Friday, February 25, 2011

Resistant Salmonella Concord from Ethiopia

APUA chapter advisor for sub-Saharan Africa, Dr. Iruka Okeke, Ph.D. and current assistant professor of biology at Haverford College offers her insights on drug-resistant Salmonella Concord infections in Ethiopian adoptees.

There have been a number of worrisome reports in the recent medical literature about drug-resistant Salmonella Concord infections in Ethiopian adoptees.  The reports come from the USA, France, Norway and Denmark, plus a case report from Spain.  Based on global epidemiology of Salmonella, which includes very little information from every country in Africa combined, Salm. Concord is unusual.  The reports about what seems to be an epidemic come from less than two hundred individuals in all over a period of about seven years.  Thus, in a sense, they represent an archetypical example of what University of Virginia’s Richard Guerrant and his co-workers referred to as the ‘eyes of the hippopotamus’  – a mere scratch on the surface of what could be a deeper problem of unimaginable girth. 
 Unfortunately, too much of what we know about pathogens and drug resistance in resource-limited areas still comes from studies performed very distant from those places -  on isolates from returning travelers, or as in the Salmonella Concord case, recent immigrants.  Is it true, as some have suggested, that selection of resistant Salmonella Concord occurs in orphanages that overuse or abuse antibiotics in order to speed up adoption and empty out needed spaces?  Could we nip the problem in the bud by restricting antibiotic use in a few institutions and prescreening international adoptees?  Or is the average Ethiopian child at equal risk of a Salmonella Concord infection, with a significantly lower chance of having it detected and treated appropriately?  And are other, less susceptible individuals transporting Salmonella genomes packed with mobile resistance genes from endemic areas with an efficiency that is analogous to human transport via concord only a decade before?  Should we be developing a Salm. Concord vaccine to deal with the last two possibilities?  Or will the current apparent outbreak burn itself out before we get started?
 Getenet Beyene and co-workers have finally performed a small, but much-needed study to address these vital questions and they’ve done so where it is needed – in Addis Ababa and rural South-West Ethiopia.  The results, published in the January 2011 issue of the Journal of Infections in Developing Countries, are clarifying, if troubling.  Working at Tikur Anbessa Hospital in Addis Ababa and Jimma University Hospital, the researchers looked for Salmonella and other pathogens in the blood of patients with fever and in stool specimens from individuals with diarrhea.  Non-typhoidal Salmonella were isolated from the blood of 26 patients and from the stool of 59 more individuals.  Salmonella enterica serovariety Concord was the most common Salmonella serovar detected, being four times as common as all other Salmonella combined, and it was more invasive than other serovarieties.   The lack of evidence of clonality among the isolates suggests that this is no new epidemic and data from a smaller study published 25 years ago report Salm. Concord from Ethiopia, strongly suggesting that this pathogen has lurked undetected for at least a quarter of a century (Ashenafi and Gedebou, 1985, Trans R Soc Trop Med Hyg 79: 719-721).  Since 1985, Salm. Concord isolates from Ethiopia appear to have become more prevalent, and resistant to more antibiotics.  The isolates in the recent report were resistant to most affordable antibacterial options in Ethiopia.
 Oddly, the literature suggests that this serovar has a narrow geographic range.  However, our perceptions can only be as broad as our vision. There are reasonably good data from Kenya, which suggest that Salm. Typhimurium and Typhi are more important there, but with next to no data from other nearby locations, we cannot be sure that the problem is not extensive. While the endemicity, invasiveness and resistance of Salm. Concord in Ethiopia all give cause for concern, as Beyene et al emphasize in their discussion, the now global problem of multidrug-resistant Salmonella Concord must be addressed from endemic areas.  The very first step is determining where these are, and what exactly are the risk factors for infection.  Everyone is at risk when any part of the world lacks the diagnostic capacity to identify, track and control resistant pathogens. Microbes made the resistance problem a global one decades ago.  To deter them, we need local surveillance worldwide. 
 Iruka N Okeke
Haverford College


  1. Rumina Hasan from Aga Khan University in Karachi, PakistanMarch 4, 2011 at 9:52 AM

    Getenet Beyene, Satheesh Nair, Daniel Asrat, Yohannes Mengistu, Howard Engers, John Wain
    J. Infect Dev Ctries 2011; 5(1): 023-033

    The article by Getenet Beyene et al published in the January 2011 issue of the Journal of Infections in Developing countries focuses on multidrug resistant Salmonella Concord infection in children from Ethiopia. There have been a number of reports documenting isolation of S. Concord from Ethiopian adoptees. Questions have been asked about the role of orphanages in sustaining these strains through poor hygienic practices and overuse of antibiotics. This recent publication clearly demonstrates however that multidrug resistant S. Concord in Ethiopia affects a larger population much beyond the small group of adoptees and orphanages.

    Nontyphoidal salmonellae (NTS) in Africa are increasingly seen to cause severe disease manifestations including septicaemia. Published reports have highlighted the fact that S. Concord in Ethiopian population is associated not only with multidrug resistance, but also with invasiveness. These observations raise questions about factors contributing to such invasiveness, bacterial related, host related or both? Increase in bacteraemia due to NTS group C is reported to coincide with increase in HIV prevalence in Thailand (Kiratisin P, 2008 Trans R Soc Trop Med Hyg 102, 384-388 ). HIV prevalence of 3.5% in Ethiopia however does not explain invasive S. Concord disease in 30.6% of patients. Beyene et al have hypothesised about role of intestinal inflammation due to other agents, nutritional factors as well as possible changes in bacterial virulence as contributory factors.

    In Asia NTS burden is much lower than in Africa with Salmonella Typhi and Paratyphi being far more prevalent (Khan MI, 2010 Trop Med Int Health 15(8), 960-963). S. Concord has been shown to predominate in Ethiopia, but S. Enteridis and S. Typhimurium are reported to be the more frequent isolates in other parts of Africa. More over in both Africa and Asia distribution of NTS has been shown to change over time. The literature begs the question as to whether there is a global distribution pattern of Salmonellae in particular of NTS, and what triggers the change. As observed by Dr. Okeke in her commentary, there is a need for local surveillance worldwide. The capacity of laboratories in endemic regions to speciate NTS is limited by a lack of resources and funding. For effective and long term surveillance strengthening such laboratories remains a priority.

    Data generated through surveillance would be helpful in developing measures to break the transmission chain. In terms of prevention while vaccines are an option, the ultimate solution for NTS as well as for other enteric pathogens rests with the urgent need to improve community infrastructure, provision of safe drinking water and sewage disposal in endemic regions.

    Drug resistance is a recognised concern in NTS globally. Beyene et al report 86.5% ESBL positivity and 70% multidrug resistance within the study S. Concord isolates (n:81). Resistance in NTS while extremely important is a reflection of a far greater problem; that of increasing antimicrobial resistance in pathogens across board. The theme of World Health day this year “antimicrobial resistance” is a reflection of the magnitude of global concern. Beyene et al call for improvement in health systems, a call, that underpins efforts at controlling antimicrobial resistance, not just for S. Concord, but for all pathogens. This is indeed a critical point as without improvement of health systems it will be hard to control the complex issue of antimicrobial resistance across the world.

  2. Dr. B.M. Pokharel (Microbiologist) and Dr.K.K.Kafle (Clinical Pharmacologist) from APUA’s Nepal ChapterMarch 7, 2011 at 10:04 AM

    1. What are the possible reasons for this microorganism not being isolated for 25 years?
    2. What are the possible mechanisms for this organism being more virulent and multi-drug resistant?
    3. What could be possible explanation of narrow geographical distribution of this micro organism; even in Kenya it is uncommon?
    4. What are the differences in biochemical and antigenic properties of S. Concord from other sero types?
    5. Sharing method of identification of S. Concord will be appreciated.
    6. Is there any evidence of S.enterica typhoid vaccine effectiveness to protect from S. Concord?
    We agree to develop surveillance mechanism locally and globally.

  3. "Eyes of the South African hippopotamus"
    I share with you the multi-resistance and the diversity of beta-lactamase mediated resistance in Salmonella spp. isolated in a single tertiary hospital in Durban South Africa. This study was conducted by Dr U Govinden for her Phd for which I served as supervisor:
    "Extended spectrum β-lactamases (ESBLs) were characterized in Salmonella spp. isolates from a pediatric ward of a hospital in Durban. Forty one Salmonella spp. were subjected to serotyping, antibiotic susceptibility testing, E-Tests for ESBL detection, iso-electric focusing, polymerase chain reaction for detection of genes and sequencing. Isolates were screened for the presence of blaTEM, blaSHV, blaCTX-M, blaOXA , blaCMY, blaDHA and blaACC genes. The most common serotype was Salmonella Typhimurium. Isolates were multi-drug resistant with 100% susceptibility only to meropenem and ciprofloxacin. Tazobactam was the most effective inhibitor. Forty-one percent of the isolates were resistant to ceftriaxone, thus limiting therapeutic options for Salmonella infections.TEM-1 was the most predominant β-lactamase found in 51% of isolates while SHV-12 found in 39 % was the most common ESBL. TEM-63 was evident in 29 %, TEM-116 in 10 % and TEM-131 was found in one isolate. The high ceftazidime MICs of isolates expressing only TEM-63 were indicative of R164S substitution which widens the binding cavity to accommodate the bulky side chains of oxyimino-aminothiazolyl cephalosporins. The identification of TEM-131 which differs from TEM-63 by 1 amino acid reiterates the evolutionary potential of the TEM-type β-lactamase. Other ESBLs identified included SHV-2, CTX-M-3, CTX-M-15 and CTX-M-37. CMY-2 and the OXA-1 β-lactamase were also detected. This is the first report of TEM-116, CTX-M-3, -15 and -37 in Salmonella spp. in South Africa. All isolates with nalidixic acid MICs > 48 µg/ml had the mutation D87N, or D87G in the QRDR of the gyrA gene. This study showed that Salmonella spp. may be multi-drug resistant with the propensity to harbour β-lactamases in unique combinations. The diversity of ESBLs and the co-expression of quinolone resistance suggests that their incidence in salmonellae needs to be monitored."

  4. Dr. Miguel Angel Peredo López VelardeMarch 15, 2011 at 11:19 AM

    The high rate of isolation of S. Concord in Ethiopia in the previous and present studies is unusual when compared to that of other countries. In the current study, a higher proportion of children under five years of age presenting with No Typhoid Salmonella infection developed bacteraemia, this finding may be attributed to lower immune status in the younger children. Dissemination of NTS might also be enhanced by intestinal inflammation resulting from chronic diarrhoeal disease, parasitic infection, or suboptimal nutrition.

    A worrying aspect of the S. Concord isolates from Ethiopian adoptees is the levels of antibiotic resistance, however, as there is now a concern over the global spread of antibiotic-resistant S. Concord, this emphasises the need for local as well as national surveillance for emerging resistance.

    S. Concord in Ethiopia needs further study to clarify the animal or food source associated with its epidemiology. Epidemiological investigations of salmonellosis in developing countries such as Ethiopia are difficult to conduct because of the limited scope of strain typing available for the studies and a lack of coordinated surveillance systems.

    It is essential for global control that countries such as Ethiopia are able to document the occurrence and trends of Salmonella serovars to detect local, regional, national, and even international outbreaks .The strain isolated was highly invasive, highly antibiotic-resistant, and represents a threat to heath care globally.
    This will enable early warning about potentially virulent strains and should facilitate the elimination of the source by suggesting preventive actions.

  5. Gabriel Adrian Popescu, MD, PhDMarch 22, 2011 at 4:02 PM

    One of the major epidemiological questions related to the situation of multi-resistant Salmonella concord isolates in internationally adopted Ethiopian children is the following: is it a global evolving problem or is it only of a local interest? As Beyene and co-workers results indicated, the treatment of Salmonella non-typhi infections in pediatric patients from Ethiopia seems to be an important problem because of the reduced susceptibility of these germs to beta-lactams and to other antimicrobials. Is it a problem outside of the endemic area(s)? Yes, it is, but to a very limited extent, due to the secondary cases already documented in the adoption families. I think that the small number of identified cases since the first communicated cases in Western Europe (i.e. more than seven years) could ensure us that those secondary cases are really rare. Could this problem be a global threat? Probably not, at least for now. Indeed there are some risks related to the capacity of Salmonella species to transfer genetic region encoding for antimicrobial resistance to other gram-negatives, including Escherichia coli, a much more frequent pathogen in northern countries where it is the largely dominant etiology of urinary tract infections. Such multi-resistance of E. coli (including ESBL presence and resistance to quinolones) in general population could be a tremendous problem for the treatment of upper urinary tract infections, which consists generally of beta-lactams and/or quinolones, exactly the antibiotics that could be compromised by horizontal transfer of resistance genes from Salmonella concord to Escherichia coli. The contribution of this phenomenon to changes in the Escherichia coli resistance is difficult to differentiate from other determinants, especially antimicrobial consumption. However, we didn’t have any data about an increase of the multi-resistance in E coli in the areas where S concord cases were reported and we can assume that such transfer is difficult. An explanation could be provided by the results of molecular studies indicating that the ESBL encoding gene CTX-M15 is chromosomally located in Salmonella concord and only the sequence qnrA encoding for a protein of resistance to quinolones is located on genetic transferable units. But even if this transfer happens, it is only in the gut of the index patient. For a horizontal transfer of multi-resistant Escherichia coli a gap in the personal hygiene is needed. Hand hygiene and food hygiene are essential for the control of water and food-borne diseases and generally for the control of a majority of infections.

    Gabriel-Adrian Popescu,
    Associate Professor of Infectious Diseases,
    “Carol Davila” School of Medicine, Bucharest, Romania