Antibiotic resistance genes in the gut microbiota of mothers and linked neonates with or without sepsis from low- and middle-income countries.

Early development of the microbiome has been shown to affect general health and physical development of the infant and, although some studies have been undertaken in high-income countries, there are few studies from low- and middle-income countries. As part of the BARNARDS study, we examined the rectal microbiota of 2,931 neonates (term used up to 60 d) with clinical signs of sepsis and of 15,217 mothers screening for blaCTX-M-15, blaNDM, blaKPC and blaOXA-48-like genes, which were detected in 56.1%, 18.5%, 0% and 4.1% of neonates' rectal swabs and 47.1%, 4.6%, 0% and 1.6% of mothers' rectal swabs, respectively. Carbapenemase-positive bacteria were identified by MALDI-TOF MS and showed a high diversity of bacterial species (57 distinct species/genera) which exhibited resistance to most of the antibiotics tested. Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae/E. cloacae complex, the most commonly found isolates, were subjected to whole-genome sequencing analysis and revealed close relationships between isolates from different samples, suggesting transmission of bacteria between neonates, and between neonates and mothers. Associations between the carriage of antimicrobial resistance genes (ARGs) and healthcare/environmental factors were identified, and the presence of ARGs was a predictor of neonatal sepsis and adverse birth outcomes.

Transmission of multidrug-resistant Gram-negative bacteria from colonized mothers to their infants: a systematic review and meta-analysis.

BACKGROUND: Neonatal sepsis remains a leading cause of neonatal mortality. Maternal bacterial colonization plays a major role in transmission to the infant, with potential for subsequent development of neonatal sepsis with maternally derived strains. AIM: To review the molecular evidence supporting transmission of multidrug-resistant Gram-negative bacteria (MDR-GNB) from colonized mothers to their infants and the risk factors for MDR-GNB transmission. METHODS: PubMed and Scopus were searched for studies investigating the mechanisms, risk factors for and/or scale of transmission of MDR-GNB from colonized mothers to their infants. Random effects meta-analyses were performed to determine pooled proportions of MDR-GNB transmission and the neonatal outcomes of transmission. FINDINGS: Eight studies were included in the narrative description and six in the meta-analysis. Five studies used pulsed-field gel electrophoresis to assess relatedness of isolates from colonized mothers and their infants. Pooled proportion of MDR-GNB transmission from colonized mothers to their infants was 27% (95% confidence interval (CI): 8-47%). Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae were the most frequently studied MDR-GNB pathogens transmitted between mother-infant pairs. Following mother-to-infant transmission of an MDR-GNB pathogen, the pooled proportion for the outcome of neonatal colonization was 19% (95% CI: 3-35%). CONCLUSION: This systematic review strongly supports MDR and/or ESBL Enterobacteriaceae transmission from colonized mothers to their infants, with subsequent infant colonization. The risk factors contributing to transmission of MDR-GNB between colonized mothers and their infants warrants further research.

Optimizing antibiotic prescribing: collective approaches to managing a common-pool resource.

BACKGROUND: Antimicrobial resistance (AMR) is one of the greatest threats in 21st century medicine. AMR has been characterized as a social dilemma. A familiar version describes the situation in which a collective resource (in this case, antibiotic efficacy) is exhausted due to over-exploitation. The dilemma arises because individuals are motivated to maximize individual payoffs, although the collective outcome is worse if all act in this way. OBJECTIVES: We aim to outline the implications for antimicrobial stewardship of characterizing antibiotic overuse as a social dilemma. SOURCES: We conducted a narrative review of the literature on interventions to promote the conservation of resources in social dilemmas. CONTENT: The social dilemma of antibiotic over-use is complicated by the lack of visibility and imminence of AMR, a loose coupling between individual actions and the outcome of AMR, and the agency relationships inherent in the prescriber role. We identify seven strategies for shifting prescriber behaviour and promoting a focus on the collectively desirable outcome of conservation of antibiotic efficacy: (1) establish clearly defined boundaries and access rights; (2) raise the visibility and imminence of the problem; (3) enable collective choice arrangements; (4) conduct behaviour-based monitoring; (5) use social and reputational incentives and sanctions; (6) address misalignment of goals and incentives; and (7) provide conflict resolution mechanisms. IMPLICATIONS: We conclude that this theoretic analysis of antibiotic stewardship could make the problem of optimizing antibiotic prescribing more tractable, providing a theory base for intervention development.

Balancing the risks to individual and society: a systematic review and synthesis of qualitative research on antibiotic prescribing behaviour in hospitals.

BACKGROUND: Antimicrobial resistance is a global health threat, partly driven by inappropriate antibiotic prescriptions for acute medical patients in hospitals. AIM: To provide a systematic review of qualitative research on antibiotic prescribing decisions in hospitals worldwide, including broad-spectrum antibiotic use. METHODS: A systematic search of qualitative research on antibiotic prescribing for adult hospital patients published between 2007 and 2017 was conducted. Drawing on the Health Belief Model, a framework synthesis was conducted to assess threat perceptions associated with antimicrobial resistance, and perceived benefits and barriers associated with antibiotic stewardship. FINDINGS: The risk of antimicrobial resistance was generally perceived to be serious, but the abstract and long-term nature of its consequences led physicians to doubt personal susceptibility. While prescribers believed in the benefits of optimizing prescribing, the direct link between over-prescribing and antimicrobial resistance was questioned, and prescribers' behaviour change was frequently considered futile when fighting the complex problem of antimicrobial resistance. The salience of individual patient risks was a key barrier to more conservative prescribing. Physicians perceived broad-spectrum antibiotics to be effective and low risk; prescribing broad-spectrum antibiotics involved low cognitive demand and enabled physicians to manage patient expectations. Antibiotic prescribing decisions in low-income countries were shaped by a context of heightened uncertainty and risk due to poor microbiology and infection control services. CONCLUSIONS: When tackling antimicrobial resistance, the tensions between immediate individual risks and long-term collective risks need to be taken into account. Efforts to reduce diagnostic uncertainty and to change risk perceptions will be critical in shifting practice.

An international survey of cleaning and disinfection practices in the healthcare environment.

BACKGROUND: Antimicrobial resistance has become an urgent global health priority. Basic hygiene practices and cleaning and disinfection of the hospital environment are key in preventing pathogen cross-transmission. AIM: To our knowledge no studies have assessed the worldwide differences in cleaning and disinfection practices in healthcare facilities. The electronic survey described here was developed in order to evaluate differences in healthcare facility cleaning practices around the world. METHODS: The International Society of Antimicrobial Chemotherapy (ISAC, formerly ISC), Infection Prevention and Control work group developed a survey with 30 multiple-choice questions. The questions were designed to assess the current cleaning practices in healthcare settings around the world. FINDINGS: A total of 110 healthcare professionals, representing 23 countries, participated in the online survey. In 96% of the facilities a written cleaning policy was present. Training of cleaning staff occurred in 70% of the facilities at the start of employment. Cleaning practices and monitoring of these practices varied. CONCLUSIONS: The survey enabled assessment and recognition of widely differing global practices in approaches to environmental cleaning and disinfection. Development of guideline recommendations for cleaning and disinfection could improve practices and set minimum standards worldwide.

Infectious disease exposures and outbreaks at a South African neonatal unit with review of neonatal outbreak epidemiology in Africa.

BACKGROUND: Hospitalized neonates are vulnerable to infection, with pathogen exposures occurring in utero, intrapartum, and postnatally. African neonatal units are at high risk of outbreaks owing to overcrowding, understaffing, and shared equipment. METHODS: Neonatal outbreaks attended by the paediatric infectious diseases and infection prevention (IP) teams at Tygerberg Children's Hospital, Cape Town (May 1, 2008 to April 30, 2016) are described, pathogens, outbreak size, mortality, source, and outbreak control measures. Neonatal outbreaks reported from Africa (January 1, 1996 to January 1, 2016) were reviewed to contextualize the authors' experience within the published literature from the region. RESULTS: Thirteen outbreaks affecting 148 babies (11 deaths; 7% mortality) over an 8-year period were documented, with pathogens including rotavirus, influenza virus, measles virus, and multidrug-resistant bacteria (Serratia marcescens, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci). Although the infection source was seldom identified, most outbreaks were associated with breaches in IP practices. Stringent transmission-based precautions, staff/parent education, and changes to clinical practices contained the outbreaks. From the African neonatal literature, 20 outbreaks affecting 524 babies (177 deaths; 34% mortality) were identified; 50% of outbreaks were caused by extended-spectrum ß-lactamase-producing Klebsiella pneumoniae. CONCLUSIONS: Outbreaks in hospitalized African neonates are frequent but under-reported, with high mortality and a predominance of Gram-negative bacteria. Breaches in IP practice are commonly implicated, with the outbreak source confirmed in less than 50% of cases. Programmes to improve IP practice and address antimicrobial resistance in African neonatal units are urgently required.

Manual cleaning of hospital mattresses: an observational study comparing high- and low-resource settings.

BACKGROUND: Hospital-associated infections (HAIs) are more frequently encountered in low- than in high-resource settings. There is a need to identify and implement feasible and sustainable approaches to strengthen HAI prevention in low-resource settings. AIM: To evaluate the biological contamination of routinely cleaned mattresses in both high- and low-resource settings. METHODS: In this two-stage observational study, routine manual bed cleaning was evaluated at two university hospitals using adenosine triphosphate (ATP). Standardized training of cleaning personnel was achieved in both high- and low-resource settings. Qualitative analysis of the cleaning process was performed to identify predictors of cleaning outcome in low-resource settings. FINDINGS: Mattresses in low-resource settings were highly contaminated prior to cleaning. Cleaning significantly reduced biological contamination of mattresses in low-resource settings (P < 0.0001). After training, the contamination observed after cleaning in both the high- and low-resource settings seemed comparable. Cleaning with appropriate type of cleaning materials reduced the contamination of mattresses adequately. Predictors for mattresses that remained contaminated in a low-resource setting included: type of product used, type of ward, training, and the level of contamination prior to cleaning. CONCLUSION: In low-resource settings mattresses were highly contaminated as noted by ATP levels. Routine manual cleaning by trained staff can be as effective in a low-resource setting as in a high-resource setting. We recommend a multi-modal cleaning strategy that consists of training of domestic services staff, availability of adequate time to clean beds between patients, and application of the correct type of cleaning products.

Costs and process of in-patient tuberculosis management at a central academic hospital, Cape Town, South Africa.

SETTING: South Africa reports more cases of tuberculosis (TB) than any other country, but an up-to-date, precise estimate of the costs associated with diagnosing, treating and preventing TB at the in-patient level is not available. OBJECTIVE: To determine the costs associated with TB management among in-patients and to study the use of personal protective equipment (PPE) at a central academic hospital in Cape Town. DESIGN: Retrospective and partly prospective cost analysis of TB cases diagnosed between May 2008 and October 2009. RESULTS: The average daily in-patient costs were US$238; the average length of stay was 9.7 days. Mean laboratory and medication costs per stay were respectively US$26.82 and US$8.68. PPE use per day cost US$0.99. The average total TB management costs were US$2373 per patient. PPE was not always properly used. DISCUSSION: The costs of in-patient TB management are high compared to community-based treatment; the main reason for the high costs is the high number of in-patient days. An efficiency assessment is needed to reduce costs. Cost reduction per TB case prevented was approximately US$2373 per case. PPE use accounted for the lowest costs. Training is needed to improve PPE use.

The potential to transmit Mycobacterium tuberculosis at a South African tertiary teaching hospital.

OBJECTIVES: To assess the risk of nosocomial transmission by confirmed pulmonary tuberculosis (PTB) patients in a high TB/HIV incidence environment. METHODS: Between November 2006 and April 2007, we carried out a cross-sectional survey of PTB patients with positive smears or cultures at an academic tertiary hospital in the Western Cape, South Africa. RESULTS: Of 394 confirmed PTB patients, only 199 (50.5%) had a known HIV status, of whom 107 (53.8%) were HIV-co-infected. Sensitivity testing for Mycobacterium tuberculosis (TB) was done in 49.3% of patients with available cultures (140/284). Of these patients, 9.3% (13/140) had multidrug-resistant (MDR) TB strains. The turnaround times (TAT) for culture and susceptibility testing were delayed: mean TAT for cultures was 27 days (range 63 days) and for susceptibility testing was 42 days (range 63 days). One fifth of PTB patients (82/394) were diagnosed from wards that do not deal with TB on a daily basis. PTB inpatients were hospitalized for an average of 13 days and were on average transferred twice. Only 14.2% of all PTB patients were notified to the South Africa Provincial Department of Health. Throughout their hospitalization, PTB patients were potentially infectious. CONCLUSIONS: The potential for nosocomial TB transmission in a setting of high TB and HIV co-infection with a high MDR prevalence, inconsistent infection prevention and control measures, and delayed diagnosis cannot be ignored. Barriers to TB infection control must urgently be addressed.

HIV risk exposure among South African children in public health facilities.

The study investigates the risk exposure to HIV infection among South African children aged 2-9 years served by public health services. Together with their biological mothers, 3471 children and were recruited from inpatient and outpatient children in the Free State Province. Blood samples were taken by professional nurses and a history taken of exposure factors associated with HIV transmission. DNA testing was used to confirm biological maternity where the child was HIV-positive and the mother HIV-negative. Mother-child pairs were stratified by mother's HIV status. Exposure factors related to the child's HIV status were examined in each stratum using a chi-square test. Independent factors were then included in a multiple logistic regression model. Having an HIV-positive mother was strongly related to HIV infection in children (OR: 310; 95%CI: 148-781). However, seven HIV-positive children had HIV-negative mothers. Transmission in this group was significantly associated with breastfeeding by a non-biological mother (OR: 437; 95%CI: 53-5020), being fed with expressed breast milk from a milk room (OR: 37.6; 95%CI: 6.2-259.0), dental injection history (OR: 31.5; 95%CI: 4.5-189.4) and visits to a dentist (OR: 26.9; 95%CI: 4.4-283.5). Although mother-to-child-transmission is shown to be the primary mode of HIV transmission in South African children, the few HIV-positive children infected by other modes of transmission suggest a potential risk of non-vertical HIV infections. These infections can be prevented through education and improved infection-control procedures.

Lowbury Lecture 2007: infection prevention and control strategies for tuberculosis in developing countries - lessons learnt from Africa.

The World Health Organization ranks South Africa among the top ten of high-burden countries for tuberculosis (TB). The Western Cape Province has the highest prevalence of TB in the country. Studies performed in healthcare facilities both at Tygerberg Hospital and from Kwa-Zulu Natal province indicate a significant risk for nosocomial transmission of tuberculosis. An audit of provision for infection prevention and control (IPC) programmes revealed that although there were adequate supplies of protective clothing, the greatest need was for training and understanding of IPC principles among healthcare workers. In establishing national IPC guidelines for TB in South Africa, it has become evident that most of these were derived from existing guidelines in developed countries. Though the principles were sound, the practices were not realistic for developing economies and generally not implemented in healthcare facilities. Factors that influence a robust TB management programme are poverty, concurrent human immunodeficiency virus infection, overcrowding, ignorance of the disease and a varied level of health service delivery. It is recommended that a foundation of sound knowledge should be established upon which best practices should be built within the framework of good IPC principles.

The antimicrobial activity of copper and copper alloys against nosocomial pathogens and Mycobacterium tuberculosis isolated from healthcare facilities in the Western Cape: an in-vitro study.

Clinical isolates of meticillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Candida albicans and Mycobacterium tuberculosis (MTB) were tested against copper (Cu) and its alloys. Stainless steel and polyvinylchloride (PVC) were used as controls. The amount of Cu required to inhibit test isolates at room temperature (24 degrees C) and at 4 degrees C was determined. At room temperature, Cu, DZR Brass (Cu 62%, Pb 2.5%, arsenate 0.13% and Zn 22.5%) and Brass 70/30 (Cu 70% and zinc 30%) inhibited C. albicans and K. pneumoniae at 60 min; nickel silver (NiAg) inhibited C. albicans at 60 min and K. pneumoniae at 270 min. P. aeruginosa was inhibited by Brass 70/30 and nickel silver (NiAg) at 180 min and at 270 min by Cu and DZR. Cu and DZR inhibited A. baumannii at 180 min while the other alloys were effective at 360 min. Stainless steel and PVC showed little or no inhibitory activity. Two M. tuberculosis strains, one isoniazid resistant (R267) and the other multidrug resistant (R432), demonstrated growth inhibition with Cu of 98% and 88% respectively compared with PVC; the other alloys were less active. Time to positivity (TTP) for R267 was >15 days with Cu and 11 days for the other alloys; with R432 it was 5 days. Effective inhibition of nosocomial pathogens and MTB by Cu and alloys was best when the Cu content was >55%.

Infection control practices in public dental care services: findings from one South African Province.

Infection control practices which increase the risk of blood-borne virus transmission with associated dental practice in one South African province were studied. All 24 state dental clinics were observed for adequate provision to carry out good infection prevention and control (IPC) practice, 75 staff including dentists, nurses and dental assistants were interviewed to assess IPC knowledge and 23 dental procedures were observed. Significant findings were the difference between knowledge and practice, despite adequate provisions for safe infection control practice. The lack of protective eye wear during a dental procedure, not washing hands between patients, not disassembling an item prior to disinfection or sterilization, and not using a sterile drill for each patient were identified. A rapid method for detection of occult blood was used as a marker for inadequate IPC practice. Contaminated dental items of equipment just prior to patient use in 25% of equipment tested and 37% of surfaces and surrounding areas in the dental clinics and units were recorded. This study concludes that, despite provision for safe dental practice available in state dental clinics, there was a lack of knowledge application in clinical practice. The risk of blood-borne virus transmission in a population with high human immunodeficiency virus (HIV) prevalence cannot be ignored.

Unexplained HIV-1 infection in children--documenting cases and assessing for possible risk factors.

BACKGROUND: In the year 2000 we reported possible horizontal transmission of HIV-1 infection between two siblings. An investigation of three families, each with an HIV-infected child but seronegative parents, permitted this finding. Sexual abuse and surrogate breast-feeding were thought unlikely. The children had overlapping hospitalisation in a regional hospital. Since then several cases of unexplained HIV infection in children have been reported. A registry was established at Tygerberg Children's Hospital for collection of data on the extent of horizontal or unexplained transmission of HIV in children. STUDY DESIGN: Retrospective chart review. RESULTS: Fourteen children were identified, 12 from the Western Cape and 1 each from the Eastern Cape and KwaZulu-Natal. Thirteen (92%) had been hospitalised previously. In the Western Cape, children had been hospitalised in 8 hospitals. Ten of 13 (77%) were admitted as neonates and 9 of 13 (69%) had 2 or more admissions. Intravascular cannulation and intravenous drug administration occurred in all but 2 children before HIV diagnosis. CONCLUSION: We have confirmed HIV infection in a number of cases where the source of infection has been inadequately explained. Circumstantial evidence supports but does not prove nosocomial transmission. Further studies and identification of medical procedures conducive to the spread of HIV are urgently needed.

Minimum standards in laboratories for infection control.

Laboratory services should be available to support every infection control programme, whether in a hospital or community setting. The services will depend upon available resources and the expectation of the clinicians using the services. Equally, resources reflect the level of staff expertise, equipment and finances supporting laboratory practice. All information given to the clinical staff should be sensible, accurate, comprehensible and in keeping with the clinical needs of the healthcare setting. Internal and external quality controls should be rigorous. Not all laboratories are expected to provide an all-encompassing service and therefore primary, secondary and tertiary or referral laboratories should be established where necessary. It is essential to have clear protocols on laboratory usage, mutually agreed between the laboratory and clinical staff to be cost effective.

New strategies for the use of mupirocin for the prevention of serious infection.

Nasal mupirocin has an important role to play in the prevention of Staphylococcus aureus infection by eliminating nasal carriage of this organism. Indeed, in many countries nasal mupirocin is one of the mainstays for controlling outbreaks of methicillin-resistant S. aureus. Eradication of nasal S. aureus with mupirocin has been shown to be effective in preventing postoperative infections in patients undergoing cardiothoracic surgery and in preventing exit-site infections in patients undergoing haemodialysis. It has been proposed that the use of mupirocin should be extended to other situations, such as the prevention of postoperative infections in patients undergoing implant surgery and the prevention of bacteraemias in high-risk patients. Clinical trials are needed to establish the efficacy of mupirocin in these situations. Both low-level and high-level resistance have been reported during treatment with nasal mupirocin. Low-level resistance does not represent a significant clinical problem but high-level resistance resulting from indiscriminate use may give grounds for concern. Further review of these issues is required. As with any antibiotic, mupirocin should be used judiciously, as part of an integrated programme of infection control.

A multi-centre study to compare meropenem and cefotaxime and metronidazole in the treatment of hospitalized patients with serious infections.

We conducted a prospective, multi-centre, open, randomized study in 11 UK hospitals to compare iv meropenem 1 g tds with the combination of iv cefotaxime 1 g tds and iv metronidazole 500 mg tds in patients with serious infections. One hundred and sixty-one patients were enrolled, of whom 131 were clinically evaluable (meropenem, n = 68; cefotaxime/metronidazole, n = 63). The most common infections were subsequent to intra-abdominal pathology (meropenem, n = 77%; cefotaxime/metronidazole, n = 75%), and were usually accompanied by septicaemia (meropenem, n = 61%; cefotaxime/metronidazole, n = 53%). The incidence of a satisfactory clinical response was similar in the two groups at the end of treatment (93% for meropenem; 92% for cefotaxime/metronidazole) and up to 8 weeks later (96% for meropenem; 93% for cefotaxime/metronidazole). Satisfactory bacteriological response (success or presumed success) was recorded at the end of therapy in 86% of meropenem and 88% of cefotaxime/metronidazole patients. Adverse events were reported in 32% of meropenem and 25% of cefotaxime/metronidazole patients, and most were mild or moderate and did not require discontinuation of therapy. Twenty-one patients (ten meropenem and 11 cefotaxime/metronidazole) died during the trial, underlining the severity of the infections being treated in this group of patients. None of the deaths was thought to be related to study therapy.

Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae.

Ciprofloxacin-resistant mutants of Streptococcus pneumoniae 7785 were generated by stepwise selection at increasing drug concentrations. Sequence analysis of PCR products from the strains was used to examine the quinolone resistance-determining regions of the GyrA and GyrB proteins of DNA gyrase and the analogous regions of the ParC and ParE subunits of DNA topoisomerase IV. First-step mutants exhibiting low-level resistance had no detectable changes in their topoisomerase quinolone resistance-determining regions, suggesting altered permeation or another novel resistance mechanism. Nine of 10 second-step mutants exhibited an alteration in ParC at Ser-79 to Tyr or Phe or at Ala-84 to Thr. Third- and fourth-step mutants displaying high-level ciprofloxacin resistance were found to have, in addition to the ParC alteration, a change in GyrA at residues equivalent to Escherichia coli GyrA resistance hot spots Ser-83 and Asp-87 or in GyrB at Asp-435 to Asn, equivalent to E. coli Asp-426, part of a highly conserved EGDSA motif in GyrB. No ParE changes were observed. Complementary analysis of two S. pneumoniae clinical isolates displaying low-level resistance to ciprofloxacin revealed a ParC change at Ser-79 to Phe or Arg-95 to Cys but no changes in GyrA, GyrB, or ParE. A highly resistant isolate, in addition to a ParC mutation, had a GyrA alteration at the residue equivalent to E. coli Asp-87. Thus, in both laboratory strains and clinical isolates, ParC mutations preceded those in GyrA, suggesting that topoisomerase IV is a primary topoisomerase target and gyrase is a secondary target for ciprofloxacin in S. pneumoniae.