></TextLink>.</ListItem></UnorderedList></Pgraph><Pgraph>Rarely, patients may develop late onset and persisting complications:</Pgraph><Pgraph><UnorderedList><ListItem level="1">relapse (14 days up to 3 months following treatment) <TextLink reference="4"></TextLink>;</ListItem><ListItem level="1">psychiatric disorders <TextLink reference="20"></TextLink>;</ListItem><ListItem level="1">neurologic disorders <TextLink reference="21"></TextLink>, <TextLink reference="22"></TextLink>, <TextLink reference="23"></TextLink>;</ListItem><ListItem level="1">ophthalmologic disorders <TextLink reference="24"></TextLink>;</ListItem><ListItem level="1">intracranial abscess (47 years following typhoid fever) <TextLink reference="25"></TextLink>;</ListItem><ListItem level="1">atrophic rhinitis <TextLink reference="26"></TextLink>.</ListItem></UnorderedList></Pgraph><Pgraph>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.</Pgraph></TextBlock>
<TextBlock linked="yes" name="Case description">
<MainHeadline>Case description</MainHeadline><Pgraph>A previously healthy, Caucasian, 18-year-old man presented at our Department of Emergency Medicine for watery diarrhoea, high-grade fever, and severe malaise. Stool samples performed by the family physician had been negative, including testing for <Mark2>Salmonella</Mark2> species (spp.). Five days after returning from travelling to various countries, e.g. India and Nepal, he developed fever, chills, cough, sore throat, and headaches, which lasted for <TextGroup><PlainText>3 da</PlainText></TextGroup>ys before diarrhoea started. The total duration of the disease on admission was 7 days.</Pgraph><SubHeadline2>Travel destinations</SubHeadline2><Pgraph><UnorderedList><ListItem level="1">day 1: Germany</ListItem><ListItem level="1">day 2–4: Kingdom of Bahrain</ListItem><ListItem level="1">day 4–8: United Arab Emirates<LineBreak></LineBreak>(Dubai: day 4–6; Abu Dhabi: day 6–8)</ListItem><ListItem level="1">day 8–11: Kathmandu, Nepal</ListItem><ListItem level="1">day 11–13: Delhi, India</ListItem><ListItem level="1">day 13–16: Kuala Lumpur, Malaysia</ListItem><ListItem level="1">day 16–18: Singapore</ListItem><ListItem level="1">day 19–23: Melbourne, Australia</ListItem><ListItem level="1">day 24–26: Taipei, Taiwan</ListItem><ListItem level="1">day 26–28: Manila, Philippines</ListItem><ListItem level="1">day 28–29: Kuwait City, Kuwait</ListItem></UnorderedList></Pgraph><Pgraph>During his travels, he experienced gastroenteritis while he was in Delhi (oral antibiotic therapy and electrolyte solution resulted in cure after 3 days), and multiple mosquito bites in malaria-endemic countries. He denied tick bites and animal contact of all kinds. Although he had received pre-travel medical advice, he did not respect alimentary precautions (he preferred vegetables and salad in local restaurants), and had refused malaria prophylaxis due to fear of side effects. The patient did not receive any vaccination against cholera or typhoid fever.</Pgraph><Pgraph>Apart from signs of exsiccosis, a thorough physical examination was unremarkable. The patient was fully conscious, had a relative bradycardia (95/min), hypotension (95/60 mmHg), high-grade fever (39°C), and normal oxygen saturation. Electrocardiogram was normal and abdominal ultrasound was consistent with diagnosis of gastroenteritis. A differential blood count demonstrated a normal white blood count, aneosinophilia and discrete thrombocytopenia (126/µl, normal: 140–200/µl). Laboratory examination revealed an elevated CRP level (<TextGroup><PlainText>93 mg</PlainText></TextGroup>/dl; normal: <5 mg/dl) and slightly elevated ALT (48 U/l, normal: <40 U/l), AST (59 U/l, normal: <41 U/l) and LDH (461 U/l, normal: <250 U/l). Creatinine levels, blood gas and urine analysis were normal. Malaria was ruled out using thick smears and rapid testing. Blood, urine, and stool cultures were performed. The latter two showed no growth.</Pgraph><Pgraph>Due to suspected typhoid fever, we started intravenous ceftriaxone (2 g once daily), fluid supplementation (2.<TextGroup><PlainText>500 ml</PlainText></TextGroup> per day), and oral antipyretics (750 mg metamizole four times daily). Liver enzymes increased to ALT 97 U/l and AST 83 U/l on day 8 after disease onset; to ALT 196 U/l and AST 165 U/l on day 9 after disease onset. Diarrhoea subsided to 15–20 times per day; fever subsided as well. On day 11 after disease onset, blood cultures revealed Gram-negative bacteria. By the time, the patient’s condition had not improved. We suspected a Gram-negative sepsis and changed the antibiotic regime to intravenous meropenem, 1 g three times per day. One day later, <Mark2>Salmonella enterica</Mark2> Serovar Typhi was identified (susceptibility testing: Table 2 <ImgLink imgNo="2" imgType="table"/>), and the therapy was continued with meropenem. Liver enzymes peaked on day 12 after the onset of initial symptoms: LDH 756 U/l, ALT 544 U/l, AST 263 U/l, alkaline phosphatase (AP) <TextGroup><PlainText>168 U</PlainText></TextGroup>/l (normal: 55–149 U/l), and Gamma-GT 196 U/l (normal: <60 U/l). Bilirubin remained normal; abdominal ultrasound displayed mild hepato- and splenomegaly. We ruled out hepatitis A/B/C/D/E (serologic tests), entero-haemorrhagic <Mark2>Escherichia coli</Mark2>, and amoebic liver disease (stool samples), and continued the treatment regime. On day 16 after disease onset (day 9 of antibiotic therapy), the patient’s condition improved, both his body temperature and his liver enzymes decreased. On day 14 of treatment (4 days ceftriaxone; 10 days meropenem), the patient had fully recovered (including complete normalization of laboratory parameters). One week after treatment, 3 stool samples (obtained on 3 different days) were negative for S. Typhi.</Pgraph><Pgraph>During a family visit in Dresden 14 days after completion of initial treatment, the patient was hospitalised again (Department of Infectious Diseases and Tropical Medicine, Städtisches Klinikum Dresden) for high-grade fever, crampy abdominal pain, and watery diarrhoea. Abdominal ultrasound revealed extended mesenteric lymph nodes. The colleagues ruled out schistosomiasis and HIV (serology), as well as helminthic infections, other parasites, and <Mark2>Clostridium difficile</Mark2> (stool analyses). Blood cultures revealed S. Typhi (susceptibility testing: Table 2 <ImgLink imgNo="2" imgType="table"/>). Urine analysis, performed because of dysuria and pollakiuria, yielded a urinary tract infection (UTI) due to <Mark2>Escherichia coli</Mark2> (4-MRGN (German Classification of Gram-negative bacteria indicating resistance to 4 clinically relevant groups of bactericidal antibiotics: cephalosporine and acylureidopenicilline antibiotics, carbapenems and fluoroquinolones <TextLink reference="7"></TextLink>), OXA-48 positive; Colony forming units: 10<Superscript>6</Superscript>/ml).</Pgraph><Pgraph>Consequently, the colleagues administered a combination antibiotic therapy according to susceptibility testing using intravenous ceftriaxone (2 g daily dose maintained for 28 days to address relapse) and oral sulfamethoxazole/trimethoprim (800/160 mg daily dose, maintained for 10 days to address the UTI). The patient fully recovered. Again, 3 stool samples following treatment were negative for S. Typhi. The patient has been free of relapse for <TextGroup><PlainText>9 months</PlainText></TextGroup>.</Pgraph></TextBlock>
<TextBlock linked="yes" name="Discussion">
<MainHeadline>Discussion</MainHeadline><Pgraph>The case report recalls the importance of individualized pre-travel medical advice, illustrates diagnostics of fever in a returning traveller, and demonstrates that increasing multi-drug resistance among Gram-negative bacteria impairs treatment and outcome of typhoid fever. Notably, delayed response to treatment with meropenem followed by relapse challenges the efficacy of a last-resort antim<TextGroup><PlainText>icro</PlainText></TextGroup>bial agent.</Pgraph><Pgraph>Overall, pre-travel medical advice of our patient was poor (no alimentary precautions, no vaccination, no malaria prophylaxis). Individualised pre-travel medical advice including vaccination against typhoid fever might have prevented the infection <TextLink reference="27"></TextLink>, <TextLink reference="28"></TextLink>. However, protection following immunisation is limited (75%), and there is an urgent need for improved typhoid fever vaccination <TextLink reference="4"></TextLink>.</Pgraph><Pgraph>The patient’s history as well as clinical and laboratory findings matched typhoid fever (compare: introduction section) <TextLink reference="4"></TextLink>. Additionally, important differential diagnoses were ruled out by clinical and laboratory examinations <TextLink reference="29"></TextLink>. Therefore, suspicion of typhoid fever and immediate administration of ceftriaxone were justified.</Pgraph><Pgraph>The decision to switch antimicrobial treatment to meropenem on day 5 of treatment was based on case deterioration and the increasing prevalence of MDR and extended spectrum of ß-lactamase producing (ESBL) Gram-negative bacteria (including<Mark2> Salmonella</Mark2> spp.) in countries which our patient had travelled to (e.g. India and Nepal) <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>. However, some reasons argue against this switch. First, the expected fever clearance time of typhoid fever is approximately 7 days from treatment initiation (range: 3–12 days), depending on the antibiotic used <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="30"></TextLink>, <TextLink reference="13"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>. Second, the patient did not match sepsis criteria by the time of the regime change <TextLink reference="34"></TextLink>. As meropenem is a last-resort antimicrobial agent for the treatment of multidrug-resistant Gram-negative infections <TextLink reference="8"></TextLink>, it would have been reasonable to wait for the results of susceptibility testing. Once the results were available (Table 2 <ImgLink imgNo="2" imgType="table"/>), return to ceftriaxone was indicated <TextLink reference="3"></TextLink>, <TextLink reference="8"></TextLink>.</Pgraph><Pgraph>Although reliable clinical data supporting the use of meropenem for the treatment of typhoid fever is limited to<Mark2> in vitro</Mark2> susceptibility testing and a few case reports <TextLink reference="9"></TextLink>, <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>, we completed treatment using meropenem. Indeed, the drug did not meet the expectations. A literature search revealed three other case reports which also questioned the clinical efficacy of meropenem <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>.</Pgraph><Pgraph>The isolates of all four cases (throughout the manuscript, all four cases refer to: this report, Kleine et al. <TextLink reference="35"></TextLink>, Godbole et al. <TextLink reference="36"></TextLink>, and Lukácová et al. <TextLink reference="37"></TextLink>) did not adequately respond to meropenem monotherapy, although the isolates were fully susceptible (Table 2 <ImgLink imgNo="2" imgType="table"/>) <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>. All four isolates demonstrated ciprofloxacin resistance and two isolates were resistant to ceftriaxone as well (Table 2 <ImgLink imgNo="2" imgType="table"/>). None of the patients displayed any underlying conditions (e.g. immunosuppression, adherence of bacteria to artificial material, abscesses) which might explain the inadequate response <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>.</Pgraph><Pgraph>Godbole et al. proposed that limited intracellular penet<TextGroup><PlainText>ration</PlainText></TextGroup> of meropenem may be responsible for treatment failures <TextLink reference="36"></TextLink>. The observation that ciprofloxacin and <TextGroup><PlainText>azithromyci</PlainText></TextGroup>n (both accumulate intracellularly, the latter even in lysosomes <TextLink reference="38"></TextLink>, <TextLink reference="39"></TextLink>) were particularly effective against susceptible S. Typhi strains, stresses the importance of an intracellular action of the antimicrobial agent <TextLink reference="36"></TextLink>. However, excellent response to treatment with meropenem was reported, too <TextLink reference="40"></TextLink>. Additionally, limited intracellular penetration (more precisely, lack of intracellular accumulation) is the case for all ß-lactam-antibiotics, including amoxicillin, ampicillin, and ceftriaxone <TextLink reference="38"></TextLink>, <TextLink reference="39"></TextLink>, which have been successfully used to treat typhoid fever <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="30"></TextLink>.</Pgraph><Pgraph>Therefore, the phenomena of tolerance and persistence (as defined by Kerster and Fortune <TextLink reference="41"></TextLink>) provide alternative explanations <TextLink reference="42"></TextLink>. Due to slow growth and dormancy, tolerant bacteria temporarily survive exposure to concentrations of antimicrobial agents, which are normally lethal <TextLink reference="42"></TextLink>. If only a small bacterial subpopulation demonstrates the same capability, this is termed persistence (not to be confused: an infection which is not effectively cleared in the host is also referred to as persistent) <TextLink reference="42"></TextLink>. The phenomena can be inherited (e.g. tolerance mutations in a toxin-antitoxin module), or acquired (e.g. induced by antibiotics) <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>. Treatment failure due to tolerance and persistence occurs, although the Minimal Inhibitory Concentration (MIC) of the antibiotic used is well below the breakpoint (matches all four cases) <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>. This implicates that survival is not related to any resistance phenotype <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>. Currently, there are two options to detect tolerance and persistence: determination of the minimum duration to kill 99% (MDK<Subscript>99</Subscript> to detect tolerance) and 99.99% (MDK<Subscript>99.99</Subscript> to detect persistence) of a given bacterial population <TextLink reference="42"></TextLink>; another, simpler option is the Tolerance Diffusion Test (TDtest) as provided by Grefen et al. <TextLink reference="43"></TextLink>. In addition, some tolerance mutations can be detected using molecular techniques (e.g. detection of a mutation in the vapBC toxin-antitoxin module) <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>. Unfortunately, none of these analyses were performed for any of the four cases.</Pgraph><Pgraph>However, S. Typhi meets the prerequisites of tolerance and persistence <TextLink reference="42"></TextLink>:</Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">phenotypic variation in host tissues, which lead to delayed eradication <TextLink reference="44"></TextLink>,</ListItem><ListItem level="1" levelPosition="2" numString="2.">formation of antibiotic-tolerant subpopulations <TextLink reference="45"></TextLink>,</ListItem><ListItem level="1" levelPosition="3" numString="3.">formation of nonreplicating persisters <TextLink reference="46"></TextLink>.</ListItem></OrderedList></Pgraph><Pgraph>We believe that the phenomena of tolerance and persistence are most appropriate to explain the limited response to meropenem in all four cases, as well as the relapse in our case.</Pgraph><Pgraph>Survival due to tolerance and/or persistence is temporary <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>. Antibiotics with a short half-life time (e.g. amoxicillin, meropenem) may therefore be more likely to help bacteria evolve tolerance (which may reach 100%), compared to antibiotics with a longer half-life time (e.g. ceftriaxone, azithromycin) <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>. Lukácová et al. obtained no response to several bactericidal antibiotics administered according to susceptibility testing, including meropenem <TextLink reference="37"></TextLink> – perhaps because switching between bactericidal antibiotics is not suitable for overcoming tolerance and persistence <TextLink reference="42"></TextLink>. Kleine et al. reported case-deterioration although they doubled the dosages of meropenem <TextLink reference="35"></TextLink>. In contrast to proper resistance, which can be overcome by increasing dosages, such action does not adequately address tolerance and persistence <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>. Response of the case (reported by Kleine et al. <TextLink reference="35"></TextLink>) following the addition of fosfomycin on day 19 of meropenem monotherapy may be coincidental – the phenomena respond to prolonged treatment durations <TextLink reference="42"></TextLink> –, or a direct effect of combination, because combination antimicrobial therapy may overcome tolerance and persistence. The efficacy of bacteriostatic antibiotics is not a<TextGroup><PlainText>ffect</PlainText></TextGroup>ed by the phenomena <TextLink reference="42"></TextLink>. Accordingly, two cases responded to bacteriostatic antibiotics (chloramphenicol: Lukácová et al. <TextLink reference="37"></TextLink>, and azithromycin: Godbole et al. <TextLink reference="36"></TextLink>) following insufficient treatment with bactericidal antibiotics, e.g. meropenem) <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>. For the case reported by Godbole et al., one may also assume an effect of combination therapy (4 days meropenem alone, <TextGroup><PlainText>10 days</PlainText></TextGroup> meropenem and azithromycin in combination) <TextLink reference="36"></TextLink>.</Pgraph><Pgraph>In fact, one study indicates that the combination of ceftriaxone and azithromycin reduced bacteria- and fever-clearance times when compared to monotherapy <TextLink reference="47"></TextLink>. Therefore, if treatment with meropenem is unavoidable, we agree with Kleine et al. and Godbole et al. that meropenem should be combined with an antimicrobial agent <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink> which preferably provides an intracellular mode of action <TextLink reference="36"></TextLink> and a long half-life time – at least for severe typhoid fever cases <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>.</Pgraph><Pgraph>Our patient relapsed 14 days after completion of treatment (relapse usually occurs within up to six weeks after treatment <TextLink reference="4"></TextLink>). If meropenem is as effective as ceftriaxone, our patient displayed only one risk factor for relapse (isolated ciprofloxacin resistance) out of seven risk factors described in medical literature:</Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">the drug chosen for treatment (cephalosporines other than ceftriaxone > ceftriaxone > ciprofloxacin > azithromycin);</ListItem><ListItem level="1" levelPosition="2" numString="2.">duration of treatment;</ListItem><ListItem level="1" levelPosition="3" numString="3.">constipation on admission;</ListItem><ListItem level="1" levelPosition="4" numString="4.">fever within 14 days of admission;</ListItem><ListItem level="1" levelPosition="5" numString="5.">HIV co-infection;</ListItem><ListItem level="1" levelPosition="6" numString="6.">infection with multi-drug resistant/ciprofloxacin resistant strains;</ListItem><ListItem level="1" levelPosition="7" numString="7.">anatomical and structural abnormalities (e.g. schistosomiasis eggs, gallstones) <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="11"></TextLink>, <TextLink reference="12"></TextLink>, <TextLink reference="13"></TextLink>, <TextLink reference="30"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>.</ListItem></OrderedList></Pgraph><Pgraph>We believe that the patient relapsed due to reactivation of dormant bacteria which disseminated from mesenteric lymph nodes, a mechanism suggested by Griffin et al. <TextLink reference="48"></TextLink>. It is quite possible that meropenem does not adequately target intracellular, dormant bacteria <TextLink reference="36"></TextLink>, <TextLink reference="42"></TextLink>. Increased treatment durations reduced relapse rates of typhoid fever patients <TextLink reference="33"></TextLink>. The fact that such action is suitable for overcoming tolerance and persistence <TextLink reference="42"></TextLink> supports our assumption. Furthermore:</Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">on admission for relapse, mesenteric lymph nodes of our patient were markedly distended;</ListItem><ListItem level="1" levelPosition="2" numString="2.">three negative stool samples indicate that the hepatobiliary system was probably not the source of relapse;</ListItem><ListItem level="1" levelPosition="3" numString="3.">clinical cure and complete normalisation of laboratory parameters (including normalisation of CRP) made relapse from abscesses unlikely.</ListItem></OrderedList></Pgraph><Pgraph>In the absence of recommendations for the treatment of relapse (in general, relapse occurs two to six weeks following initial treatment <TextLink reference="4"></TextLink>), we performed a long-term treatment (ceftriaxone for 28 days). Others preferred even longer treatment durations (e.g. 60 days) <TextLink reference="5"></TextLink>. Azithromycin would most likely have been a better option <TextLink reference="2"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="13"></TextLink>, <TextLink reference="30"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>, but unfortunately, our susceptibility testing (Table 2 <ImgLink imgNo="2" imgType="table"/>) did not include the drug.</Pgraph><Pgraph>With the urinary tract infection that resulted from a multi-drug resistant <Mark2>Escherichia coli</Mark2> (4-MRGN, OXA-48 positive), the case came full circle. Plasmid-encoded resistance genes are highly transmissible among Gram-negative bacteria. Since regions where multi-drug resistant Gram-negative infections frequently occur (e.g. India) largely overlap with regions where typhoid fever is endemic, we might soon be faced with the challenge of untreatable typhoid fever <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>.</Pgraph></TextBlock>
<TextBlock linked="yes" name="Conclusions">
<MainHeadline>Conclusions</MainHeadline><Pgraph>The case report illustrates that emerging multi-drug resistant typhoid fever is a threat to people residing in or travelling to endemic countries. Our analysis stresses the need for reliable clinical data evaluating the efficacy of carbapenems (e.g. meropenem) for the treatment of typhoid fever, and emphasizes the importance to further investigate the impact of tolerance and persistence on treatment and outcome (e.g. correlate the results of TD tests with clinical outcome). New strategies for infection prevention (e.g. new and better vaccines) and new treatment options (e.g. new antimicrobial agents) are urgently needed.</Pgraph></TextBlock>
<TextBlock linked="yes" name="Notes">
<MainHeadline>Notes</MainHeadline><SubHeadline>Competing interests</SubHeadline><Pgraph>The authors declare that they have no competing interests.</Pgraph><SubHeadline>Financial disclosure</SubHeadline><Pgraph>The authors received no funding for this analysis.</Pgraph><SubHeadline>Acknowledgements</SubHeadline><Pgraph>The authors thank their colleagues (physicians and nurses, laboratory, radiology, and cleaning staff) for their great support in daily practise. The authors also thank Susan Rüther, teacher for English language and history at Gymnasium Aspel in Rees, Germany, for English language editing. CGB thanks his former colleagues from the General Hospital Lübbecke-Rahden (the case was diagnosed and followed-up in this hospital) for their great support during collaboration.</Pgraph><SubHeadline>Authors’ contributions</SubHeadline><Pgraph>CGB conceived the idea for this article, performed literature search and drafted the first version of the manuscript. CGB, GM, and TD guided diagnosis, treatment, and follow-up of the patient. All authors reviewed the results of literature search and contributed to the final version of the manuscript. All authors read and approved the final version of the article.</Pgraph></TextBlock>
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<Caption><Pgraph><Mark1>Table 1: Red flag features with corresponding complications (modified after Upadhyay R et al. [4])</Mark1></Pgraph></Caption>
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<Caption><Pgraph><Mark1>Table 2: Susceptibility testing of this report and the three previously published cases indicating limited clinical efficacy of meropenem for the treatment of typhoid fever</Mark1></Pgraph></Caption>
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