Treatment Strategies of Colistin Resistance Acinetobacter baumannii Infections.

Acinetobacter baumannii has emerged as a pressing challenge in clinical practice, mainly due to the development of resistance to multiple antibiotics, including colistin, one of the last-resort treatments. This review highlights all the possible mechanisms of colistin resistance and the genetic basis contributing to this resistance, such as modifications to lipopolysaccharide or lipid A structures, alterations in outer membrane permeability via porins and heteroresistance. In light of this escalating threat, the review also evaluates available treatment options. The development of new antibiotics (cefiderocol, sulbactam/durlobactam) although not available everywhere, and the use of various combinations and synergistic drug combinations (including two or more of the following: a polymyxin, ampicillin/sulbactam, carbapenems, fosfomycin, tigecycline/minocycline, a rifamycin, and aminoglycosides) are discussed in the context of overcoming colistin resistance of A. baumannii infections. Although most studied combinations are polymyxin-based combinations, non-polymyxin-based combinations have been emerging as promising options. However, clinical data remain limited and continued investigation is essential to determine optimal therapeutic strategies against colistin-resistant A. baumannii.

Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia: a systematic review and meta-analysis.

BACKGROUND: Cefiderocol is a last resort option for carbapenem-resistant (CR) Gram-negative bacteria, especially metallo-ß-lactamase-producing Pseudomonas aeruginosa and CR Acinetobacter baumannii. Monitoring global levels of cefiderocol non-susceptibility (CFDC-NS) is important. OBJECTIVES: To systematically collate and examine studies investigating in vitro CFDC-NS and estimate the global prevalence of CFDC-NS against major Gram-negative pathogens. DATA SOURCES: PubMed and Scopus, up to May 2023. STUDY ELIGIBILITY CRITERIA: Eligible were studies reporting CFDC-NS in Enterobacterales, P. aeruginosa, A. baumannii, or Stenotrophomonas maltophilia clinical isolates. RISK-OF-BIAS ASSESSMENT: Two independent reviewers extracted study data and assessed the risk of bias on the population, setting, and measurement (susceptibility testing) domains. DATA SYNTHESIS: Binomial-Normal mixed-effects models were applied to estimate CFDC-NS prevalence by species, coresistance phenotype, and breakpoint definition (EUCAST, CLSI, and FDA). Sources of heterogeneity were investigated by subgroup and meta-regression analyses. RESULTS: In all, 78 studies reporting 82 035 clinical isolates were analysed (87% published between 2020 and 2023). CFDC-NS prevalence (EUCAST breakpoints) was low overall but varied by species (S. maltophilia 0.4% [95% CI 0.2-0.7%], Enterobacterales 3.0% [95% CI 1.5-6.0%], P. aeruginosa 1.4% [95% CI 0.5-4.0%]) and was highest for A. baumannii (8.8%, 95% CI 4.9-15.2%). CFDC-NS was much higher in CR Enterobacterales (12.4%, 95% CI 7.3-20.0%) and CR A. baumannii (13.2%, 95% CI 7.8-21.5%), but relatively low for CR P. aeruginosa (3.5%, 95% CI 1.6-7.8%). CFDC-NS was exceedingly high in New Delhi metallo-ß-lactamase-producing Enterobacterales (38.8%, 95% CI 22.6-58.0%), New Delhi metallo-ß-lactamase-producing A. baumannii (44.7%, 95% CI 34.5-55.4%), and ceftazidime/avibactam-resistant Enterobacterales (36.6%, 95% CI 22.7-53.1%). CFDC-NS varied considerably with breakpoint definition, predominantly among CR bacteria. Additional sources of heterogeneity were single-centre investigations and geographical regions. CONCLUSIONS: CFDC-NS prevalence is low overall, but alarmingly high for specific CR phenotypes circulating in some institutions or regions. Continuous surveillance and updating of global CFDC-NS estimates are imperative while cefiderocol is increasingly introduced into clinical practice. The need to harmonize EUCAST and CLSI breakpoints was evident.

Daptomycin as an option for lock therapy: a systematic literature review.

Aim: To review preclinical and clinical data relevant to daptomycin lock therapy in catheter-related bloodstream infection (CRBSI). Methods: Systematic review in PubMed, Scopus and clinical trial registries. Results: Preclinical data demonstrate daptomycin lock solution stability and compatibility with heparin, good biofilm penetration, bactericidal activity against biofilm-embedded bacteria, and high efficacy in vitro and in animal catheter infection models. Clinical data remain limited (two case reports and five case series totaling n = 65 CRBSI episodes), albeit promising (successful catheter salvage in about 80% of cases). Conclusion: Despite theoretical advantages of daptomycin, clinical data remain scarce. Comparative studies versus alternative lock solutions are needed, as well as studies to define optimal daptomycin lock regimen (including optimal concentration, dwell time and lock duration).

Some patients, such as those needing cancer treatments, kidney dialysis or to be fed through a vein, need long-term access to central veins by a tube called a catheter. These central venous catheters can often become infected and will need to be removed and replaced. Sometimes, the catheter can be saved by 'locking' the tube with a solution to kill any germs. In this review, we discuss the potential to use an antibiotic called daptomycin as the solution in lock therapy. Available data are reviewed and advantages over alternative antimicrobial lock solutions are discussed. Finally, directions for future research are proposed.

A Retrospective Study of Staphylococcus aureus Bacteremia in a Tertiary Hospital and Factors Associated with Mortality.

Staphylococcus aureus bacteremia (SAB) is a severe infection frequently associated with significant morbidity and mortality. Recent studies have shown that SAB mortality has decreased during the last decades. However, about 25% of patients suffering from the disease will ultimately die. Hence, there is an urgent need for more timely and efficient treatment of patients with SAB. The aim of the present study was to retrospectively evaluate a cohort of SAB patients hospitalized in a tertiary hospital and to identify factors independently associated with mortality. All 256 SAB patients hospitalized from January 2005 to December 2021 in the University Hospital of Heraklion, Greece, were evaluated. Their median age was 72 years, while 101 (39.5%) were female. Most SAB patients were cared for in medical wards (80.5%). The infection was community-acquired in 49.5%. Among all strains 37.9% were methicillin-resistant S. aureus (MRSA), however, definite treatment with an antistaphylococcal penicillin was given only in 22% of patients. Only 14.4% of patients had a repeat blood culture after the initiation of antimicrobial treatment. Infective endocarditis was present in 8%. In-hospital mortality has reached 15.9%. Female gender, older age, higher McCabe score, previous antimicrobial use, presence of a central venous catheter, neutropenia, severe sepsis, septic shock, and MRSA SAB were positively associated with in-hospital mortality, while monomicrobial bacteremia was negatively associated. The multivariate logistic regression model identified only severe sepsis (p = 0.05, odds ratio = 12.294) and septic shock (p = 0.007, odds ratio 57.18) to be independently positively associated with in-hospital mortality. The evaluation revealed high rates of inappropriate empirical antimicrobial treatment and non-adherence to guidelines, as shown, by the lack of repeat blood cultures. These data underline the urgent need for interventions with antimicrobial stewardship, increased involvement of infectious diseases physicians, educational sessions, and creation and implementation of local guidelines for improvement of the necessary steps for timely and efficient SAB treatment. Optimization of diagnostic techniques is needed to overcome challenges such as heteroresistance that may affect treatment. Clinicians should be aware of the factors associated with mortality in patients with SAB to identify those who are at a higher risk and optimize medical management.

A Point Prevalence Survey of Healthcare-Associated Infections and Antimicrobial Use in Public Acute Care Hospitals in Crete, Greece.

BACKGROUND: Both healthcare-associated infections (HAIs) and antimicrobial resistance are associated with an increased length of stay and hospital costs, while they have also been linked to high morbidity and mortality rates. In 2016 and 2017, the latest point prevalence survey (PPS) of HAIs and antimicrobial use in European acute care hospitals highlighted an HAI prevalence of 6.5%, while Greece had a higher HAI prevalence of 10%. The aim of this PPS was to record the prevalence of HAIs and antimicrobial use in all eight public acute care hospitals in Crete, Greece during the COVID-19 pandemic in order to highlight the types of infections and antimicrobial practices that need to be prioritized for infection control initiatives. METHODS: The PPS was conducted between 30 March and 15 April 2022, according to the ECDC standardized relevant protocol (version 5.3). Statistics were extracted using the ECDC Helics.Win.Net application (software version 4.1.0). RESULTS: A total of 1188 patients were included. The overall point prevalence of patients with at least one HAI was 10.6%. The most frequent types of infections were pneumonia (34.3%), bloodstream infections (10.5%), systemic infections and urinary tract infections (10.5% and 9.1%, respectively). In 14 (12.4%) cases, the pathogen responsible for HAI was SARS-CoV-2 following onsite spread, accounting for almost 10% of all HAIs. Microorganisms were identified in 60.1% of HAIs. Antimicrobials were administered in 711 (59.8%) patients, with 1.59 antimicrobials used per patient. CONCLUSION: The prevalence of HAI and antimicrobial use among hospitalized patients in Crete, Greece was similar to the national HAI prevalence in 2016 despite the enormous pressure on public hospitals due to the COVID-19 pandemic. Nevertheless, both HAI prevalence and antimicrobial use remain high, underlining the need to implement adequate infection control and antimicrobial stewardship interventions.

Co-isolates of Acinetobacter baumannii complex in polymicrobial infections: a meta-analysis.

Background. Acinetobacter baumannii complex (ABC) infections are commonly polymicrobial. Examining which pathogens are most commonly co-isolated with ABC is an important first step for assessing disease potential due to pathogen-pathogen interactions. Methods. Based on a systematic search of PubMed, Scopus and CENTRAL, we estimated percent proportions of co-isolates in polymicrobial pulmonary and bloodstream ABC infections using random-effects meta-analysis. Results: Twenty-eight eligible studies were analysed reporting 575 polymicrobial bloodstream and 290 polymicrobial pulmonary infections. Common co-isolates in pulmonary infections were P. aeruginosa (36%, 95% CI 24-49%, I2 71%), S. aureus (28%, 95% CI 19-38%, I2 44%) and Klebsiella spp. (11%, 95% CI 6-20 %, I2 56%), while the prevalence of other co-pathogens did not exceed 5%. Most common co-isolates in bloodstream infections were coagulase-negative Staphylococci (21%, 95% CI 12-34 %, I2 84%), Enterococci (15%, 95% CI 9-26%, I2 73%), P. aeruginosa (12%, 95% CI 6-22%, I2 74%), Klebsiella spp. (10%, 95% CI 6-16%, I2 42%), Enterobacter spp. (10%, 95% CI 6-16 %, I2 38%) and S. aureus (8%, 95% CI 4-15%, I2 58%). Conclusion: The common co-isolation of certain pathogens (especially P. aeruginosa ) with ABC suggests potential beneficial between-pathogen interactions, which may have treatment implications for polymicrobial infections and requires further study.

Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance.

Cefiderocol appears promising, as it can overcome most ß-lactam resistance mechanisms (including ß-lactamases, porin mutations, and efflux pumps). Resistance is uncommon according to large multinational cohorts, including against isolates resistant to carbapenems, ceftazidime/avibactam, ceftolozane/tazobactam, and colistin. However, alarming proportions of resistance have been reported in some recent cohorts (up to 50%). A systematic review was conducted in PubMed and Scopus from inception to May 2022 to review mechanisms of resistance, prevalence of heteroresistance, and in vivo emergence of resistance to cefiderocol during treatment. A variety of mechanisms, typically acting in concert, have been reported to confer resistance to cefiderocol: ß-lactamases (especially NDM, KPC and AmpC variants conferring resistance to ceftazidime/avibactam, OXA-427, and PER- and SHV-type ESBLs), porin mutations, and mutations affecting siderophore receptors, efflux pumps, and target (PBP-3) modifications. Coexpression of multiple ß-lactamases, often in combination with permeability defects, appears to be the main mechanism of resistance. Heteroresistance is highly prevalent (especially in A. baumannii), but its clinical impact is unclear, considering that in vivo emergence of resistance appears to be low in clinical studies. Nevertheless, cases of in vivo emerging cefiderocol resistance are increasingly being reported. Continued surveillance of cefiderocol's activity is important as this agent is introduced in clinical practice.

Editorial for the Special Issue: "Epidemiology, Prognosis and Antimicrobial Treatment of Extensively Antibiotic-Resistant Bacterial Infections".

The increasing consumption of broad-spectrum antimicrobials is fuelling a vicious cycle leading to extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria [...].

Importance of antimicrobial stewardship in solid organ transplant recipients: An ESCMID perspective.

BACKGROUND: In the last decades, solid organ transplantation (SOT) has emerged as an important method in the management of chronic kidney, liver, heart, and lung failure. Antimicrobial use has led to a significant reduction of morbidity and mortality due to infectious complications among patients with SOT; however, it can lead to adverse events and drive the development of antimicrobial resistance; thus, antimicrobial stewardship is of extreme importance. Even though there are ongoing efforts of transplant societies to implement principles of antimicrobial stewardship in everyday practice in SOT, there is still a lack of guidelines in this patient population. AIM: The aim of this study was to review the status of antimicrobial stewardship in patients with SOT, highlight its importance from the perspective of an ongoing vivid dialogue among ESCMID experts in the field of antimicrobial stewardship, and depict opportunities for future study in the field. REVIEW: Antimicrobial stewardship programs are important in order to allow appropriate initiation and termination of antimicrobials in SOT recipients, and also aid in the most appropriate dosing and choosing of the route of administration of antimicrobials. Application of already known antimicrobial stewardship principles and application of currently used biomarkers and newly developed molecular rapid diagnostic testing tools can aid to the rationalization of antimicrobial prescribing and to a more targeted treatment of infections. Finally, physicians caring for SOT recipients should be actively involved in antimicrobial stewardship in order to assure optimization of antimicrobial prescribing and become familiar with the principles of antimicrobial stewardship.

In search for a synergistic combination against pandrug-resistant A. baumannii; methodological considerations.

PURPOSE: Pending approval of new antimicrobials, synergistic combinations are the only treatment option against pandrug-resistant A. baumannii (PDRAB). Considering the lack of a standardized methodology, the aim of this manuscript is to systematically review the methodology and discuss unique considerations for assessing antimicrobial combinations against PDRAB. METHODS: Post-hoc analysis of a systematic review (conducted in PubMed and Scopus from inception to April 2021) of studies evaluating antimicrobial combination against A. baumannii, based on antimicrobials that are inactive in vitro alone. RESULTS: Eighty-four publications were reviewed, using a variety of synergy testing methods, including; gradient-based methods (n = 11), disk-based methods (n = 6), agar dilution (n = 2), checkerboard assay (n = 44), time-kill assay (n = 50), dynamic in vitro PK/PD models (n = 6), semi-mechanistic PK/PD models (n = 5), and in vivo animal models (n = 11). Several variations in definitions of synergy and interpretation of each method were observed and are discussed. Challenges related to testing combinations of antimicrobials that are inactive alone (with regards to concentrations at which the combinations are assessed), as well as other considerations (assessment of stasis vs killing, clinical relevance of re-growth in vitro after initial killing, role of in vitro vs in vivo conditions, challenges of clinical testing of antimicrobial combinations against PDRAB infections) are discussed. CONCLUSION: This review demonstrates the need for consensus on a standardized methodology and clinically relevant definitions for synergy. Modifications in the methodology and definitions of synergy as well as a roadmap for further development of antimicrobial combinations against PDRAB are proposed.

Actinotignum schaalii infection - a case series from a tertiary hospital in Greece.

Introduction: Actinotignum schaalii is a small Gram-positive facultative anaerobic coccoid rod that was reclassified in 1997 from the genus Actinomyces and is difficult to culture with usual microbiological techniques, as it is slowly growing. A. schaalii is an emerging human pathogen that is most commonly implicated in urinary tract infections (UTIs), but has also been isolated less frequently from abscesses of various sites (such as the skin, the genitourinary tract, surgical sites or intraabdominal). Methods: All cases where A. schaalii was identified during a 6-year period (January 2016 - January 2022) in the University Hospital of Heraklion were reviewed. Results: A. schaalii was isolated in 11 cultures from 10 patients. The site of infection was skin and soft tissue in nine out of eleven cultures (81.8%) and the bone was the site of infection in two patients (18.2%). Most cultures were polymicrobial. The median age of patients was 55.5 years (interquartile range 34-63 years), and 80% (n=8) were male. A. schaalii was susceptible to beta-lactams, quinolones and vancomycin, but resistant to clindamycin, erythromycin and metronidazole. Moreover, two cases of diabetic patients diagnosed with polymicrobial diabetic foot osteomyelitis from this organism are presented in detail. Both patients were successfully managed with targeted antimicrobial treatment and prompt surgical management. Conclusions: A. schaalii is an emerging pathogen that is likely under-reported due to difficulties in isolation and identification. Herein two cases of diabetic foot osteomyelitis are also presented in detail, successfully managed with targeted antimicrobial therapy and surgical debridement.

Indications for medical antibiotic prophylaxis and potential targets for antimicrobial stewardship intervention: a narrative review.

BACKGROUND: Most of the antimicrobial stewardship (AMS) literature has focused on antimicrobial consumption for the treatment of infections, for the prophylaxis of surgical site infection and for the prevention of endocarditis. The role of AMS for medical antibiotic prophylaxis (AP) has not been adequately addressed. AIMS: To identify targets for AMS interventions for medical AP in adult patients. SOURCES: Targeted searches were conducted in PubMed. CONTENT: The various indications for medical AP and relevant evidence from practice guidelines are outlined. The following were identified as potential targets for AMS interventions: (a) addressing under-utilization of antibiotic-sparing strategies (e.g. for recurrent urinary tract infections, recurrent soft-tissue infections, recurrent exacerbations associated with bronchiectasis or chronic obstructive pulmonary disease), (b) reducing unnecessary AP beyond recommended indications (e.g. for acute pancreatitis, bite wounds, or urinary catheter manipulations), (c) reducing the use of AP with a broader spectrum than necessary, (d) reducing the use of AP for longer than the recommended duration (e.g. AP for prevention of osteomyelitis in open fractures or AP in high-risk neutropenia), (e) evaluating the role of antibiotic cycling to prevent the emergence of resistance during prolonged AP (e.g. in recurrent urinary tract infections or prophylaxis for spontaneous bacterial peritonitis), and (f) addressing research gaps regarding appropriate indications or antibiotic regimens for medical prophylaxis. IMPLICATIONS: This review summarizes current trends in AP and proposes targets for AMS interventions.

Systematic Review of Antimicrobial Combination Options for Pandrug-Resistant Acinetobacter baumannii.

Antimicrobial combinations are at the moment the only potential treatment option for pandrug-resistant A. baumannii. A systematic review was conducted in PubMed and Scopus for studies reporting the activity of antimicrobial combinations against A. baumannii resistant to all components of the combination. The clinical relevance of synergistic combinations was assessed based on concentrations achieving synergy and PK/PD models. Eighty-four studies were retrieved including 818 eligible isolates. A variety of combinations (n = 141 double, n = 9 triple) were tested, with a variety of methods. Polymyxin-based combinations were the most studied, either as double or triple combinations with cell-wall acting agents (including sulbactam, carbapenems, glycopeptides), rifamycins and fosfomycin. Non-polymyxin combinations were predominantly based on rifampicin, fosfomycin, sulbactam and avibactam. Several combinations were synergistic at clinically relevant concentrations, while triple combinations appeared more active than the double ones. However, no combination was consistently synergistic against all strains tested. Notably, several studies reported synergy but at concentrations unlikely to be clinically relevant, or the concentration that synergy was observed was unclear. Selecting the most appropriate combinations is likely strain-specific and should be guided by in vitro synergy evaluation. Furthermore, there is an urgent need for clinical studies on the efficacy and safety of such combinations.

Systematic review and meta-analysis of the proportion and associated mortality of polymicrobial (vs monomicrobial) pulmonary and bloodstream infections by Acinetobacter baumannii complex.

BACKGROUND: Differentiating Acinetobacter baumannii complex (ABC) infection from colonization remains difficult and further complicated in polymicrobial infections. PURPOSE: To assess the frequency of polymicrobial ABC infections and associated mortality. We hypothesized a lower mortality in polymicrobial infections if ABC isolation reflects colonization in some polymicrobial infections. METHODS: A systematic review was conducted in PubMed, Scopus and CENTRAL for studies reporting ABC pulmonary and bloodstream infections. The proportion of infections that were polymicrobial and the magnitude of the association between polymicrobial (vs monomicrobial) infection and mortality were estimated with meta-analyses. RESULTS: Based on 80 studies (9759 infections) from 23 countries, the pooled proportion of polymicrobial infection was 27% (95% CI 22-31%) and was similarly high for bloodstream and pulmonary infections. Polymicrobial infection was variably and insufficiently defined in most (95%) studies. Considerable heterogeneity (I2 = 95%) was observed that persisted in subgroup analyses and meta-regressions. Based on 17 studies (2675 infections), polymicrobial infection was associated with lower 28-day mortality (OR = 0.75, 95% CI 0.58-0.98, I2 = 36%). However, polymicrobial infection was not associated with in-hospital mortality (OR = 0.97, 95% CI 0.69-1.35, I2 = 0%) based on 14 studies (953 infections). The quality of evidence (GRADE) for the association of polymicrobial (vs monomicrobial) infection with mortality was low and at high risk of bias. CONCLUSION: Polymicrobial ABC infections are common and may be associated with lower 28-day mortality. Considering the heterogeneity of polymicrobial infections and limitations of the available literature, more research is required to clarify the clinical impact of polymicrobial (vs monomicrobial) ABC infection.

Knowledge and Perceptions about COVID-19 among Health Care Workers: Evidence from COVID-19 Hospitals during the Second Pandemic Wave.

Health care workers (HCWs) face a higher risk of infection, since they work at the front line of COVID-19 patients' management. Misinterpretations of current scientific evidence among HCWs may impact the delivery of appropriate care to COVID-19 patients and increase the risk of SARS-CoV-2 transmission in the hospital setting. Moreover, knowledge may affect HCWs perceptions depending on their broad beliefs and past experiences. The aim of this study was to explore the knowledge and perceptions of HCWs regarding COVID-19 issues during the second wave of the pandemic. A cross-sectional survey, involving a printed questionnaire, was conducted from 21 October 2020 to 31 January 2021 in four tertiary care hospitals located at four distant geographical regions in Greece. In total, 294 HCWs participated in this study. The majority of HCWs provided precise responses regarding general knowledge, perceptions, and practices concerning the COVID-19 pandemic. However, responses on hand hygiene and antimicrobial use in HCWs with COVID-19 were mistaken. This study reveals a certain degree of misconceptions and knowledge gaps in HCWs everyday practice, especially regarding hand hygiene and antimicrobial use in COVID-19 patients.

Transmission of SARS-CoV-2 variant B.1.1.7 among vaccinated health care workers.

BACKGROUND: Vaccination against COVID-19 is among the most effective measures to stop the spread of the disease. However, acceptance of vaccination against COVID-19 among HCWs has not been universal and emergence of new variants with increased transmissibility, reduced neutralization by BNT162b2 vaccine-elicited sera and ability to cause breakthrough infections in vaccinated individuals is concerning. The aim of this study was to compare viral load, clinical presentation at diagnosis and type of exposure among vaccinated (with BNT162b2) and non-vaccinated healthcare workers (HCWs). METHODS: Prospective cohort of HWCs diagnosed with COVID-19 by nasopharyngeal PCR from 4 January to 14 April. Viral loads were expressed by the cycle threshold (Ct) in PCR. RESULTS: During the study period 55 HCWs were found positive for SARS-CoV-2, most of whom (44/55) were identified from March 28 to April 14 during an in-hospital COVID-19 outbreak. Of the 55 HCWs, 21 were fully vaccinated and another three had received one dose. Most cases (54/55) were due to variant B.1.1.7. Vaccinated and unvaccinated HCWs did not differ significantly in regards to age, gender, site of acquisition, presence of symptoms at diagnosis and viral load. CONCLUSIONS: This study found a similar viral load in vaccinated and non-vaccinated HCWs infected by SARS-CoV-2 variant B.1.1.7, suggesting potentially reduced efficacy of BNT162b2 in preventing transmission of B.1.1.7.