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Biological Health Hazard – Antibiotic resistance, Salmonella: Africa (sub-Sahara)


Published Date: 2016-06-17 17:54:37
Subject: PRO/AH/EDR> Antibiotic resistance, Salmonella – Africa: (sub-Saharan) fluoroquinolones
Archive Number: 20160617.4293589

Date: Tue 14 Jun 2016
Source: EurekAlert!, American Association for the Advancement of Science (AAAS) [edited]

“The affected countries will have a major problem if we do not manage to control _Salmonella_ bloodstream infections with new antibiotics such as ciprofloxacin,” cautions Prof Jürgen May. He has conducted numerous studies on _Salmonella_ infections in sub-Saharan Africa, particularly in Kumasi in Ghana, where the Bernhard Nocht Institute and the DZIF [German Centre for Infection Research] are in close partnership with researchers from the Kumasi Centre for Collaborative Research in Tropical Medicine.

Nowadays, bloodstream infections with the _Salmonella_ species _S. enterica_ are a particular problem in developing countries; infections of the gut occur through contaminated food and unclean water. Annually, approximately 22 million people contract typhoid fever, which is probably the best known infection caused by _Salmonella_. They [typhoid fever] are specifically caused by _Salmonella_ Typhi bacteria, a _S. enterica_ serotype. Symptoms of typhoid fever include fever, stomachache and bowel obstruction, and the infection can be fatal if left untreated. Additionally, so-called non-typhoid _Salmonella_ infections exist which are caused by other _S. enterica_ serotypes. They also cause bloodstream infections, affecting a further estimated 90 million people per year. It is not known why the pathogen so often enters the bloodstream in these countries. A simultaneous malaria infection seems to be a facilitating factor.

Since the early 1990’s, multidrug-resistant _Salmonella_ strains that are insensitive to commonly used antibiotics like ampicillin and chloramphenicol have been emerging more and more frequently. Consequently, the WHO recommended using 3rd generation antibiotics, such as ciprofloxacin from the fluoroquinolone group. In a study in Ghana, May and his team investigated whether this new antibiotic now also triggers the development of resistance. From 2007 to 2012, over 300 isolates of invasive _Salmonella_ were collected from blood cultures, that is, those that cause bloodstream infections.

The results from the study are a 1st warning sign: reduced susceptibility to ciprofloxacin was found in some _Salmonella_ serotypes; in one serotype, even half of the isolates were affected. Isolates of _Salmonella_ Typhi, the pathogen that causes typhoid fever, did not show reduced susceptibility. However, in a multi-country analysis, _Salmonella_ Typhi has already been found to have reduced sensitivity to ciprofloxacin; this being particularly high in Kenya. “This is worrying because ciprofloxacin is going to be used more frequently with decreasing costs,” explains May.

Furthermore, the scientists have detected single mutations in the pathogen’s hereditary information, which are responsible for the reduced sensitivity. “These results highlight that the emergence of multidrug-resistant _Salmonella_ strains must be observed carefully in order to control the burden of neglected diseases such as typhoid fever and non-typhoid _Salmonella_ infections,” May emphasizes. “An important step to improving the situation has been establishing the Typhoid Fever Surveillance in Africa Program (TSAP), a multinational research programme which, together with the DZIF, collected the data in sub-Saharan Africa.” In this programme, May and other scientists also conducted studies on hygiene measures, pathogen spread, vaccines and diagnostics. The studies are published in the current Clinical Infectious Diseases journal supplement [references 1-3 and moderator comments below].

1. Eibach D, Al-Emran HM, Dekker DM, et al: The emergence of reduced ciprofloxacin susceptibility in _Salmonella enterica_ causing bloodstream infections in rural Ghana. CID 2016, 62(S1): 32-6 [available at].
2. Al-Emran HM, Eibach D, Krumkamp R, et al: A multicountry molecular analysis of _Salmonella enterica_ serovar Typhi with reduced susceptibility to ciprofloxacin in sub-Saharan Africa. CID 2016, 62(S1): S42-6 [available at]
3. Baker S, Hombach J, Marks F: What have we learned from the typhoid fever surveillance in Africa program? Clin Infect Dis. 2016; 62 (suppl 1): S1-S3; [available at].

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ProMED-mail from HealthMap Alerts

[The news report above says that “it is not known why the pathogen [nontyphoidal _Salmonella_ (NTS)] so often enters the bloodstream in these countries [in sub-Saharan Africa].” However, it is known that the frequency of NTS bacteremia varies geographically: Africa has the highest incidence (Ao TT, Feasey NA, Gordon MA, et al: Global burden of invasive nontyphoidal _Salmonella_ disease, 2010. Emerg Infect Dis. 2015; 21(6) doi: 10.3201/eid2106.140999). In this region, infants and young children are most affected by NTS infection and higher rates of bacteremia have been reported in this age group (

Other host factors that are known to be associated with an increased frequency of NTS bacteremia and that may contribute to the frequency of NTS bacteremia in sub-Saharan Africa include:
1. HIV infection (;
2. Hemolytic anemias, such as, sickle cell disease and malaria (Kaye D, Hook EW: The influence of hemolysis on susceptibility to _Salmonella_ infection: additional observations. J. Immunol. 1963; 91: 518-27);
3. Rotavirus infection (Hung TY, Liu MC, Hsu CF, Lin YC: Rotavirus infection increases the risk of bacteremia in children with nontyphoid _Salmonella_ gastroenteritis. Eur J Clin Microbiol Infect Dis. 2009; 28(4): 425-8); abstract available at; and
4. Schistosomiasis (Rocha H, Kirk JW; Hearey CD Jr: Prolonged _Salmonella_ bacteremia in patients with _Schistosoma mansoni_ infection. Arch Intern Med. 1971; 128(2): 254-7; abstract available at

Below are abstracts for the 3 publications cited in the news report above:

1. Eibach D, Al-Emran HM, Dekker DM, et al: The emergence of reduced ciprofloxacin susceptibility in _Salmonella enterica_ causing bloodstream infections in rural Ghana. CID 2016, 62(S1): 32-6 [available at].

“Background. _Salmonella_ ranks among the leading causes of bloodstream infections in sub-Saharan Africa. Multidrug resistant typhoidal and nontyphoidal _Salmonella_ (NTS) isolates have been previously identified in this region. However, resistance to ciprofloxacin has rarely been reported in West Africa. This study aims to assess susceptibility against ciprofloxacin in _Salmonella_ causing invasive bloodstream infections among children in rural Ghana.

“Methods. From May 2007 until May 2012, children attending a rural district hospital in central Ghana were eligible for recruitment. _Salmonella enterica_ isolated from blood cultures were assessed for ciprofloxacin susceptibility by Etest (susceptible minimum inhibitory concentration [MIC] 0.06 microg/mL or less). The gyrA, gyrB, parC, and parE genes were sequenced to identify mutations associated with changes in susceptibility to fluoroquinolones.

“Results. 285 _Salmonella enterica_ isolates from 5211 blood cultures were most commonly identified as _S. enterica_ serovar Typhimurium (n = 129 [45 percent]), _S. enterica_ serovar Typhi (n = 89 [31 percent]), _S. enterica_ serovar Dublin (n = 20 [7 percent]), and _S. enterica_ serovar Enteritidis (n = 19 [7 percent]). All _S._ Typhi and _S._ Dublin were susceptible to ciprofloxacin. Reduced susceptibility (MIC greater than 0.06 microg/mL) was found in 53 percent (10/19) of _S._ Enteritidis and in 2 percent (3/129) of _S._ Typhimurium isolates. Sequencing detected a single gyrB mutation (Glu466Asp) and a single gyrA mutation (Ser83Tyr) in all 3 _S._ Typhimurium isolates, while 9 of 10 _S._ Enteritidis harbored single gyrA mutations (Asp87Gly, Asp87Asn, or Asp87Tyr). No mutations were found in the parC and parE genes.

“Conclusions. Ciprofloxacin susceptibility in invasive NTS in rural Ghana is highly dependent on serotype. Although reduced ciprofloxacin susceptibility is low in _S._ Typhimurium, more than half of all _S._ Enteritidis isolates are affected. Healthcare practitioners in Ghana should be aware of potential treatment failure in patients with invasive _S._ Enteritidis infections.”

2. Al-Emran HM, Eibach D, Krumkamp R, et al: A multicountry molecular analysis of _Salmonella enterica_ serovar Typhi with reduced susceptibility to ciprofloxacin in Sub-Saharan Africa. CID 2016, 62(S1): S42-6 [available at].

“Background. _Salmonella enterica_ serovar Typhi is a predominant cause of bloodstream infections in sub-Saharan Africa (SSA). Increasing numbers of _S._ Typhi with resistance to ciprofloxacin have been reported from different parts of the world. However, data from SSA are limited. In this study, we aimed to measure the ciprofloxacin susceptibility of _S._ Typhi isolated from patients with febrile illness in SSA.

“Methods. Febrile patients from 9 sites within 6 countries in SSA with a body temperature of 38.0 deg C [100.4 deg F] or higher were enrolled in this study. Blood samples were obtained for bacterial culture, and Salmonella isolates were identified biochemically and confirmed by multiplex polymerase chain reaction (PCR). Antimicrobial susceptibility of all _Salmonella_ isolates was performed by disk diffusion test, and minimum inhibitory concentrations (MICs) against ciprofloxacin were measured by Etest. All _Salmonella_ isolates with reduced susceptibility to ciprofloxacin (MIC greater than 0.06 microg/mL) were screened for mutations in quinolone resistance-determining regions in target genes, and the presence of plasmid-mediated quinolone resistance (PMQR) genes was assessed by PCR.

“Results. A total of 8161 blood cultures were performed, and 100 (1.2 percent) _S._ Typhi, 2 (less than 0.1 percent) _S. enterica_ serovar Paratyphi A, and 27 (0.3 percent) nontyphoid _Salmonella_ (NTS) were isolated. Multidrug-resistant _S._ Typhi were isolated in Kenya (79 percent [n = 38]) and Tanzania (89 percent [n = 8]) only. Reduced ciprofloxacin-susceptible (22 percent [n = 11]) _S._ Typhi were isolated only in Kenya. Among those 11 isolates, all had a Glu133Gly mutation in the gyrA gene combined with either a gyrA (Ser83Phe) or gyrB mutation (Ser464Phe). One _Salmonella_ Paratyphi A isolate with reduced susceptibility to ciprofloxacin was found in Senegal, with one mutation in gyrA (Ser83Phe) and a 2nd mutation in parC (Ser57Phe). Mutations in the parE gene and PMQR genes were not detected in any isolate.

“Conclusions. _Salmonella_ Typhi with reduced susceptibility to ciprofloxacin was not distributed homogenously throughout SSA. Its prevalence was very high in Kenya, and was not observed in other study countries. Continuous monitoring of antimicrobial susceptibility is required to follow the potential spread of antimicrobial-resistant isolates throughout SSA.”

3. Baker S, Hombach J, Marks F: What have we learned from the typhoid fever surveillance in Africa program? Clin Infect Dis. 2016; 62 (suppl 1): S1-S3; [available at].

“The Typhoid Fever Surveillance in Africa Program (TSAP) was established in 2009 to fill the data void concerning invasive _Salmonella_ disease in sub-Saharan Africa, and to specifically estimate the burden of bloodstream infections caused by the key pathogen, _Salmonella enterica_ serovar Typhi. TSAP has achieved this ambitious target, finding high incidences of typhoid fever in both rural and urban populations in several countries in sub-Saharan Africa. The results of TSAP will undoubtedly dictate the direction of future typhoid fever research in Africa, and at last provides a key piece of the disease burden jigsaw puzzle. With the dawn of new Vi conjugate vaccines against _Salmonella_ Typhi, the next priority for the typhoid community must be providing the required data on these vaccines so they can be licensed and provided to those in high-risk groups and locations across sub-Saharan Africa.”
– Mod.ML

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See Also

Salmonellosis – USA (08): FDA, contaminated raw retail meat & poultry, resistance 20160501.4195399
Salmonellosis, st I 4,[5, 12:i:- – USA: (WA) pork, 2015 20160415.4160048

Antibiotic resistance – Netherlands: colistin, MCR-1, salmonella, poultry meat 20151217.3870429
Antibiotic resistance – Denmark: colistin, MCR-1, salmonella, human, chicken, RFI 20151206.3844715
Typhoid fever – Africa, Asia: multidrug resistant 20150512.3357675

Salmonellosis, st. Paratyphi A – Japan: ex India, multidrug resistance 20131117.2057055

Antibiotic resistance, Salmonella typhi – India (02): (Mumbai) fluoroquinolone 20111105.3296
Antibiotic resistance, Salmonella typhi – India: (Mumbai) fluoroquinolones 20111031.3235

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ProMED-mail is a program of the International Society for Infectious Diseases

Note: Category B bioterrorism pathogens are the second highest priority organisms/biological agents. They are moderately easy to disseminate, result in moderate morbidity rates and low mortality rates and require specific enhancements for diagnostic capacity and enhanced disease surveillance

These pathogens include Food safety threats: (Salmonella species, E coli O157:H7, Shigella, Staphylococcus aureus).  Category B agents are bacteria and viruses that cause only mild disease to humans, or are difficult to contract via aerosol in a lab setting,.

See also: WHO Biosafety and Laboratory Biosecurity Program

List of Sub-Saharan African Countries

Burkina Faso
Cape Verde
Central African Republic
Congo (Brazzaville)
Congo (Democratic Republic)
Côte d’Ivoire
Equatorial Guinea
The Gambia
Sao Tome and Principe
Sierra Leone
South Africa
Western Sahara
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