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BACKGROUND: This study gives an overview of a decade (2007-2017) of hospital-based Salmonella Typhi bloodstream infection (BSI) surveillance in the Democratic Republic of the Congo (DRC), at 4 main sampling sites. METHODS: Blood cultures were sampled in hospital-admitted patients with suspected BSI, according to standardized clinical indications. The results of the surveillance period 2015-2017 were compiled with those of previous surveillance periods (2007-2010 and 2011-2014). Whole genome sequencing of isolates with decreased ciprofloxacin susceptibility (DCS) was performed. RESULTS: Salmonella Typhi was isolated in 1.4% (531/37 388) and 10.3% (531/5177) of suspected and culture-confirmed BSI episodes, respectively. Salmonella Typhi ranked first among the BSI pathogens in adults (n = 220), but was mostly (n = 301 [56.7%]) isolated from children, of which 72.1% (217/301) and 31.6% (95/301) were <10 years and <5 years old, respectively. Multidrug resistance (MDR), DCS, and combined MDR/DCS were found in 38.3% (n = 180), 24.5% (n = 115), and 11.9% (n = 56) of 470 first isolates, respectively. MDR and DCS rates had increased since 2007, but remained stable during 2015-2017 with no geographical clustering at the province level. Most (91/93 [97.8%]) DCS isolates sequenced belonged to Genotyphi genotype 2.5.1, and gyr S83 was the most frequent DCS mutation (76/93 [81.7%]). Infections occurred perennially, but increased during the rainy season. CONCLUSIONS: Salmonella Typhi was a frequent cause of BSI in adults and children in DRC, with high rates of antibiotic resistance. Sustainable surveillance and implementation of vaccination are compelling.
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Bacteriemia/epidemiología , Cultivo de Sangre , Monitoreo Epidemiológico , Salmonella typhi/aislamiento & purificación , Fiebre Tifoidea/epidemiología , Adolescente , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacteriemia/microbiología , Niño , Preescolar , República Democrática del Congo/epidemiología , Farmacorresistencia Bacteriana Múltiple , Genotipo , Humanos , Lactante , Recién Nacido , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Salmonella typhi/efectos de los fármacos , Salmonella typhi/genética , Estaciones del Año , Factores de Tiempo , Adulto JovenRESUMEN
We report a typhoid fever case with a Salmonella enterica serovar Typhi isolate showing extended spectrum ß-lactamase (ESBL) production in the Democratic Republic of the Congo. Whole genome sequencing revealed that the strain carried a plasmid-mediated CTX-M-15 ESBL gene and did not belong to the dominant H58 Salmonella Typhi clade.
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Salmonella typhi/enzimología , beta-Lactamasas/metabolismo , Niño , República Democrática del Congo/epidemiología , Genoma Bacteriano/genética , Humanos , Masculino , Filogenia , Salmonella typhi/genética , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/microbiología , beta-Lactamasas/genéticaRESUMEN
BACKGROUND: In sub-Saharan Africa, non-typhoidal Salmonella (NTS) can cause bloodstream infections, referred to as invasive non-typhoidal Salmonella disease (iNTS disease); it can occur in outbreaks and is often preceded by malaria. Data from Central Africa is limited. METHODS: Clinical, microbiological and molecular findings of NTS recovered in a blood culture surveillance project (2009-2014) were analyzed. RESULTS: In March-July 2012 there was an epidemic increase in malaria infections in the Oriental Province of the Democratic Republic of the Congo (DRC). In one referral hospital, overall hospital admissions in June 2012 were 2.6 times higher as compared to the same period in the years before and after (336 versus an average of 128 respectively); numbers of malaria cases and blood transfusions were nearly three- and five-fold higher respectively (317 versus 112 and 250 versus 55). Case fatality rates (in-hospital deaths versus all admissions) peaked at 14.6 %. Salmonella Typhimurium and Salmonella Enteritidis together accounted for 88.9 % of pathogens isolated from blood cultures collected during an outreach visit to the affected districts in June 2012. Children infected with Salmonella Enteritidis (33 patient files available) tended to be co-infected with Plasmodium falciparum more often than children infected with Salmonella Typhimurium (40 patients files available) (81.8 % versus 62.5 %). Through the microbiological surveillance project (May 2009-May 2014) 113 unique NTS isolates were collected (28.5 % (113/396) of pathogens); most (95.3 %) were recovered from children < 15 years. Salmonella Typhimurium (n = 54) and Salmonella Enteritidis (n = 56) accounted for 47.8 % and of 49.6 % NTS isolates respectively. Multilocus variable-number tandem-repeat analysis (MLVA) revealed more heterogeneity for Salmonella Typhimurium than for Salmonella Enteritidis. Most (82/96, 85.4 %) NTS isolates that were available for antibiotic susceptibility testing were multidrug resistant. All isolates were susceptible to ceftriaxone and azithromycin. CONCLUSION: During the peak of an epidemic increase in malaria in the DRC in 2012, a high proportion of multidrug resistant Salmonella Typhimurium and Salmonella Enteritidis were isolated from blood cultures. Overall, the two serovars showed subtle differences in clinical presentation and genetic diversity.
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Bacteriemia/epidemiología , Coinfección/epidemiología , Malaria Falciparum/epidemiología , Infecciones por Salmonella/epidemiología , Adolescente , Adulto , Antibacterianos/uso terapéutico , Pueblo Asiatico , Azitromicina/uso terapéutico , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Bacteriemia/fisiopatología , Ceftriaxona/uso terapéutico , Niño , Preescolar , República Democrática del Congo/epidemiología , Brotes de Enfermedades , Farmacorresistencia Bacteriana Múltiple , Femenino , Hospitalización , Humanos , Lactante , Recién Nacido , Malaria/epidemiología , Masculino , Infecciones por Salmonella/tratamiento farmacológico , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/fisiopatología , Salmonella enteritidis/genética , Salmonella enteritidis/aislamiento & purificación , Salmonella enteritidis/fisiología , Salmonella typhimurium/genética , Salmonella typhimurium/aislamiento & purificación , Salmonella typhimurium/fisiología , Serogrupo , Secuencias Repetidas en TándemRESUMEN
BACKGROUND: This study reports the microbiological landscape of Salmonella Typhi and invasive nontyphoidal Salmonella (iNTS) in the Democratic Republic of the Congo (DRC). METHODS: Blood cultures obtained from hospital-admitted patients suspected of bloodstream infection (BSI) in 4 of 11 provinces in DRC (Kinshasa, Bas-Congo, Equateur, and Orientale) were processed. Sampling had started in 2007; the results for the period 2011-2014 are reported. RESULTS: Salmonella Typhi and iNTS were cultured from 194 (1.4%) and 840 (5.9%), respectively, of 14,110 BSI episodes and ranked first among BSI pathogens in adults (65/300 [21.7%]) and children (783/1901 [41.2%]), respectively. A total of 948 of 1034 (91.7%) isolates were available for analysis (164 Salmonella Typhi and 784 iNTS). Salmonella Typhimurium and Salmonella Enteritidis represented 386 (49.2%) and 391 (49.9%), respectively, of iNTS isolates, fluctuating over time and geography and increasing during the rainy season. Adults accounted for <5% of iNTS BSI episodes. Children <5 years accounted for 20.3% of Salmonella Typhi BSI episodes. Among Salmonella Typhi, rates of multidrug resistance and decreased ciprofloxacin susceptibility (DCS) were 37.8% and 37.2%, respectively, and 18.3% displayed combined multidrug resistance and DCS; rates of azithromycin and ceftriaxone resistance were 0.6% and absent, respectively. Among NTS isolates, ≥80% (79.7% of Salmonella Enteritidis and 90.2% of Salmonella Typhimurium isolates) showed multidrug resistance, and <2.5% showed DCS. Combined extended-spectrum ß-lactamase production (blaTEM-1 gene) and azithromycin resistance was noted in 12.7% of Salmonella Typhimurium isolates, appearing in Bas-Congo from 2013 onward. CONCLUSIONS: Salmonella Typhi and NTS are major causes of BSI in DRC; their antimicrobial resistance is increasing.
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Bacteriemia/epidemiología , Bacteriemia/microbiología , Infecciones por Salmonella/epidemiología , Infecciones por Salmonella/microbiología , Adolescente , Adulto , Anciano , Antibacterianos/farmacología , Azitromicina/farmacología , Niño , Preescolar , Ciprofloxacina/farmacología , República Democrática del Congo/epidemiología , Farmacorresistencia Bacteriana Múltiple , Monitoreo Epidemiológico , Femenino , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Salmonella/clasificación , Salmonella/efectos de los fármacos , Salmonella/aislamiento & purificación , Salmonella enteritidis/efectos de los fármacos , Salmonella enteritidis/aislamiento & purificación , Salmonella typhi/efectos de los fármacos , Salmonella typhi/aislamiento & purificación , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/aislamiento & purificación , Estaciones del Año , Adulto Joven , beta-Lactamasas/metabolismoRESUMEN
BACKGROUND: Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines. METHODS: A hybrid design, hospital-based prospective surveillance with population-based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (≥37·5°C axillary or ≥38·0°C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model. FINDINGS: 27â866 (33·8%) of 82â491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27â544 (98·8%) of enrolled participants. Clinically significant organisms were detected in 2136 (7·7%) of these cultures, and 346 (16·2%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100â000 person-years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (16·4%) of 280 tested isolates showed ciprofloxacin non-susceptibility. INTERPRETATION: High disease incidence (ie, >100 per 100â000 person-years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices. FUNDING: The Bill & Melinda Gates Foundation.
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Fiebre Tifoidea , Vacunas , Humanos , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Ghana , Madagascar , Burkina Faso/epidemiología , Etiopía , Incidencia , Nigeria , Estudios Prospectivos , Teorema de Bayes , República Democrática del CongoRESUMEN
Nontyphoidal Salmonella are a leading cause of community-onset bacteremia and other serious infections in sub-Saharan African countries where large studies indicate that they are an uncommon cause of moderate-to-severe diarrhea. Approximately 535 000 nontyphoidal Salmonella invasive disease illnesses and 77 500 deaths were estimated to occur in 2017; 422 000 (78.9%) illnesses and 66 500 (85.9%) deaths in countries in sub-Saharan Africa. Lineages of Salmonella enterica serovar Typhimurium sequence type (ST) 313 and lineages of Salmonella enterica serovar Enteritidis ST11 dominate as causes of invasive disease. A major reservoir for these specific strains outside of humans has not been identified to date. Human fecal shedding of such strains is common in areas where nontyphoidal Salmonella invasive disease incidence is high. The case-fatality ratio of nontyphoidal Salmonella invasive disease is approximately 15%. Early diagnosis and treatment are needed to avert fatal outcomes. Antimicrobial resistance, including multiple drug resistance, decreased fluoroquinolone susceptibility, and resistance to third-generation cephalosporins, is increasing in prevalence and is likely to further compromise patient outcomes. Naturally acquired immunity against invasive disease develops in children aged >3 years in endemic areas, likely mediated in part by the sequential acquisition of T-cell immunity, followed by antigen-specific immunoglobulin G antibodies. Vaccines in preclinical or clinical development include live-attenuated S. enterica serovar Typhimurium, nontyphoidal S. enterica core and O-polysaccharide glycoconjugates, multiple antigen-presenting system complexes, and generalized modules for membrane antigens vaccines. The latter are in phase I trials in Europe and Africa. Both vaccine use, and other effective, evidence-based nonvaccine interventions, are needed to prevent and control nontyphoidal Salmonella invasive disease.
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BACKGROUND: Prompt appropriate treatment reduces mortality of severe febrile illness in sub-Saharan Africa. We studied the health itinerary of children under-five admitted to the hospital with severe febrile illness in a setting endemic for Plasmodium falciparum (Pf) malaria and invasive non-typhoidal Salmonella infections, identified delaying factors and assessed their associations with in-hospital death. METHODOLOGY: Health itinerary data of this cohort study were collected during 6 months by interviewing caretakers of children (>28 days - <5 years) admitted with suspected bloodstream infection to Kisantu district hospital, DR Congo. The cohort was followed until discharge to assess in-hospital death. PRINCIPAL FINDINGS: From 784 enrolled children, 36.1% were admitted >3 days after fever onset. This long health itinerary was more frequent in children with bacterial bloodstream infection (52.9% (63/119)) than in children with severe Pf malaria (31.0% (97/313)). Long health itinerary was associated with in-hospital death (OR = 2.1, p = 0.007) and two thirds of deaths occurred during the first 3 days of admission. Case fatality was higher in bloodstream infection (22.8% (26/114)) compared to severe Pf malaria (2.6%, 8/309). Bloodstream infections were mainly (74.8% (89/119)) caused by non-typhoidal Salmonella. Bloodstream infections occurred in 20/43 children who died in-hospital before possible enrolment and non-typhoidal Salmonella caused 16 out of these 20 bloodstream infections. Delaying factors associated with in-hospital death were consulting traditional, private and/or multiple providers, rural residence, prehospital intravenous therapy, and prehospital overnight stays. Use of antibiotics reserved for hospital use, intravenous therapy and prehospital overnight stays were most frequent in the private sector. CONCLUSIONS: Long health itineraries delayed appropriate treatment of bloodstream infections in children under-five and were associated with increased in-hospital mortality. Non-typhoidal Salmonella were the main cause of bloodstream infection and had high case fatality. TRIAL REGISTRATION: NCT04289688.
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Infecciones Bacterianas , Malaria Falciparum , Malaria , Sepsis , Humanos , Niño , Lactante , República Democrática del Congo/epidemiología , Estudios de Cohortes , Mortalidad Hospitalaria , Malaria/tratamiento farmacológico , Malaria/epidemiología , Salmonella , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiologíaRESUMEN
Invasive non-typhoidal Salmonella (iNTS) (serotypes Typhimurium and Enteritidis) are major causes of bloodstream infections in sub-Saharan Africa, but their reservoir is unknown. Aiming to demonstrate human carriers as a reservoir, we assessed an iNTS disease endemic rural community (Kikonka health area, Democratic Republic of the Congo) for intestinal carriage of iNTS. After a census, healthy subjects from randomly selected households provided three successive stool samples for Salmonella culture. We next compared the stool isolates for genetic relatedness with time and health area-matched blood culture isolates obtained from hospitalized patients by multiple locus variable-number tandem repeat analysis (MLVA) and performed whole genome sequencing (WGS) on a subset of stool and blood isolates. Among 2,354 eligible subjects, 2,234 (94.9%) consented and provided at least one stool sample, and 2,219 (94.3%) provided three stool samples. The cumulative proportion of Salmonella carriers after 3 days was 4.4% (n = 98). S. Typhimurium and Enteritidis were found in 26 and 3 carriers, respectively, representing 1.3% (29 out of 2,234) of participants living in 6.0% (26 out of 482) of households. MLVA types of all 26 S. Typhimurium stool isolates matched with the corresponding MLVA types of blood isolates. The MLVA type of one out of three Enteritidis stool isolates matched the single MLVA type of the five Enteritidis blood isolates. WGS analysis of S. Typhimurium (n = 20) and S. Enteritidis (n = 4) isolates revealed Typhimurium multilocus sequence type (ST)313 Lineage 2 and Enteritidis ST11 Central/Eastern African and Outlier clades and confirmed the MLVA clustering. More than three-quarters of Typhimurium isolates showed combined multidrug resistance, ceftriaxone resistance, and fluoroquinolone non-susceptibility. In conclusion, the present study demonstrated iNTS carriage among healthy community members, with stool isolates that were genetically similar to blood culture isolates obtained in patients from the same community. These findings contribute to the evidence of a human reservoir of iNTS.
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Background: Typhoid intestinal perforation (TIP) remains the most serious complication of typhoid fever. In many countries, the diagnosis of TIP relies on intraoperative identification, as blood culture and pathology capacity remain limited. As a result, many cases of TIP may not be reported as typhoid. This study demonstrates the burden of TIP in sites in Burkina Faso, Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria. Methods: Patients with clinical suspicion of nontraumatic intestinal perforation were enrolled and demographic details, clinical findings, surgical records, blood cultures, tissue biopsies, and peritoneal fluid were collected. Participants were then classified as having confirmed TIP, probable TIP, possible TIP, or clinical intestinal perforation based on surgical descriptions and cultures. Results: A total of 608 participants were investigated for nontraumatic intestinal perforation; 214 (35%) participants had surgically-confirmed TIP and 33 participants (5%) had culture-confirmed typhoid. The overall proportion of blood or surgical site Salmonella enterica subspecies enterica serovar Typhi positivity in surgically verified TIP cases was 10.3%. TIP was high in children aged 5-14 years in DRC, Ghana, and Nigeria. We provide evidence for correlation between monthly case counts of S. Typhi and the occurrence of intestinal perforation. Conclusions: Low S. Typhi culture positivity rates, as well as a lack of blood and tissue culture capability in many regions where typhoid remains endemic, significantly underestimate the true burden of typhoid fever. The occurrence of TIP may indicate underlying typhoid burden, particularly in countries with limited culture capability.
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Invasive non-typhoidal Salmonella (iNTS) disease manifesting as bloodstream infection with high mortality is responsible for a huge public health burden in sub-Saharan Africa. Salmonella enterica serovar Typhimurium (S. Typhimurium) is the main cause of iNTS disease in Africa. By analysing whole genome sequence data from 1303 S. Typhimurium isolates originating from 19 African countries and isolated between 1979 and 2017, here we show a thorough scaled appraisal of the population structure of iNTS disease caused by S. Typhimurium across many of Africa's most impacted countries. At least six invasive S. Typhimurium clades have already emerged, with ST313 lineage 2 or ST313-L2 driving the current pandemic. ST313-L2 likely emerged in the Democratic Republic of Congo around 1980 and further spread in the mid 1990s. We observed plasmid-borne as well as chromosomally encoded fluoroquinolone resistance underlying emergences of extensive-drug and pan-drug resistance. Our work provides an overview of the evolution of invasive S. Typhimurium disease, and can be exploited to target control measures.
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Infecciones por Salmonella , Salmonella typhimurium , Humanos , África del Sur del Sahara/epidemiología , Farmacorresistencia Microbiana , Genómica , Infecciones por Salmonella/epidemiología , Salmonella typhimurium/genéticaRESUMEN
OBJECTIVE: Azithromycin is an alternative to treat invasive non-typhoidal Salmonella (iNTS) infections. We determined its epidemiological cut-off (ECOFF) and compared azithromycin susceptibility testing methods for iNTS. METHODS: We used EUCAST ECOFFinder to determine the minimum inhibitory concentrations (MIC; obtained by broth microdilution) ECOFF and corresponding disk zone diameters of 515 iNTS from blood cultures in Democratic Republic of Congo, Burkina Faso, Rwanda, and Cambodia. Transferable resistance mechanisms were determined by polymerase chain reaction. We compared azithromycin susceptibility testing by semi-automated broth microdilution (customized Sensititre panel; reference), agar dilution, gradient tests (bioMérieux, Liofilchem, HiMedia; read at 80% (MIC80%) and 100% inhibition (MIC100%)), and disk diffusion (Rosco, Oxoid, BD, Liofilchem) for 161 wild- and 198 non-wild-type iNTS. RESULTS: Azithromycin MIC ECOFF was 16 mg/L corresponding to a 12 mm zone diameter; mphA was detected in 192/197 non-wild- and 0/47 wild-type iNTS. Categorical agreement was excellent (≥98%) for all methods. Essential agreement was very good for agar dilution (>90%) but moderate for gradient tests (MIC80%: 52% to 71% and MIC100%: 72% to 91%). Repeatability was good for all methods/brands. Interreader agreement was high for broth microdilution and agar dilution (all ≤1 twofold dilution difference) and disk diffusion (>96% ≤3 mm difference) but lower for gradient tests (MIC80% & MIC100%: 83% to 94% ≤1 twofold dilution difference). DISCUSSION: Azithromycin ECOFF of iNTS was 16 mg/L, i.e. equal to Salmonella Typhi. Disk diffusion is an accurate, precise, and user-friendly alternative for agar dilution and broth microdilution. Reading gradient tests at 100% instead of 80% inhibition improved accuracy and precision.
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Infecciones por Salmonella , Fiebre Tifoidea , Humanos , Azitromicina/farmacología , Agar , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , SalmonellaRESUMEN
Salmonella enterica serovar Typhimurium causes a devastating burden of invasive disease in sub-Saharan Africa with high levels of antimicrobial resistance. No licensed vaccine is available, but O-antigen-based candidates are in development, as the O-antigen moiety of lipopolysaccharides is the principal target of protective immunity. The vaccines under development are designed based on isolates with O-antigen O-acetylated at position C-2 of abequose, giving the O:5 antigen. Serotyping data on recent Salmonella Typhimurium clinical isolates from the Democratic Republic of the Congo (DRC), however, indicate increasing levels of isolates without O:5. The importance and distribution of this loss of O:5 antigen in the population as well as the genetic mechanism responsible for the loss and chemical characteristics of the O-antigen are poorly understood. In this study, we Illumina whole-genome sequenced 354 Salmonella Typhimurium isolates from the DRC, which were isolated between 2002 and 2017. We used genomics and phylogenetics combined with chemical approaches (1H nuclear magnetic resonance [NMR], high-performance anion-exchange chromatography with pulsed amperometric detection [HPAEC-PAD], high-performance liquid chromatography-PAD [HPLC-PAD], and HPLC-size exclusion chromatography [HPLC-SEC]) to characterize the O-antigen features within the bacterial population. We observed convergent evolution toward the loss of the O:5 epitope predominantly caused by recombination events in a single gene, the O-acetyltransferase gene oafA. In addition, we observe further O-antigen variations, including O-acetylation of the rhamnose residue, different levels of glucosylation, and the absence of O-antigen repeating units. Large recombination events underlying O-antigen variation were resolved using long-read MinION sequencing. Our study suggests evolutionary pressure toward O-antigen variants in a region where invasive disease by Salmonella Typhimurium is highly endemic. This needs to be taken into account when developing O-antigen-based vaccines, as it might impact the breadth of coverage in such regions. IMPORTANCE The bacterium Salmonella Typhimurium forms a devastating burden in sub-Saharan Africa by causing invasive bloodstream infections. Additionally, Salmonella Typhimurium presents high levels of antimicrobial resistance, jeopardizing treatment. No licensed vaccine is available, but candidates are in development, with lipopolysaccharides being the principal target of protective immunity. The vaccines under development are designed based on the O:5 antigen variant of bacterial lipopolysaccharides. Data on recent Salmonella Typhimurium clinical isolates from the Democratic Republic of the Congo (DRC), however, indicate increasing levels of isolates without this O:5 antigen. We studied this loss of O:5 antigen in the population at the genetic and chemical levels. We genome sequenced 354 isolates from the DRC and used advanced bioinformatics and chemical methods to characterize the lipopolysaccharide features within the bacterial population. Our results suggest evolutionary pressure toward O-antigen variants. This needs to be taken into account when developing vaccines, as it might impact vaccine coverage.
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Antiinfecciosos , Infecciones por Salmonella , Salmonella enterica , Sepsis , República Democrática del Congo/epidemiología , Humanos , Lipopolisacáridos , Antígenos O/genética , Infecciones por Salmonella/microbiología , Salmonella enterica/genética , Salmonella typhimurium , SerogrupoRESUMEN
OBJECTIVE: In the Democratic Republic of Congo and other low-resource countries, community-acquired pathogens are increasingly resistant to most locally available antibiotics. To guide efforts to optimize antibiotic use to limit antibiotic resistance, we quantified healthcare provider-specific and community-wide antibiotic use. METHODS: From household surveys, we estimated monthly healthcare visit rates by provider. From healthcare visit exit surveys, we estimated prevalence, defined daily doses, and access/watch/reserve distribution of antibiotic use by provider. Combining both, we estimated community-wide antibiotic use rates. RESULTS: Of 88.7 (95% CI 81.9-95.4) healthcare visits per 1000 person-months (n = 31221), visits to private clinics (31.0, 95% CI 30.0-32.0) and primary health centres (25.5, 95% CI 24.6-26.4) were most frequent. Antibiotics were used during 64.3% (95% CI 55.2-73.5%, 162/224) of visits to private clinics, 51.1% (95% CI 45.1-57.2%, 245/469) to health centres, and 48.8% (95% CI 44.4-53.2%, 344/454) to medicine stores. Antibiotic defined daily doses per 1000 inhabitants per day varied between 1.75 (95% CI 1.02-2.39) in rural Kimpese and 10.2 (95% CI 6.00-15.4) in (peri) urban Kisantu, mostly explained by differences in healthcare utilisation (respectively 27.8 versus 105 visits per 1000 person-months), in particular of private clinics (1.23 versus 38.6 visits) where antibiotic use is more frequent. The fraction of Watch antibiotics was 30.3% (95% CI 24.6-35.9%) in private clinics, 25.6% (95% CI 20.2-31.1%) in medicine stores, and 25.1% (95% CI 19.0-31.2%) in health centres. Treatment durations <3 days were more frequent at private clinics (5.3%, 9/169) and medicine stores (4.1%, 14/338) than at primary health centres (1.8%, 5/277). DISCUSSION: Private healthcare providers, ubiquitous in peri-urban settings, contributed most to community-wide antibiotic use and more frequently dispensed Watch antibiotics and shortened antibiotic courses. Efforts to optimize antibiotic use should include private providers at community level.
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Antibacterianos , Personal de Salud , Antibacterianos/uso terapéutico , República Democrática del Congo/epidemiología , Farmacorresistencia Microbiana , Humanos , Población RuralRESUMEN
Non-typhoidal Salmonella (NTS) ranks first among causes of bloodstream infection in children under five years old in the Democratic Republic of Congo and has a case fatality rate of 15%. Main host-associated risk factors are Plasmodium falciparum malaria, anemia and malnutrition. NTS transmission in sub-Saharan Africa is poorly understood. NTS bloodstream infections mostly occur during the rainy season, which may reflect seasonal variation in either environmental transmission or host susceptibility. We hypothesized that environment- and host-associated factors contribute independently to the seasonal variation in NTS bloodstream infections in children under five years old admitted to Kisantu referral hospital in 2013-2019. We used remotely sensed rainfall and temperature data as proxies for environmental factors and hospital data for host-associated factors. We used principal component analysis to disentangle the interrelated environment- and host-associated factors. With timeseries regression, we demonstrated a direct association between rainfall and NTS variation, independent of host-associated factors. While the latter explained 17.5% of NTS variation, rainfall explained an additional 9%. The direct association with rainfall points to environmental NTS transmission, which should be explored by environmental sampling studies. Environmental and climate change may increase NTS transmission directly or via host susceptibility, which highlights the importance of preventive public health interventions.
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Hospitalización/estadística & datos numéricos , Infecciones por Salmonella/epidemiología , Salmonella enteritidis/aislamiento & purificación , Salmonella typhimurium/aislamiento & purificación , Estaciones del Año , Sepsis/epidemiología , Antibacterianos/uso terapéutico , Preescolar , República Democrática del Congo/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Factores de Riesgo , Infecciones por Salmonella/tratamiento farmacológico , Infecciones por Salmonella/microbiología , Sepsis/tratamiento farmacológico , Sepsis/microbiologíaRESUMEN
In this paper, we describe the first complete genome sequence of Providencia vermicola species, a clinical multidrug-resistant strain harboring the New Delhi Metallo-ß-lactamase-1 (NDM-1) gene, isolated at the Kinshasa University Teaching Hospital, in Democratic Republic of the Congo. Whole genome sequencing of an imipenem-resistant clinical Gram-negative P. vermicola P8538 isolate was performed using MiSeq and Gridion, and then complete genome analysis, plasmid search, resistome analysis, and comparative genomics were performed. Genome assembly resulted in a circular chromosome sequence of 4,280,811-bp and 40.80% GC and a circular plasmid (pPV8538_NDM-1) of 151,684-bp and 51.93%GC, which was identified in an Escherichia coli P8540 strain isolated in the same hospital. Interestingly, comparative genomic analysis revealed multiple sequences acquisition within the P. vermicola P8538 chromosome, including three complete prophages, a siderophore biosynthesis NRPS cluster, a Type VI secretion system (T6SS), a urease gene cluster, and a complete Type-I-F CRISPR-Cas3 system. Β-lactamase genes, including blaCMY-6 and blaNDM-1, were found on the recombinant plasmid pPV8538_NDM-1, in addition to other antibiotic resistance genes such as rmtC, aac6'-Ib3, aacA4, catA1, sul1, aac6'-Ib-cr, tetA, and tetB. Genome comparison with Providencia species revealed 82.95% of average nucleotide identity (ANI), with P. stuartii species exhibiting 90.79% of proteome similarity. We report the first complete genome of P. vermicola species and for the first time the presence of the blaNDM-1 gene in this species. This work highlights the need to improve surveillance and clinical practices in DR Congo in order to reduce or prevent the spread of such resistance.
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BACKGROUND: Non-typhoidal Salmonella (NTS) serotypes Typhimurium and Enteritidis are a major cause of bloodstream infections in children in sub-Saharan Africa but their reservoir is unknown. We compared pairs of NTS blood and stool isolates (with the same NTS serotype recovered in the same patient) for genetic similarity. METHODS: Between November 2013 and April 2017, hospital-admitted children (29 days to 14 years) with culture-confirmed NTS bloodstream infections were enrolled in a cross-sectional study at Kisantu Hospital, DR Congo. Stool cultures for Salmonella were performed on a subset of enrolled children, as well as on a control group of non-febrile hospital-admitted children. Pairs of blood and stool NTS isolates were assessed for genetic similarity by multiple-locus variable-number of tandem repeats (MLVA) and genomics analysis. RESULTS: A total of 299 children with NTS grown from blood cultures (Typhimurium 68.6%, Enteritidis 30.4%, other NTS 1.0%) had a stool sample processed; in 105 (35.1%) of them NTS was detected (Typhimurium 70.5%, Enteritidis 25.7%, other NTS 3.8%). A total of 87/105 (82.9%) pairs of blood and stool NTS isolates were observed (representing 29.1% of the 299 children). Among 1598 controls, the proportion of NTS stool excretion was 2.1% (p < 0.0001). MLVA types among paired isolates were identical in 82/87 (94.3%) pairs (27.4% of the 299 children; 61/66 (92.4%) in Typhimurium and 21/21 (100%) in Enteritidis pairs). Genomics analysis confirmed high genetic similarity within 41/43 (95.3%) pairs, showing a median SNP difference of 1 (range 0-77) and 1 (range 0-4) for Typhimurium and Enteritidis pairs respectively. Typhimurium and Enteritidis isolates belonged to sequence types ST313 lineage II and ST11 respectively. CONCLUSION: Nearly 30% of children with NTS bloodstream infection showed stool excretion of an NTS isolate with high genetic similarity, adding to the evidence of humans as a potential reservoir for NTS.
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Bacteriemia/microbiología , Heces/microbiología , Salmonella/genética , Adolescente , Niño , Preescolar , Estudios Transversales , Humanos , Lactante , Polimorfismo de Nucleótido Simple , Salmonella/clasificaciónRESUMEN
BACKGROUND: Clinical observations and animal studies have suggested that Salmonella intestinal carriage is promoted by concurrent Schistosoma infection. The present study assessed association of Salmonella intestinal carriage and Schistosoma mansoni infection among individuals in a Schistosoma endemic area in sub-Saharan Africa. METHODS: From November 2015 to March 2016, a cross-sectional community-wide study was conducted in Kifua II, a rural village in Kongo Central Province, Democratic Republic of Congo. Stool samples were collected and analyzed for Salmonella intestinal carriage (culture) and Schistosoma mansoni infection (Kato Katz microscopy with determination of egg load). Salmonella Typhimurium and Enteritidis isolates were assessed for genetic similarity with blood culture isolates obtained during the same period in a neighboring hospital using multi-locus variable-numbers tandem repeat analysis (MLVA). RESULTS: A total of 1,108 participants were included (median age 15 years (IQR: 7-36), male-to-female ratio of 1:1.1). The overall prevalence of Schistosoma mansoni infection and non-typhoidal Salmonella carriage was 51.2% (95% CI: 48.2-54.1) and 3.4% (95% CI: 2.5-4.7) respectively, with 2.2% (95% CI: 1.5-3.2) of participants coinfected. The proportion of Salmonella carriage tended to be higher among Schistosoma mansoni infected participants compared to non-infected participants but this difference did not reach statistical significance (4.2% versus 2.6%, p = 0.132). However, the proportion of Salmonella carriage among participants with a heavy Schistosoma mansoni infection was significantly higher compared to those with a light and moderate infection (8.7% versus 3.2%, p = 0.012) and compared to Schistosoma mansoni negatives (8.7% versus 2.6%, p = 0.002). The 38 Salmonella isolates comprised five and four Enteritidis and Typhimurium serotypes respectively, the majority of them had MLVA types identical or similar to those observed among blood culture isolates. CONCLUSION: Salmonella intestinal carriage was associated with a heavy intensity of Schistosoma mansoni infection. Further studies are needed to address causation.
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Portador Sano/microbiología , Intestinos/microbiología , Salmonella typhimurium/aislamiento & purificación , Esquistosomiasis mansoni/parasitología , Adolescente , Adulto , Animales , Portador Sano/epidemiología , Niño , Coinfección/epidemiología , Coinfección/microbiología , Coinfección/parasitología , Estudios Transversales , República Democrática del Congo/epidemiología , Femenino , Humanos , Masculino , Población Rural , Salmonella typhimurium/genética , Schistosoma mansoni/genética , Schistosoma mansoni/aislamiento & purificación , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Non-typhoidal Salmonella (NTS) are a major cause of bloodstream infection (BSI) in sub-Saharan Africa. This study aimed to assess its longitudinal evolution as cause of BSI, its serotype distribution and its antibiotic resistance pattern in Kisantu, DR Congo. METHODS: As part of a national surveillance network, blood cultures were sampled in patients with suspected BSI admitted to Kisantu referral hospital from 2015-2017. Blood cultures were worked-up according to international standards. Results were compared to similar data from 2007 onwards. RESULTS: In 2015-2017, NTS (n = 896) represented the primary cause of BSI. NTS were isolated from 7.6% of 11,764 suspected and 65.4% of 1371 confirmed BSI. In children <5 years, NTS accounted for 9.6% of suspected BSI. These data were in line with data from previous surveillance periods, except for the proportion of confirmed BSI, which was lower in previous surveillance periods. Salmonella Typhimurium accounted for 63.1% of NTS BSI and Salmonella Enteritidis for 36.4%. Of all Salmonella Typhimurium, 36.9% did not express the O5-antigen (i.e. variant Copenhagen). O5-negative Salmonella Typhimurium were rare before 2013, but increased gradually from then onwards. Multidrug resistance was observed in 87.4% of 864 NTS isolates, decreased ciprofloxacin susceptibility in 7.3%, ceftriaxone resistance in 15.7% and azithromycin resistance in 14.9%. A total of 14.2% of NTS isolates, that were all Salmonella Typhimurium, were multidrug resistant and ceftriaxone and azithromycin co-resistant. These Salmonella isolates were called extensively drug resistant. Compared to previous surveillance periods, proportions of NTS isolates with resistance to ceftriaxone and azithromycin and decreased ciprofloxacin susceptibility increased. CONCLUSION: As in previous surveillance periods, NTS ranked first as the cause of BSI in children. The emergence of O5-negative Salmonella Typhimurium needs to be considered in the light of vaccine development. The high proportions of antibiotic resistance are worrisome.
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Antibacterianos/farmacología , Bacteriemia/epidemiología , Bacteriemia/microbiología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Infecciones por Salmonella/epidemiología , Infecciones por Salmonella/microbiología , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/aislamiento & purificación , Adolescente , Adulto , Azitromicina , Ceftriaxona , Niño , Preescolar , Ciprofloxacina , Congo/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Salmonella/efectos de los fármacos , Infecciones por Salmonella/diagnóstico , Salmonella enteritidis/efectos de los fármacos , Serogrupo , Fiebre Tifoidea/tratamiento farmacológico , Adulto JovenRESUMEN
Bloodstream infections by Salmonella enterica serovar Typhimurium constitute a major health burden in sub-Saharan Africa (SSA). These invasive non-typhoidal (iNTS) infections are dominated by isolates of the antibiotic resistance-associated sequence type (ST) 313. Here, we report emergence of ST313 sublineage II.1 in the Democratic Republic of the Congo. Sublineage II.1 exhibits extensive drug resistance, involving a combination of multidrug resistance, extended spectrum ß-lactamase production and azithromycin resistance. ST313 lineage II.1 isolates harbour an IncHI2 plasmid we name pSTm-ST313-II.1, with one isolate also exhibiting decreased ciprofloxacin susceptibility. Whole genome sequencing reveals that ST313 II.1 isolates have accumulated genetic signatures potentially associated with altered pathogenicity and host adaptation, related to changes observed in biofilm formation and metabolic capacity. Sublineage II.1 emerged at the beginning of the 21st century and is involved in on-going outbreaks. Our data provide evidence of further evolution within the ST313 clade associated with iNTS in SSA.