Quarterly Round-up of Notable Articles (August 2024–October 2024)

PROSTHETIC JOINT INFECTIONS DUE TO CANDIDA SPECIES: A MULTICENTER INTERNATIONAL STUDY Prosthetic joint infection (PJI) is one of the most serious complications following arthroplasty, affecting 1–2% of all procedures. Among PJIs, fungal infections are rare but significant, accounting for about 1.3% of cases, with Candida species responsible for over 90% of fungal PJIs. The incidence of these infections has risen in recent years, likely due to an aging population and an increase in immunosuppressed individuals. Candida species have a strong ability to adhere to medical devices and form biofilms, which contributes to the persistence and recurrence of these infections. Despite their clinical importance, there is limited high-quality evidence on the optimal management of Candida PJIs, and no standardized guidelines currently exist. Various antifungal and surgical strategies have been reported in the literature, but understanding of the epidemiology, treatment options, and outcomes of Candida PJIs remains incomplete. To address this gap, a large multicenter international cohort study was conducted to explore the epidemiology, treatment approaches, and outcomes of Candida PJIs. The study compared different surgical strategies (prosthesis removal vs. retention) and medical treatments (azole therapy vs. antifungals with antibiofilm activity) when also identifying factors associated with treatment failure. Methodology A large international multicenter retrospective study[1] was conducted with a support from the European Study Group for Implant-Associated Infections (ESGIAI) and the European Society of Clinical Microbiology and Infectious Diseases. The study included data from 19 hospitals in seven countries, using a standardized questionnaire and a central database developed by the ESGIAI. Patients were followed for at least 12 months after treatment to track recurrences. Cases were identified through hospital records or PJI-specific databases, with inclusion criteria based on the 2021 European Bone and Joint Infection Society (EBJIS) definition. This required microbiological confirmation of Candida PJI from at least two sterile intraoperative specimens, along with clinical signs of infection. Risk factors, including immunosuppression, prior antibiotic use, multiple surgeries, and previous Candida infections, were recorded. The study collected information on patient demographics, comorbidities, surgical interventions, antifungal treatments, and outcomes. Patients were categorized by the pathogen involved and their surgical and medical treatment strategies. Antifungal agents were classified based on biofilm activity, with echinocandins and amphotericin B considered effective, whereas azoles were not. The outcomes were classified as “cure” (no infection after 2 years) or “failure” (relapse, suppressive therapy, or death). Over a 10-year period, 279 cases of Candida PJIs were documented across 19 hospitals, with 269 cases included in the final analysis. The median patient age was 73 years, and 10.8% were immunosuppressed. The most common infection sites were the hip (53.5%) and knee (43.1%). Patients typically underwent a median of three prior surgeries at the infected site, with 30.1% occurring within the last month. A history of prior infections at the same site was reported in 75.8% of cases, and common clinical signs included inflammation (50.6%), fistulas (33.8%), and wound dehiscence (30.9%). Surgical strategies included debridement, antibiotics, and implant retention (DAIR) in 35.7% of cases, while one- or two-stage exchange procedures were performed in 28.3% and 29%, respectively. Microbiological analysis revealed Candida albicans (55.8%) and Candida parapsilosis (29.4%) as the most common species, with bacterial coinfections present in 51.3% of cases. Antibiotics had been administered within the previous 3 months in 72.5% of patients. Azoles were the most frequently used antifungals (75.8%), followed by echinocandins (30.9%), with a median treatment duration of 92 days. The cure rates after 1 year were 58%. Multivariate analysis found that age over 70 years and DAIR were associated with higher failure rates, while C. parapsilosis infection was linked to better outcomes. In patients without bacterial coinfection (46.9%), DAIR remained associated with treatment failure, while C. parapsilosis had better outcomes. Sensitivity analyses confirmed better outcomes with exchange surgeries (both one- and two-stage) compared to DAIR. Prosthetic loosening, a contraindication for DAIR, was linked to lower recurrence rates when treated with exchange surgery. No significant differences were observed between treatment durations (6–12 weeks vs. >12 weeks) or antifungal susceptibility among Candida species. RESULTS This international multicenter study represents the largest cohort of Candida PJIs to date, using the 2021 EBJIS definition and a 2-year follow-up. Candida PJIs predominantly affected elderly patients with comorbidities, though fewer than 11% were immunosuppressed. The infections were mostly chronic and indolent, often linked to prior surgeries or infections. C. albicans (48% failure rate) was the most common pathogen, while C. parapsilosis (31.6% failure rate) was associated with better outcomes. Prosthesis removal significantly improved outcomes, while DAIR procedures had high failure rates, reflecting the biofilm-forming nature of Candida. Exchange surgeries (one- or two-stage) were superior to retention strategies. Antifungals like azoles and echinocandins showed no added benefit in cases where prostheses were removed. The median antifungal treatment duration was 3 months, aligning with recent guidelines, but further research is needed to confirm optimal durations. Risk factors for failure included advanced age, DAIR procedures, and C. albicans infection. While antifungal-impregnated spacers were rarely used (6.5%), their role remains controversial. The study highlights the complexity of managing Candida PJIs, emphasizing the necessity of prosthesis removal for better outcomes. Despite limitations due to its retrospective design and heterogeneous management across centers, this is the largest study addressing this rare and challenging condition. Randomized trials remain difficult due to its rarity. Comment This multicenter study highlights the challenges of managing Candida PJIs, rare yet serious complications often linked to prior surgeries and comorbidities. Prosthesis removal was associated with better outcomes compared to retention strategies like DAIR, which often fail due to Candida’s biofilm-forming ability. The study also found worse outcomes with C. albicans compared to C. parapsilosis, reflecting species-specific differences in infection severity. An emerging concern is the rise of resistant nonalbicans Candida species like Candida auris PJIs, a multidrug-resistant (MDR) species complicating treatment. Unlike other Candida species, C. auris often requires prolonged intravenous antifungals, such as echinocandins or liposomal amphotericin B, increasing treatment complexity, and resource demands. DAIR is even less effective in C. auris infections, making aggressive surgical strategies like one- or two-stage prosthesis exchange essential. The study’s limited use of antifungal-impregnated cement spacers suggests an area for further research, as these may deliver high local antifungal concentrations to overcome resistance. In addition, while this study reported a median antifungal treatment duration of 3 months, C. auris infections may necessitate even longer courses, raising concerns about drug toxicity and resistance. In conclusion, multidisciplinary strategies, optimized surgical approaches, and further research into antifungal delivery and treatment duration are critical to improving outcomes. IN VITRO ACTIVITY OF ZIDEBACTAM/CEFEPIME (WCK 5222): A β-LACTAM ENHANCER/β-LACTAM COMBINATION AGAINST CARBAPENEM- AND COLISTIN-RESISTANTKLEBSIELLA PNEUMONIAE ISOLATES The rising carbapenem resistance among Gram-negative bacteria has driven increased use of colistin and polymyxin B, leading to the emergence of colistin-resistant pathogens that are challenging to treat. In some regions, such as Italy (43%), Spain (31%), and Greece (20.8%), colistin resistance in Klebsiella pneumoniae is alarmingly high. India also reports widespread colistin resistance among Gram-negative organisms, contributing to the rise of pan-drug-resistant bacteria reminiscent of the preantibiotic era. Colistin resistance mechanisms, often involving lipid A modifications via chromosomal or plasmid-mediated resistance genes, typically do not impose a fitness cost, enabling efficient selection and spread. In some cases, compensatory mutations further mitigate any fitness burden. The prevalence of colistin resistance, particularly among carbapenem-resistant (CR) K. pneumoniae, highlights its overuse and limited treatment options for infections caused by these MDR and extensively drug-resistant (XDR) pathogens. As most new antibiotics lack activity against CR bacteria, colistin or polymyxin B remains a treatment option despite its suboptimal efficacy and toxicity, especially against metallo-β-lactamase (MBL)-producing pathogens. This underscores the urgent need for novel therapies with comprehensive activity against MDR/XDR Gram-negative bacteria, including colistin-resistant strains. WCK 5222, a Phase 3-stage antibiotic combining cefepime with zidebactam, offers a promising alternative. Zidebactam uniquely binds to Gram-negative protein binding protein 2 (PBP2), enhancing cefepime’s PBP3 inhibition. This dual mechanism provides broad-spectrum coverage against MDR/XDR pathogens, including colistin-resistant isolates. Recent studies have assessed the efficacy of cefepime-zidebactam against carbapenem-nonsusceptible, colistin-resistant K. pneumoniae, highlighting its potential as a crucial treatment option for these challenging infections. Methodology The study isolates[2] were collected from two tertiary care hospitals in India: Christian Medical College, Vellore, and All India Institute of Medical Sciences, New Delhi. A total of 185 nonduplicate K. pneumoniae isolates resistant to colistin were collected during 2018–2019, primarily from sputum and blood samples of both pediatric and adult patients. The species were identified using matrix assisted laser desorption ionization-time of flight (MALDI-TOF)-based VITEKR MS, and the presence of carbapenemase genes was tested by multiplex polymerase chain reaction. A subset of 123 isolates were further analyzed for mcr1 and mcr3 genes and clonal relatedness using multilocus sequence typing (MLST), and mgrB mutations were sequenced. Minimum inhibitory concentration (MIC) testing was conducted for several antibiotics, including cefepime, zidebactam/cefepime, imipenem, meropenem, colistin, amikacin, ceftazidime/avibactam, imipenem/relebactam, and piperacillin/tazobactam using the CLSI broth microdilution method. For zidebactam/cefepime, a 1:1 ratio was used for MIC determination. The results showed that none of the isolates carried plasmid-mediated colistin resistance genes (mcr1 and mcr3), but 36 of 109 isolates had mutations in mgrB, indicating chromosomal colistin resistance. Carbapenemase genes were present in 180/185 isolates, with the majority (65.4%) harboring the blaOXA-48-like gene and 27.6% carrying both blaOXA-48-like and blaNDM. MLST analysis revealed 14 unique sequence types, with ST231 being the most prevalent (41.5%). In terms of antibiotic activity, colistin-resistant K. pneumoniae isolates showed poor susceptibility to cefepime, while zidebactam/cefepime demonstrated potent activity. Zidebactam/cefepime was effective even against isolates expressing dual carbapenemases (OXA-48-like and NDM). Ceftazidime/avibactam was effective against OXA-48-like producers but not against NDM producers, and imipenem/relebactam showed limited activity, particularly against NDM-producing isolates. Amikacin had low efficacy (10.8% susceptibility), and all isolates were resistant to piperacillin/tazobactam. Results The concurrent resistance to colistin and carbapenems among Gram-negative pathogens presents a significant challenge for clinicians. This study assessed the effectiveness of zidebactam/cefepime against such highly resistant pathogens. The key findings were as follows: (i) colistin resistance in K. pneumoniae was always associated with carbapenem resistance, (ii) OXA-48-like carbapenemase was the most common enzyme linked to colistin resistance, followed by dual carbapenemases (OXA-48-like + NDM), (iii) no isolates had the blaKPC gene, (iv) mcr1 and mcr3 plasmid-mediated colistin resistance was absent, (v) colistin resistance was clonal, with ST231 being the most common, and (vi) zidebactam/cefepime demonstrated strong activity against these colistin-resistant isolates. The association between colistin and carbapenem resistance is well documented, particularly in India, where reliance on polymyxins to treat CR K. pneumoniae may contribute to the rising rates of colistin resistance. Studies have shown that increased use of polymyxins correlates with higher resistance rates. Although national data on colistin resistance in India are scarce, regional studies indicate a growing issue, with no plasmid-mediated resistance found in this study, consistent with previous reports. The link between colistin resistance (often chromosomal) and OXA-48-like carbapenemases (typically plasmid-borne) in this study suggests a shift in carbapenemase patterns in India, with rising dual carbapenemases, such as OXA-48-like + NDM. Thankfully, KPC remains rare in India. Zidebactam/cefepime has shown strong activity against CR Enterobacterales globally, with low MIC values supporting its potential for treating MDR/XDR infections. Unlike other β-lactamase inhibitors like avibactam and relebactam, zidebactam enhances cefepime’s efficacy by binding to PBP2 in Gram-negative organisms, including K. pneumoniae. This mechanism helps maintain activity against isolates expressing β-lactamases that would typically hydrolyze cefepime, giving zidebactam/cefepime a therapeutic advantage over other β-lactam agents. Comment The growing global threat of antibiotic resistance, especially in Gram-negative pathogens, is creating significant challenges for clinicians. The increasing resistance to both carbapenems and colistin, often seen together, has resulted in a serious reduction in treatment options. This study reveals that colistin resistance in K. pneumoniae is predominantly associated with carbapenem resistance due to the presence of OXA-48-like carbapenemases, with some strains also harboring dual carbapenemases, such as NDM and OXA-48-like. Interestingly, the resistance appears chromosomal, with no plasmid-mediated colistin resistance genes (mcr1 or mcr3) detected, and a wide clonality observed, particularly with the ST231 lineage. These findings highlight the pressing need for alternative therapies as polymyxins, particularly colistin, despite being a last-resort option, are increasingly ineffective due to resistance, along with their well-documented nephrotoxicity and inconsistent clinical efficacy. The reliance on polymyxins for treating CR infections in many regions, including India, has led to a vicious cycle of resistance development. The current study, however, brings hope by demonstrating the potent activity of zidebactam/cefepime against colistin-resistant K. pneumoniae strains, even those expressing multiple carbapenemases. This combination shows promise as a safer and more effective alternative to colistin. TACKLING THE UNYIELDING: TESTING TWO NOVEL APPROACHES AGAINST NDM-PRODUCINGENTEROBACTERALESANDPSEUDOMONAS AERUGINOSA ISOLATES COLLECTED IN INDIA MBLs, especially New Delhi Metallo-β-lactamase (NDM), are a major threat to treatment options, as they can hydrolyze carbapenems and are not inhibited by current β-lactamase inhibitors. In India, NDM is a leading mechanism of carbapenem resistance in Enterobacterales and Pseudomonas aeruginosa, with about 90% of CR Escherichia coli and 60% of K. pneumoniae harboring NDM. In addition, many NDM-producing strains carry amino acid inserts in PBP3, reducing the effectiveness of cefiderocol and aztreonam. The situation is worsened by the coproduction of OXA-48-like carbapenemases in over 90% of NDM-producing K. pneumoniae. Against these resistant strains, newer β-lactam/β-lactamase inhibitor combinations, such as ceftazidime/avibactam, imipenem/relebactam, and meropenem/vaborbactam, are ineffective as they cannot neutralize MBLs, and relebactam and vaborbactam do not inhibit OXA-48-like enzymes. This study examined the effectiveness of cefiderocol and cefepime/zidebactam against NDM-producing Enterobacterales and P. aeruginosa from India. Cefiderocol showed limited activity, with only 39.3% of E. coli isolates susceptible under CLSI/FDA criteria, and a dramatic drop in susceptibility under european committee on antimicrobial susceptibility testing (EUCAST) criteria. In contrast, cefepime/zidebactam was highly effective, inhibiting all tested isolates at 1 mg/L. The study[3] found that cefiderocol’s reduced efficacy against NDM producers is likely due to both NDM’s hydrolytic activity and the presence of PBP3 inserts in E. coli. Previous studies also found limited efficacy of cefiderocol against NDM-producing E. coli and K. pneumoniae. While cefepime/zidebactam shows promise, especially against K. pneumoniae and P. aeruginosa, its activity is less affected by PBP3 modifications. Comment The findings of the interim data of PROVE study[4] conducted in the USA found that cefiderocol demonstrated good effectiveness in cases of CR Gram-negative bacterial infections, including P. aeruginosa, Acinetobacter baumannii, CR Enterobacterales, and Stenotrophomonas maltophilia in a variety of infection types, including respiratory tract, urinary tract, and bloodstream infections. Contrary to those findings, this study found that cefiderocol has limited efficacy against our CR-isolates, which underscores the need for new therapies, like cefepime/zidebactam, for NDM-producing pathogens in India. However, ongoing surveillance is critical to guide the use of these drugs in this region. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.