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.

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.

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.

Pandrug-resistant Gram-negative bacteria: a systematic review of current epidemiology, prognosis and treatment options.

BACKGROUND: The literature on the epidemiology, mortality and treatment of pandrug-resistant (PDR) Gram-negative bacteria (GNB) is scarce, scattered and controversial. OBJECTIVES: To consolidate the relevant literature and identify treatment options for PDR GNB infections. METHODS: A systematic search in MEDLINE, Scopus and clinical trial registries was conducted. Studies reporting PDR clinical isolates were eligible for review if susceptibility testing for all major antimicrobials had been performed. Characteristics and findings of retrieved studies were qualitatively synthesized. RESULTS: Of 81 studies reviewed, 47 (58%) were published in the last 5 years. The reports reflected a worldwide dissemination of PDR GNB in 25 countries in 5 continents. Of 526 PDR isolates reported, Pseudomonas aeruginosa (n=175), Acinetobacter baumannii (n=172) and Klebsiella pneumoniae (n=125) were most common. PDR GNB were typically isolated in ICUs, but several studies demonstrated wider outbreak potential, including dissemination to long-term care facilities and international spread. All-cause mortality was high (range 20%-71%), but appeared to be substantially reduced in studies reporting treatment regimens active in vitro. No controlled trial has been performed to date, but several case reports and series noted successful use of various regimens, predominantly synergistic combinations, and in selected patients increased exposure regimens and newer antibiotics. CONCLUSIONS: PDR GNB are increasingly being reported worldwide and are associated with high mortality. Several treatment regimens have been successfully used, of which synergistic combinations appear to be most promising and often the only available option. More pharmacokinetic/pharmacodynamic and outcome studies are needed to guide the use of synergistic combinations.

Is coverage of S. aureus necessary in cellulitis/erysipelas? A literature review.

BACKGROUND: Empirical treatment of patients with cellulitis/erysipelas usually targets both streptococci and methicillin-sensitive S. aureus (MSSA). However, the recommendation to empirically cover MSSA is weak and based on low-quality evidence. METHODS AND OBJECTIVE: A systematic review was conducted in PubMed and clinical trial registries to assess the role of S. aureus in cellulitis/erysipelas and the need for empirical MSSA coverage. RESULTS: Combined microbiological and serological data, and response to penicillin monotherapy suggest that streptococci are responsible for the vast majority of cases of cellulitis/erysipelas. However, most cases are non-culturable and the specificity of microbiological and serological studies is questionable based on recent studies using molecular techniques. According to epidemiological data and three randomized controlled trials, empirical coverage of methicillin-resistant S. aureus (MRSA) is not recommended for most patients, despite the high prevalence of MRSA in many areas. If MRSA is indeed not an important cause of uncomplicated cellulitis/erysipelas, then the same may apply to MSSA. Based on indirect comparison of data from clinical studies, cure rates with penicillin monotherapy (to which most MSSA are resistant) are comparable to the cure rates reported in many studies using wider-spectrum antibiotics. CONCLUSION: Considering the limitations of microbiological studies in identifying the pathogens responsible for cellulitis/erysipelas, treatment needs to be guided by clinical trials. Trials comparing penicillin or amoxicillin monotherapy to MSSA-covering regimens are needed to definitively answer whether empirical coverage of MSSA is needed and to identify the subset of patients that can be safely treated with penicillin or amoxicillin monotherapy.

Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline: an approach based on the mechanisms of resistance to carbapenems.

The management of carbapenem-resistant infections is often based on polymyxins, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review, we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, polymyxins and tigecycline (CAPT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CAPT-resistant GNB are scarce and based exclusively on few case reports and small case series, but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review, we consolidate the available literature to inform clinicians dealing with CAPT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CAPT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Several treatment options are currently available for CAPT-resistant K. pneumonia. Newer ß-lactam-ß-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-ß-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-ß-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g., polymyxin- or fosfomycin-based synergistic combinations) may represent a last resort option, but their use against CAPT-resistant GNB requires further study.

Missing the early signs of thiamine deficiency. A case associated with a liquid-only diet.

BACKGROUND: Wernicke encephalopathy (WE) predominantly occurs in alcoholic patients. Few case reports have described this diagnosis as a result of dieting. The diagnosis is often missed or delayed resulting in permanent and severe neurologic sequelae and even death. The typical neurological signs may be absent or missed during the early stages of thiamine deficiency. CASE REPORT: A 23-year-old female presented to the hospital with confusion, bilateral lateral rectus palsy, and ataxia. Based on the typical neurological triad, WE was suspected. The brain MRI was also typical for WE. Prompt clinical improvement was seen within days after intravenous thiamine supplementation. A detailed medical history revealed that during the past 3 months she had been following a liquid-only diet and had lost about 30 kg. During that time, she had visited the emergency department on multiple occasions due to fatigue, nausea, and vomiting. CONCLUSION: A high level of suspicion is required by physicians to recognize that fatigue, nausea, and vomiting may represent early signs of thiamine deficiency in patients at risk for nutritional deficiencies. Empirical thiamine supplementation may be reasonable in such cases.

Evaluation and management of Staphylococcus aureus bacteriuria: an updated review.

BACKGROUND AND AIMS: There is little guidance regarding the evaluation and management of patients with Staphylococcus aureus bacteriuria (SABU). Here, we aimed to provide an up-to-date review of the literature. METHODS: We searched PubMed, Scopus, and clinical trial registries for articles evaluating the epidemiology of SABU, risk factors of SABU, the association of SABU with urinary tract infection, bacteremia and invasive S. aureus infections, and the management of patients with SABU. RESULTS: S. aureus is an uncommon isolate in urine cultures. It is more common among certain patients, e.g., patients with indwelling urinary tract devices or prior urinary tract instrumentation. SABU may represent asymptomatic bacteriuria, primary urinary tract infection, or hematogenous seeding of the urinary tract associated with other foci of infection. SABU may also serve as the focus for subsequent bacteremia and invasive infections. We did not find any clinical trials regarding the management of patients with SABU. CONCLUSIONS: Based on our review, we suggest an algorithmic approach for the evaluation and management of patients with SABU. However, evidence from clinical trials is lacking and there are several gaps in the current literature. These are discussed in this review.

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.

Disseminated Cryptococcosis With Prostate Involvement in a Patient With T-cell Prolymphocytic Leukemia and Prostate Cancer.

T-cell prolymphocytic leukemia (T-PLL) presents unique treatment challenges because of its rarity and aggressiveness. Allogeneic hematopoietic stem cell transplantation offers a potentially curative option, but its safety in patients with concurrent invasive fungal infections and solid malignancies remains uncertain. We present a case of a 68-year-old male with T-PLL who developed disseminated cryptococcal disease with prostate involvement and concurrent prostate cancer (PCa). Despite the challenges, successful control of the infection and radical prostatectomy enabled the patient to proceed safely to allogeneic transplantation. The case highlights the importance of vigilance for unusual infections, such as Cryptococcus, in immunocompromised patients presenting with lower urinary tract symptoms. Clinicians should consider the possibility of PCa in this population, particularly in the context of chronic leukemia. Concurrently, the potential association between fungal prostate infections and PCa warrants further investigation.

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.