Extremely and pandrug-resistant bacteria extra-deaths: myth or reality?

In 2009, the European Centre for Disease Prevention and Control (ECDC) estimated that multidrug-resistant (MDR) bacterial infections were responsible for 25,000 extra-deaths per year. In 2015, another report estimated that 12,500 extra-deaths were attributable to MDR bacteria every year in France. Recently, the United Nations claimed that resistance to antimicrobials was a global scourge, forecasting 10 million deaths in 2050. Surprisingly, our antibiotic resistance surveillance system in Marseille, France, did not allowed us to observe similar trends. We herein compared our data on extremely drug-resistant (XDR)/pandrug-resistant (PDR) patient extra-deaths to evaluations and predictions from these reports. First, we retrospectively collect and analyze antibiotic resistance data produced by our settings between November 2009 and March 2015 to look for 30-day deaths attributable to XDR/PDR strains belonging to 11 bacterial species/genus. In parallel, we performed a PubMed literature search to look for articles published prior to July 2016 and describing human deaths due to PDR strains. Overall, 35,723 patients were infected by at least one bacterial species/genus of interest and 85 by XDR/PDR strains. Of these patients, only one death was attributable to a XDR bacterial infection in a patient with strong comorbidities and two consecutive septic shocks. Our literature review shows that only four articles described human deaths due to PDR bacteria. All together, these data allowed us to conclude that there is a large discrepancy between the real count of deaths attributable to XDR/PDR bacteria and alarmist predictions.

Evaluating the Clinical Burden and Mortality Attributable to Antibiotic Resistance: The Disparity of Empirical Data and Simple Model Estimations.

Given the proliferation of cataclysmic predictions about antibiotic resistance, cases of which are estimated to amount to 12500 per year in France, we herein decided to compare the empirical clinical microbiology data from our institution with estimates and predictions from 10 major international scientific articles and reports. The analysis of 7 years of antibiotic resistance data from 10 bacterial species and genera of clinical interest from our institution identified no deaths that were directly attributable to extremely drug-resistant bacteria. By comparing our observations to the 10 articles and reports studied herein, we concluded that their results lack empirical data. Interventions are urgently needed to significantly reduce both mortality and the healthcare costs associated with bacterial infections, including the implementation of local and national laboratory data-based surveillance systems for the routine surveillance of antibiotic resistance that would be helpful for a better understanding of how to manage antibiotic-resistant bacteria in the future.

Implementation and Initial Analysis of a Laboratory-Based Weekly Biosurveillance System, Provence-Alpes-Côte d'Azur, France.

We describe the implementation of an automated infectious disease surveillance system that uses data collected from 210 microbiologic laboratories throughout the Provence-Alpes-Côte d'Azur region in France. Each week, these facilities report bacterial species that have been isolated from patients in their area. An alarm is triggered whenever the case count for a bacterial species infection exceeds 2 SDs of the historical mean for that species at the participating laboratory. At its inception in July 2013, the system monitored 611 bacterial species. During July 1, 2013-March 20, 2016, weekly analyses of incoming surveillance data generated 34 alarms signaling possible infectious disease outbreaks; after investigation, 14 (41%) of these alarms resulted in health alerts declared by the regional health authority. We are currently improving the system by developing an Internet-based surveillance platform and extending our surveillance to include more laboratories in the region.

Real-Time Microbiology Laboratory Surveillance System to Detect Abnormal Events and Emerging Infections, Marseille, France.

Infectious diseases are a major threat to humanity, and accurate surveillance is essential. We describe how to implement a laboratory data-based surveillance system in a clinical microbiology laboratory. Two historical Microsoft Excel databases were implemented. The data were then sorted and used to execute the following 2 surveillance systems in Excel: the Bacterial real-time Laboratory-based Surveillance System (BALYSES) for monitoring the number of patients infected with bacterial species isolated at least once in our laboratory during the study periodl and the Marseille Antibiotic Resistance Surveillance System (MARSS), which surveys the primary ß-lactam resistance phenotypes for 15 selected bacterial species. The first historical database contained 174,853 identifications of bacteria, and the second contained 12,062 results of antibiotic susceptibility testing. From May 21, 2013, through June 4, 2014, BALYSES and MARSS enabled the detection of 52 abnormal events for 24 bacterial species, leading to 19 official reports. This system is currently being refined and improved.

Correlation between sputum and bronchoalveolar lavage fluid cultures.

A correlation study of the cultured bacteria from paired sputum and bronchoalveolar lavage fluid samples was performed. The rates of concordant culture-positive paired specimens that were isolated within 1 or 7 days were 93.7% and 96.5%, respectively, suggesting that the culture of readily collectable sputum specimens may result in useful microbiologic diagnosis.

Emergence of clusters of CRF02_AG and B human immunodeficiency viral strains among men having sex with men exhibiting HIV primary infection in southeastern France.

The number of new HIV diagnoses is increasing in the western world and transmission clusters have been recently identified among men having sex with men despite Highly Active Antiretroviral Therapy efficacy. The objective of this study was to assess temporal trends, epidemiological, clinical and virological characteristics of primary HIV infections. A retrospective analysis of 79 patients presenting primary HIV infections from 2005 to 2012 was performed in Marseille University Hospitals, southeastern France. Clinical, epidemiological and immunovirological data including phylogeny based on the polymerase gene were collected. 65 males and 14 females were enrolled. The main transmission route was homosexual contact (60.8%). Patients were mostly infected with subtype B (73.4%) and CRF02_AG (21.5%) HIV-1 strains. An increase in the annual number of HIV seroconversions among new HIV diagnoses from 5% in 2005 to 11.2% in 2012 (P = 0.06) and of the proportion of CRF02_AG HIV strains among primary HIV infections in 2011-2012 as compared to 2005-2010 (P = 0.055) was observed. Phylogenetic analysis revealed four transmission clusters including three transmission clusters among men having sex with men: two large clusters of nine CRF02_AG, six B HIV strains; and one small cluster of three B HIV strains. Clusters involved more frequently men (P = 0.01) belonging to caucasian ethicity (P = 0.05), with a higher HIV RNA load at inclusion (P = 0.03). These data highlight the importance of improving epidemiological surveillance and of implementing suitable prevention strategies to control the spread of HIV transmission among men having sex with men.

Salmonella and Campylobacter contamination of ready-to-eat street-vended pork meat dishes in Antananarivo, Madagascar: a risk for the consumers?

Street-food vending has been increasing in many developing countries and particularly in Madagascar since 2000. Gastroenteric diseases cause 37% of all deaths each year, and 50% of children <5 years are infected with intestinal pathogens. However, there has been little information regarding the incidence of street-food-related diseases, or foodborne pathogens in pork, which is the most commonly eaten meat, along with chicken. Thus, the aim of this study was to investigate the safety of traditional ready-to-eat street-vended pork dishes and to assess the association of restaurant characteristics and cooking practices with Salmonella and Campylobacter contamination of these meals. Sixty street-restaurants were studied from March 2012 to August 2012 in Antananarivo. A questionnaire was submitted to the managers, and samples of ready-to-eat pork dishes were bought. Salmonella spp. were isolated in 10% of the 60 street-restaurants studied and in 5% samples of pork dishes. The most prevalent serovars isolated were Salmonella Typhimurium (44%) and Senftenberg (33%). Campylobacter was not detected. Only 4 of the 43 variables tested in the screening analysis were significantly associated with Salmonella spp. contamination of the street-restaurants. The risk for a restaurant to be Salmonella positive decreased when there were specific premises for the restaurant and when the staff was wearing specific clothes when working. Conversely, that risk increased when the temperature of ready-to-eat pork was <52 °C and when tablecloths were used in the restaurant.

Identification of rare pathogenic bacteria in a clinical microbiology laboratory: impact of matrix-assisted laser desorption ionization-time of flight mass spectrometry.

During the past 5 years, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) has become a powerful tool for routine identification in many clinical laboratories. We analyzed our 11-year experience in routine identification of clinical isolates (40 months using MALDI-TOF MS and 91 months using conventional phenotypic identification [CPI]). Among the 286,842 clonal isolates, 284,899 isolates of 459 species were identified. The remaining 1,951 isolates were misidentified and required confirmation using a second phenotypic identification for 670 isolates and using a molecular technique for 1,273 isolates of 339 species. MALDI-TOF MS annually identified 112 species, i.e., 36 species/10,000 isolates, compared to 44 species, i.e., 19 species/10,000 isolates, for CPI. Only 50 isolates required second phenotypic identifications during the MALDI-TOF MS period (i.e., 4.5 reidentifications/10,000 isolates) compared with 620 isolates during the CPI period (i.e., 35.2/10,000 isolates). We identified 128 bacterial species rarely reported as human pathogens, including 48 using phenotypic techniques (22 using CPI and 37 using MALDI-TOF MS). Another 75 rare species were identified using molecular methods. MALDI-TOF MS reduced the time required for identification by 55-fold and 169-fold and the cost by 5-fold and 96-fold compared with CPI and gene sequencing, respectively. MALDI-TOF MS was a powerful tool not only for routine bacterial identification but also for identification of rare bacterial species implicated in human infectious diseases. The ability to rapidly identify bacterial species rarely described as pathogens in specific clinical specimens will help us to study the clinical burden resulting from the emergence of these species as human pathogens, and MALDI-TOF MS may be considered an alternative to molecular methods in clinical laboratories.

Antibiotic resistance surveillance systems: A review.

OBJECTIVES: Epidemiological surveillance is one critical approach to estimate and fight the burden of antibiotic resistance (AR). Here we summarise the characteristics of surveillance systems devoted to the surveillance of AR worldwide and published in the literature. METHODS: We performed a systematic review of the literature available on PubMed from January 2007 to July 2019 (12.5 years). The keywords ('surveillance system' OR 'laboratory-based surveillance' OR 'syndromic surveillance' OR 'sentinel surveillance' OR 'integrated surveillance' OR 'population-based surveillance') AND ('antibiotic resistance' OR 'antimicrobial resistance') were used. This research was completed with AR monitoring systems available on websites. RESULTS: We identified 71 AR surveillance systems described by 90 publications from 35 countries, including 64 (90.1%) national and 7 (9.9%) multinational surveillance systems. Two regions accounted for ∼72% of systems: European region (37; 52.1%) and Region of the Americas (14; 19.7%). Fifty-three focused on AR surveillance in humans, 12 studied both humans and animals, and 6 focused only on animals. The two most common bacterial species reported were Staphylococcus aureus (42; 59.2%) and Escherichia coli (39; 54.9%). Of the 71 AR surveillance systems, 20 (28.2%) used prevalence as an indicator, 3 (4.2%) used incidence and 7 (9.9%) used both. Methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococcus spp., S. aureus and Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and extended-spectrum ß-lactamase (ESBL)-producing and carbapenem-resistant E. coli and Klebsiella pneumoniae were monitored. CONCLUSIONS: Our results showed heterogeneous surveillance systems. A 'One Health' approach is needed to monitor AR, with reference to the WHO Global Action Plan.

Prospective case-control analysis of the aetiologies of acute undifferentiated fever in Vietnam.

Acute undifferentiated fever (AUF) is frequently observed in tropical settings, but diagnosing the cause of AUF is often a challenge for local physicians and the physicians treating returning travellers. We conducted a case-control study in central Vietnam in 2016. A total of 378 febrile adult patients (AUFs) with a fever for ≤21 days, no evidence of localized infection and negative screening tests for dengue and malaria, and 384 afebrile adult patients (Controls) were prospectively enrolled. Whole blood, plasma, eschar swab, throat swab and urine specimens were collected and analysed. Quantitative PCR and RT-PCR were used to test for 55 bacteria, viruses and their subtypes. Serological tests were also used to test for rickettsial agents. The most common aetiology was influenza virus (20.9% in AUFs vs. 0% in Controls), followed by rickettsial agents (mainly Orientia tsutsugamushi and Rickettsia typhi) (10.8% vs. 0.3%), dengue virus (7.7% vs. 0.5%), Leptospira (4.8% vs. 0.8%), adenovirus (4.8% vs. 1.0%), and enterovirus (2.1% vs. 0%) (p < .05). The real proportion of dengue in AUF cases was underestimated because patients with dengue-positive rapid diagnosis tests were excluded from the study. The emerging agent Rickettsia felis, which had not been previously observed in Vietnam, was detected in this study. In total, 216 patients (57.1%) were given causative diagnoses, comprising 143 (66.2%) monoinfections and 73 (33.8%) coinfections. The infections caused by these agents should be considered in clinical practice and further studies. Additionally, agents susceptible to doxycycline were detected in 15.6% of AUFs; thus, this drug should be included in the panel used to treat AUF patients.

Parallel Decline of Malaria and Rickettsia felis Infections in Senegal.

Rickettsia felis is a common emerging pathogen in sub-Saharan Africa. Comparing dynamics of morbidities due to malaria and R. felis infections in two Senegalese villages, we found a strong and significant correlation between them. Malaria morbidity is strongly decreasing because of the implementation of long-lasting insecticidal nets, so we hypothesize that the same measure may decrease the R. felis infections.

Why new antibiotics are not obviously useful now.

For several years, the threat of antibiotic resistance and its health cost has dramatically risen and various alarming figures have been proposed to illustrate the mortality due to antibiotic resistance. However, predictions concerning different living beings are doomed to failure, as theorised in Alice's 'living croquet' theory. Actors of antibiotic resistance are the doctors, the patient and the bacteria. Considering that animals and the environment are involved, future disasters are unpredictable. Here we evaluate in a rational manner the reliability of scientific sources showing increasing resistance to antibiotics or increasing mortality related to antibiotic resistance, and we finally consider antibiotic resources to face the situation.

Low Level of Resistance in Enterococci Isolated in Four Hospitals, Marseille, France.

Enterococci are gram-positive cocci responsible for various infections worldwide, and their prevalence of antibiotic resistance greatly varies worldwide. This study investigates the prevalence of resistance to antibiotics in enterococci from patients admitted in the four university hospitals of Marseille between January 2013 and September 2014. Two thousand nine hundred seventy-six patients-bacteria couples were identified (2,507 Enterococcus faecalis and 469 Enterococcus faecium) in the four university hospitals of Marseille. 1.3%, 8.9%, 1.4%, and 0% of E. faecalis strains were resistant to amoxicillin, gentamicin, teicoplanin, and vancomycin, respectively, and 83.9%, 49.2%, 1.3%, and 0.2% of E. faecium strains were resistant to amoxicillin, gentamicin, teicoplanin, and vancomycin, respectively. Resistance to aminoglycosides and vancomycin in strains isolated from blood cultures was significantly lower than that of most European countries included in the 2012 European Antimicrobial Resistance Surveillance Network report. Our low percentage of antibiotic resistance in enterococci is likely due to a low level of E. faecium infections, underlining the need to implement surveillance systems, especially to monitor the E. faecalis/E. faecium ratio evolution in blood cultures and others.

Decreasing level of resistance in invasive Klebsiella pneumoniae strains isolated in Marseille, January 2012-July 2015.

BACKGROUND: Klebsiella pneumoniae is a Gram-negative bacterial species well known for its capacity to cause infections in humans, and to carry and spread a wide variety of resistance genes including extended-spectrum beta-lactamase genes, carbapenem resistance genes, and colistin resistance genes. Recently, our real-time laboratory-based surveillance system MARSS (the Marseille Antibiotic Resistance Surveillance System) allowed us to observe a intringing dramatic decrease in the beta-lactam resistance level of the K. pneumoniae strains routinely isolated from patients hospitalized in our settings since 2013. Here we study the evolution of the prevalence of K. pneumoniae infections in Marseille university hospitals, France, from January 2012 to July 2015, and study their antibiotic resistance profiles. METHODS: We collected data referring to patients hostpitalized for K. pneumoniae infections in the 4 university hospitals of Marseille from January 2012 to July 2015. We then study their antibiotic resistance profiles according the clinical sites from which each strain was collected. Antibiotic consumption data from our four hospitals were also analyzed from January 2013 to July 2015. RESULTS: Overall, 4868 patients were admitted in our settings for K. pneumoniae infections over the study period. Overall, 40.1, 22.3, 25.6, 0.4, 29.9, 14.8, 27.3 and 37.0 % of the strains were resistant to amoxicillin plus clavulanic acid, piperacillin-tazobactam, ceftriaxone, imipenem, ciprofloxacin, gentamicin, trimethoprim-sulfamethoxazole and furan, respectively. 447 were invasive infections. The resistance level of our invasive strains was significantly lower than that presented by 11, 7, 10 and 11 other European countries included in the 2013 European Antimicrobial Resistance Surveillance Network report for ceftriaxone, imipenem, ciprofloxacin and gentamicin, respectively, but significantly higher than that of 13, 1, 17 and 13 European countries for the same antibiotics. We also observed that the percentages of resistance of our invasive strains to three of the four antibiotics decreased over the study. In parallel, antibiotic consumption remained stable in our four hospitals from January 2013 to July 2015. CONCLUSIONS: Altogether, our results underline that automated antibiotic-susceptibility testing results-based surveillance systems are crucial to better understand the evolving epidemiology of dangerous pathogenic bacterial species, like K. pneumoniae, at local scales.

Enterococcus faecalis urinary-tract infections: Do they have a zoonotic origin?

Major human pathogens are frequently isolated from meat-producing animals, particularly poultry. Among them is Enterococcus faecalis, which is known to be one of the main cause of human urinary-tract infections worldwide. Early in 2015, we detected several, consecutive abnormal increases in the weekly number of human E. faecalis infections in various medical settings in the Provence-Alpes-Côte d'Azur region of France, especially including community-acquired urinary-tract infections. Speculating that this region-wide epidemiological event may have originated from animal-based food, we initiated this work to provide an overview of the epidemiology of E. faecalis, with a particular focus on the possible link between E. faecalis clones isolated from food-producing animals and those responsible for human urinary-tract infections. At that time, only one study had clearly identified strong epidemiological links between E. faecalis clones isolated from food-producing animals and human E. faecalis urinary-tract infections. This observation, coupled with our region-wide epidemiological experience, leads us to strongly believe that E. faecalis is a real zoonotic pathogen with potentially highly significant impact on human health. This is of particular concern because of its ability to acquire antibiotic-resistance genes and to infect animals and humans. Various strategies must be urgently implemented to address this public health threat, in particular through the development and implementation of large integrated automated surveillance systems based on animal and human health data to enable us to detect E. faecalis epidemiological events.