Triggered Release of Ampicillin from Metallic Implant Coatings for Combating Periprosthetic Infections.

Periprosthetic infections caused by Staphylococcus aureus (S. aureus) pose unique challenges in orthopedic surgeries, in part due to the bacterium's capacity to invade surrounding bone tissues besides forming recalcitrant biofilms on implant surfaces. We previously developed prophylactic implant coatings for the on-demand release of vancomycin, triggered by the cleavage of an oligonucleotide (Oligo) linker by micrococcal nuclease (MN) secreted by the Gram-positive bacterium, to eradicate S. aureus surrounding the implant in vitro and in vivo. Building upon this coating platform, here we explore the feasibility of extending the on-demand release to ampicillin, a broad-spectrum aminopenicillin ß-lactam antibiotic that is more effective than vancomycin in killing Gram-negative bacteria that may accompany S. aureus infections. The amino group of ampicillin was successfully conjugated to the carboxyl end of an MN-sensitive Oligo covalently integrated in a polymethacrylate hydrogel coating applied to titanium alloy pins. The resultant Oligo-Ampicillin hydrogel coating released the ß-lactam in the presence of S. aureus and successfully cleared nearby S. aureus in vitro. When the Oligo-Ampicillin-coated pin was delivered to a rat femoral canal inoculated with 1000 cfu S. aureus, it prevented periprosthetic infection with timely on-demand drug release. The clearance of the bacteria from the pin surface as well as surrounding tissue persisted over 3 months, with no local or systemic toxicity observed with the coating. The negatively charged Oligo fragment attached to ampicillin upon cleavage from the coating did diminish the antibiotic's potency against S. aureus and Escherichia coli (E. coli) to varying degrees, likely due to electrostatic repulsion by the anionic surfaces of the bacteria. Although the on-demand release of the ß-lactam led to adequate killing of S. aureus but not E. coli in the presence of a mixture of the bacteria, strong inhibition of the colonization of the remaining E. coli on hydrogel coating was observed. These findings will inspire considerations of alternative broad-spectrum antibiotics, optimized drug conjugation, and Oligo linker engineering for more effective protection against polymicrobial periprosthetic infections.

Methicillin-Resistant Staphylococcus aureus Carriage among Neonate Mothers, Healthcare Workers, and Environmental Samples in Neonatal Intensive Care Units: A Systematic Review.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of morbidity and mortality among neonates admitted to neonatal intensive care units (NICUs). The MRSA colonization of neonates, attributed to various sources, including mothers, healthcare workers, and environmental surfaces, can lead to severe infection, prolonged hospital stays, and even death, imposing substantial economic burdens. Given the pressing need to mitigate MRSA spread in these vulnerable environments, further examination of the subject is warranted. This systematic review is aimed at synthesizing available evidence on MRSA carriage proportions among mothers of newborns, healthcare workers, and environmental surfaces in NICUs. Methodology. We included observational studies published in English or French from database inception to March 21, 2023. These studies focused on MRSA in nonoutbreak NICU settings, encompassing healthy neonate mothers and healthcare workers, and environmental surfaces. Literature search involved systematic scanning of databases, including Medline, Embase, Web of Science, Global Health, and Global Index Medicus. The quality of the selected studies was assessed using the Hoy et al. critical appraisal scale. The extracted data were summarized to calculate the pooled proportion of MRSA positives, with a 95% confidence interval (CI) based on the DerSimonian and Laird random-effects model. Results: A total of 1891 articles were retrieved from which 16 studies were selected for inclusion. Most of the studies were from high-income countries. The pooled proportion of MRSA carriage among 821 neonate mothers across four countries was found to be 2.1% (95% CI: 0.3-5.1; I2 = 76.6%, 95% CI: 36.1-91.5). The proportion of MRSA carriage among 909 HCWs in eight countries was determined to be 9.5% (95% CI: 3.1-18.4; I2 = 91.7%, 95% CI: 87.1-94.6). The proportion of MRSA carriage among HCWs was highest in the Western Pacific Region, at 50.00% (95% CI: 23.71-76.29). In environmental specimens from five countries, a pooled proportion of 16.6% (95% CI: 3.5-36.0; I2 = 97.7%, 95% CI: 96.6-98.4) was found to be MRSA-positive. Conclusion: With a significant heterogeneity, our systematic review found high MRSA carriage rates in neonate mothers, healthcare workers, and across various environmental surfaces in NICUs, posing a potential risk of nosocomial infections. Urgent interventions, including regular screening and decolonization of MRSA carriers, reinforcing infection control measures, and enhancing cleaning and disinfection procedures within NICUs, are crucial. This trial is registered with CRD42023407114.

Feasibility of using a combination of staphylococcal superantigen-like proteins 3, 7 and 11 in a fusion vaccine for Staphylococcus aureus.

Staphylococcus aureus is a significant bacterial pathogen in both community and hospital settings, and the escalation of antimicrobial-resistant strains is of immense global concern. Vaccination is an inviting long-term strategy to curb staphylococcal disease, but identification of an effective vaccine has proved to be challenging. Three well-characterized, ubiquitous, secreted immune evasion factors from the staphylococcal superantigen-like (SSL) protein family were selected for the development of a vaccine. Wild-type SSL3, 7 and 11, which inhibit signaling through Toll-like receptor 2, cleavage of complement component 5 and neutrophil function, respectively, were successfully combined into a stable, active fusion protein (PolySSL7311). Vaccination of mice with an attenuated form of the PolySSL7311 protein stimulated significantly elevated specific immunoglobulin G and splenocyte proliferation responses to each component relative to adjuvant-only controls. Vaccination with PolySSL7311, but not a mixture of the individual proteins, led to a > 102 reduction in S. aureus tissue burden compared with controls after peritoneal challenge. Comparable antibody responses were elicited after coadministration of the vaccine in either AddaVax (an analog of MF59) or an Alum-based adjuvant; but only AddaVax conferred a significant reduction in bacterial load, aligning with other studies that suggest both cellular and humoral immune responses are necessary for protective immunity to S. aureus. Anti-sera from mice immunized with PolySSL7311, but not individual proteins, partially neutralized the functional activities of SSL7. This study confirms the importance of these SSLs for the survival of S. aureus in vivo and suggests that PolySSL7311 is a promising vaccine candidate.

Preventing Staphylococci Surgical Site Infections with a Nitric Oxide-Releasing Poly(lactic acid-co-glycolic acid) Suture Material.

Of the 27 million surgeries performed in the United States each year, a reported 2.6% result in a surgical site infection (SSI), and Staphylococci species are commonly the culprit. Alternative therapies, such as nitric oxide (NO)-releasing biomaterials, are being developed to address this issue. NO is a potent antimicrobial agent with several modes of action, including oxidative and nitrosative damage, disruption of bacterial membranes, and dispersion of biofilms. For targeted antibacterial effects, NO is delivered by exogenous donor molecules, like S-nitroso-N-acetylpenicillamine (SNAP). Herein, the impregnation of SNAP into poly(lactic-co-glycolic acid) (PLGA) for SSI prevention is reported for the first time. The NO-releasing PLGA copolymer is fabricated and characterized by donor molecule loading, leaching, and the amount remaining after ethylene oxide sterilization. The swelling ratio, water uptake, static water contact angle, and tensile strength are also investigated. Furthermore, its cytocompatibility is tested against 3T3 mouse fibroblast cells, and its antimicrobial efficacy is assessed against multiple Staphylococci strains. Overall, the NO-releasing PLGA copolymer holds promise as a suture material for eradicating surgical site infections caused by Staphylococci strains. SNAP impregnation affords robust antibacterial properties while maintaining the cytocompatibility and mechanical integrity.

A comprehensive synthetic library of poly-N-acetyl glucosamines enabled vaccine against lethal challenges of Staphylococcus aureus.

Poly-ß-(1-6)-N-acetylglucosamine (PNAG) is an important vaccine target, expressed on many pathogens. A critical hurdle in developing PNAG based vaccine is that the impacts of the number and the position of free amine vs N-acetylation on its antigenicity are not well understood. In this work, a divergent strategy is developed to synthesize a comprehensive library of 32 PNAG pentasaccharides. This library enables the identification of PNAG sequences with specific patterns of free amines as epitopes for vaccines against Staphylococcus aureus (S. aureus), an important human pathogen. Active vaccination with the conjugate of discovered PNAG epitope with mutant bacteriophage Qß as a vaccine carrier as well as passive vaccination with diluted rabbit antisera provides mice with near complete protection against infections by S. aureus including methicillin-resistant S. aureus (MRSA). Thus, the comprehensive PNAG pentasaccharide library is an exciting tool to empower the design of next generation vaccines.

Catheter salvage or removal in catheter-related bloodstream infections with Staphylococcus aureus in children with chronic intestinal failure receiving home parenteral nutrition and the use of prophylactic taurolidine catheter lock solution: A descriptive cohort study.

BACKGROUND: Children with chronic IF require long-term home parenteral nutrition (HPN), administered through a central venous catheter. Catheter-related bloodstream infection (CRBSI) with Staphylococcus aureus is known to be a serious infection with a high mortality rate and risk of complications. A standardized protocol on the management of S aureus CRBSIs in children receiving HPN is lacking. The aim of this study is to evaluate the effectiveness and safety of the current management in an HPN expertise center in the Netherlands. METHODS: We performed a retrospective descriptive cohort study between 2013 and 2022 on children 0-18 years of age with chronic IF requiring long-term HPN. Our primary outcomes were the incidence of S aureus CRBSI per 1000 catheter days, catheter salvage attempt rate, and successful catheter salvage rate. Our secondary outcomes included complications and mortality. RESULTS: A total of 74 patients (39 male; 53%) were included, covering 327.8 catheter years. Twenty-eight patients (38%) had a total of 52 S aureus CRBSIs, with an incidence rate of 0.4 per 1000 catheter days. The catheter salvage attempt rate was 44% (23/52). The successful catheter salvage rate was 100%. No relapse occurred, and no removal was needed after catheter salvage. All complications that occurred were already present at admission before the decision to remove the catheter or not. No patients died because of an S aureus CRBSI. CONCLUSION: Catheter salvage in S aureus CRBSIs in children receiving HPN can be attempted after careful consideration by a multidisciplinary team in an HPN expertise center.

FacZ is a GpsB-interacting protein that prevents aberrant division-site placement in Staphylococcus aureus.

Staphylococcus aureus is a Gram-positive pathogen responsible for antibiotic-resistant infections. To identify vulnerabilities in cell envelope biogenesis that may overcome resistance, we enriched for S. aureus transposon mutants with defects in cell surface integrity or cell division by sorting for cells that stain with propidium iodide or have increased light-scattering properties, respectively. Transposon sequencing of the sorted populations identified more than 20 previously uncharacterized factors impacting these processes. Cells inactivated for one of these proteins, factor preventing extra Z-rings (FacZ, SAOUHSC_01855), showed aberrant membrane invaginations and multiple FtsZ cytokinetic rings. These phenotypes were suppressed in mutants lacking the conserved cell-division protein GpsB, which forms an interaction hub bridging envelope biogenesis factors with the cytokinetic ring in S. aureus. FacZ was found to interact directly with GpsB in vitro and in vivo. We therefore propose that FacZ is an envelope biogenesis factor that antagonizes GpsB function to prevent aberrant division events in S. aureus.

Dose regimen optimization of cephalothin for surgical prophylaxis against Staphylococcus aureus and coagulase negative staphylococci in dogs by pharmacokinetic/pharmacodynamic modeling.

First generation cephalosporins such cephalothin of cefazolin are indicated for antimicrobial prophylaxis for clean and clean contaminated surgical procedures because its antimicrobial spectrum, relative low toxicity and cost. Anesthesia and surgery could alter the pharmacokinetic behavior of different drugs administered perioperative by many mechanisms that affect distribution, metabolism or excretion processes. Intravenous administration of the antimicrobial within 30 and 60 min before incision is recommended in order to reach therapeutic serum and tissue concentrations and redosing is recommended if the duration of the procedure exceeds two half-life of the antimicrobial. To the author's knowledge there are no pharmacokinetic studies of cephalothin in dogs under anesthesia/surgery conditions. The aim of this study was (1) to evaluate the pharmacokinetics of cephalothin in anesthetized dogs undergoing ovariohysterectomy by a nonlinear mixed-effects model and to determine the effect of anesthesia/surgery and other individual covariates on its pharmacokinetic behavior; (2) to determine the MIC and conduct a pharmacodynamic modeling of time kill curves assay of cephalothin against isolates of Staphylococcus spp. isolated from the skin of dogs; (3) to conduct a PK/PD analysis by integration of the obtained nonlinear mixed-effects models in order to evaluate the antimicrobial effect of changing concentrations on simulated bacterial count; and (4) to determine the PK/PD endpoints and PK/PDco values in order to predict the optimal dose regimen of cephalothin for antimicrobial prophylaxis in dogs. Anesthesia/surgery significantly reduced cephalothin clearance by 18.78%. Based on the results of this study, a cephalothin dose regimen of 25 mg/kg q6h by intravenous administration showed to be effective against Staphylococcus spp. isolates with MIC values ≤2 µg/mL and could be recommended for antimicrobial prophylaxis for clean surgery in healthy dogs.

An overview of risk factors, management and prevention of cochlear implant infections.

PURPOSE OF REVIEW: With cochlear implantation becoming increasingly performed worldwide, an understanding of the risk factors, preventive measures, and management of cochlear implant (CI) infection remains important given the significant morbidity and cost it conveys. RECENT FINDINGS: At the turn of the 21st century there was a decrease in rates of CI infection, particularly meningitis, following the discontinuation of positioner use for CI. However, in more recent years rates of CI infection have remained largely static. Recently, studies evaluating preventive measures such as pneumococcal vaccination, S. aureus decolonization and surgical antibiotic prophylaxis have emerged in the literature. SUMMARY: Prompt recognition of CI infection and appropriate investigation and management are key, however at present treatment is largely informed by cohort and case-control studies and expert opinion. Preventive measures including pneumococcal vaccination, S. aureus decolonization and preoperative antibiotic prophylaxis play a role in reducing rates of CI infection. However, there remains a need for well designed clinical trials to provide higher level evidence to better guide preventive measures for, and management decisions of, CI infections in the future.

Impact of active surveillance and decolonization strategies for methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit.

OBJECTIVE: To assess the impact of active surveillance and decolonization strategies on methicillin-resistant Staphylococcus aureus (MRSA) infection rates in a NICU. STUDY DESIGN: MRSA infection rates were compared before (2014-2016) and during (2017-2022) an active surveillance program. Eligible infants were decolonized with chlorohexidine gluconate (CHG) bathing and/or topical mupirocin. Successful decolonization and rates of recolonization were assessed. RESULTS: Fifty-two (0.57%) of 9 100 hospitalized infants had invasive MRSA infections from 2014 to 2022; infection rates declined non-significantly. During the 6-year surveillance program, the risk of infection was 16.9-times [CI95 8.4, 34.1] higher in colonized infants than uncolonized infants. Those colonized with mupirocin-susceptible MRSA were more likely successfully decolonized (aOR 9.7 [CI95 4.2, 22.5]). Of 57 infants successfully decolonized who remained hospitalized, 34 (60%) became recolonized. CONCLUSIONS: MRSA infection rates did not significantly decline in association with an active surveillance and decolonization program. Alternatives to mupirocin and CHG are needed to facilitate decolonization.

In nursing homes, universal decolonization vs. routine care reduced transfers to hospital for infection.

SOURCE CITATION: Miller LG, McKinnell JA, Singh RD, et al. Decolonization in nursing homes to prevent infection and hospitalization. N Engl J Med. 2023;389:1766-1777. 37815935.

Should Contact Precautions Be Used for Patients with MRSA Infection and Colonization in Acute Care Settings?

Are Contact Precautions for Patients with MRSA Useful?MRSA infections lead to substantial morbidity and mortality. Hospitals commonly implement "contact precautions" to reduce MRSA transmission; however, recent studies have challenged the effectiveness of this strategy, and the use of contact precautions has been associated with certain adverse events. This article reviews the existing evidence and proposes a randomized trial to assess the efficacy of contact precautions in preventing MRSA transmission.

Isolation and encapsulation of bacteriophage with chitosan nanoparticles for biocontrol of multidrug-resistant methicillin-resistant Staphylococcus aureus isolated from broiler poultry farms.

This study was divided into two parts. The first part, the determination of methicillin-resistant Staphylococcus aureus (MRSA) prevalence in 25 broiler chicken farms, with the detection of multidrug resistant MRSA strains. The prevalence of MRSA was 31.8% (159 out of 500 samples) at the level of birds and it was 27% (27 out of 100) in the environmental samples. The highest antimicrobial resistance of the recovered MRSA strains was recorded to streptomycin (96%). All isolates (100%) had multidrug resistance (MDR) to four or more antibiotics with 16 distinct antibiotic resistant patterns, and multiple antibiotic resistance index (MARI) of 0.4-1. The second part, implementing novel biocontrol method for the isolated multidrug resistant MRSA strains through the isolation of its specific phage and detection of its survival rate at different pH and temperature degrees and lytic activity with and without encapsulation by chitosan nanoparticles (CS-NPs). Encapsulated and non-encapsulated MRSA phages were characterized using transmission electron microscope (TEM). Encapsulation of MRSA phage with CS-NPs increasing its lytic activity and its resistance to adverse conditions from pH and temperature. The findings of this study suggested that CS-NPs act as a protective barrier for MRSA phage for the control of multidrug resistant MRSA in broiler chicken farms.

MRSA throat carriage in two healthcare workers. / MRSA-halsbærerskap hos to helsearbeidere.

Background: Healthcare workers colonised with methicillin-resistant Staphylococcus aureus (MRSA) experience negative consequences due to work restrictions, long-term sick leave, stigmatisation, eradication failures and psychosocial stress. Throat colonisation is associated with prolonged carriage and non-successful treatment. Case presentation: We describe two Norwegian healthcare students with persistent MRSA throat carriage. After several eradication failures, MRSA eradication was successful only after tonsillectomy. Interpretation: Tonsillectomy is not the solution for persistent MRSA throat carriage in healthcare workers. However, their stories illustrate the challenges they faced during repeated eradication attempts. They suffered considerable psychological stress due to the risk of study disruption and limited career options. The impact of laws and strict guidelines for MRSA-colonised healthcare workers, needs to be re-assessed in order to reduce transmission. We argue that healthcare workers without individual risk factors should be able to work in units considered to pose no risk as long as they undergo individual training in basic infection control measures.

Factors associated with patient-to-healthcare personnel (HCP) and HCP-to-subsequent patient transmission of methicillin-resistant Staphylococcus aureus.

BACKGROUND: Transient acquisition of methicillin-resistant Staphylococcus aureus (MRSA) on healthcare personnel (HCP) gloves and gowns following patient care has been examined. However, the potential for transmission to the subsequent patient has not been studied. We explored the frequency of MRSA transmission from patient to HCP, and then in separate encounters from contaminated HCP gloves and gowns to a subsequent simulated patient as well as the factors associated with these 2 transmission pathways. METHODS: We conducted a prospective cohort study with 2 parts. In objective 1, we studied MRSA transmission from random MRSA-positive patients to HCP gloves and gowns after specific routine patient care activities. In objective 2, we simulated subsequent transmission from random HCP gloves and gowns without hand hygiene to the next patient using a manikin proxy. RESULTS: For the first objective, among 98 MRSA-positive patients with 333 randomly selected individual patient-HCP interactions, HCP gloves or gowns were contaminated in 54 interactions (16.2%). In a multivariable analysis, performing endotracheal tube care had the greatest odds of glove or gown contamination (OR, 4.06; 95% CI, 1.3-12.6 relative to physical examination). For the second objective, after 147 simulated HCP-patient interactions, the subsequent transmission of MRSA to the manikin proxy occurred 15 times (10.2%). CONCLUSION: After caring for a patient with MRSA, contamination of HCP gloves and gown and transmission to subsequent patients following HCP-patient interactions occurs frequently if contact precautions are not used. Proper infection control practices, including the use of gloves and gown, can prevent this potential subsequent transmission.

Efficacy of novel staphylococcal surface associated protein vaccines against Staphylococcus aureus and non-aureus staphylococcal mastitis in dairy cows.

Mastitis is an inflammation of the mammary gland commonly caused by bacteria or fungi. Staphylococcus aureus is a major bacterium that causes mastitis in dairy cows. Non-aureus staphylococci are also increasingly reported, with Staphylococcus chromogenes being the most common species. Current staphylococcal mastitis control programs are not fully effective, and treatment with antibiotics is not sustainable. Non-antibiotic sustainable control tools, such as effective vaccines, are critically needed. We previously developed S. aureus surface-associated proteins (SASP) and S. chromogenes surface-associated proteins (SCSP) vaccines that conferred partial protective effects. We hypothesized that vaccination with SASP or SCSP would reduce the incidence of S. aureus mastitis throughout the lactation period. The objective of this study was to evaluate the efficacy of SASP and SCSP vaccines against S. aureus and non-aureus staphylococcal mastitis under natural exposure over 300 days of lactation. Pregnant Holstein dairy cows (n = 45) were enrolled and assigned to receive SASP (n = 15) or SCSP (n = 16) vaccines or unvaccinated control (n = 14). Cows were vaccinated with 1.2 mg of SASP or SCSP with Emulsigen-D adjuvant. Control cows were injected with phosphate-buffered saline with Emulsigen-D adjuvant. Three vaccine injections were given subcutaneously at 60, 40, and 20 days before the expected calving. Booster vaccinations were given at 120 and 240 days in milk. Cows were monitored for mastitis at quarter and cow levels, staphylococcal mastitis incidence, changes in serum and milk anti-SASP and anti-SCSP antibody titers, bacterial counts in milk, adverse reactions, milk yield and milk somatic cells count over 300 days of lactation. The SCSP vaccine conferred a significant reduction in the incidence of staphylococcal mastitis. Milk and serum anti-SASP and anti-SCSP antibody titers were increased in the vaccinated cows compared to unvaccinated control cows. Anti-SASP and anti-SCSP antibody titers decreased at about 120 days in milk, indicating the duration of immunity of about four months. In conclusion, the SASP and SCSP vaccines conferred partial protection from natural infection.