Emerging therapies and diagnostic innovations for multidrug-resistant infections in kidney allograft recipients: Challenges and future directions

Table 1 Key multidrug-resistant phenotypes in kidney transplant recipients - epidemiology, risk factors, and outcomes

Phenotype	Epidemiology	Risk factors	Outcomes
Extended-spectrum beta-lactamase-Enterobacterales	Cause 18%-31% of post-transplant urinary tract infections. Cause 29%-71% of Gram-negative bloodstream infections. Genitourinary tract is the predominant source of bloodstream infection	Diabetes mellitus. Previous antibiotic use. Delayed graft function. Relapsing infection/previous urinary tract infection. Perianal extended-spectrum beta-lactamase carriage (rectal swab). Second kidney transplantation/induction therapy	3 × greater risk of recurrent urinary tract infection. Increased hospitalization needs. Lower 1-year epidermal growth factor receptor. Lower long-term death-censored graft survival. High mortality in bloodstream infection
Carbapenem-resistant Enterobacterales	Incidence in solid organ transplant is 5 × higher than general population. Common species: Klebsiella, Enterobacter. Sites: Urinary tract infection > surgical site infection > catheter-related bloodstream infection	Colonization (21%-38% of colonized patients develop infection). Recipient age > 50 years. Lymphopenia (median 700 cells/mm3). Prior carbapenem use. Colonization by polymyxin-resistant strains	Mortality up to 42%. Higher mortality compared to carbapenem-susceptible infections
Difficult to treat resistant Pseudomonas aeruginosa	Accounts for up to 15% of solid organ transplant bloodstream infections. Up to 43% of isolates in solid organ transplant are multidrug-resistant-Pseudomonas aeruginosa	Prior intensive care unit admission. Nosocomial acquisition. Previous carbapenem therapy	Mortality associated with: Age, urinary catheter, high-risk source, carbapenem resistance, severity of infection. Correct empirical therapy reduces mortality
Carbapenem-resistant Acinetobacter baumannii	Almost exclusively nosocomial. Sites: Soft tissue, urinary tract infection, catheter bloodstream infection, ventilator-associated pneumonia	Hospital/intensive care unit exposure. Mechanical ventilation/invasive devices	Highest mortality among solid organ transplant multidrug-resistant organism infections (> 40%)
Vancomycin-resistant Enterococci	Enterococcus causes 19% of urinary tract infections (mostly Escherichia faecalis). Vancomycin-resistant Enterococci colonization prevalence approximately 14% in kidney transplant recipients. Escherichia faecium has higher vancomycin resistance rates	Perioperative prophylaxis targeting Gram-negatives. Previous vancomycin use. Ureteral stents	Differentiating colonization from infection is vital; colonization does not always lead to infection
Methicillin-resistant Staphylococcus aureus	1.9% of kidney transplant recipients are methicillin-resistant Staphylococcusaureus carriers. Infections occur early post-transplant	Pre-operative colonization. Presence of central venous catheters. Dialysis history	Pre-operative colonization is an independent predictor of renal allograft failure at 5 years
Clostridioides difficile infection	Leading cause of post-transplant diarrhea. Prevalence approximately 2.4%	Antimicrobial exposure (3rd gen cephalosporins, clindamycin, imipenem)	Associated with worse outcomes in kidney transplant recipients

Table 2 Preferred and alternative agents for multidrug-resistant pathogens in kidney transplant: Dosing, key toxicities, and transplant-specific caveats

Pathogen	Preferred agents	Alternative agents	Dosing/administration	Key toxicities and transplant caveats
Extended-spectrum beta-lactamase-Enterobacterales	Cystitis/pyelonephritis (if susceptible): Trimethoprim-sulfamethoxazole, ciprofloxacin, or levofloxacin. If resistant/toxic or non-urinary source: Ertapenem, meropenem, or imipenem-cilastatin	Pyelonephritis/complicated urinary tract infections: Aminoglycosides	Duration: Short course (6-10 days) may be comparable to longer courses (11-21 days) for complicated urinary tract infections	Aminoglycosides: Use restricted by potential nephrotoxicity. Step-down: Lack of oral options (due to fluoroquinolone/trimethoprim-sulfamethoxazole co-resistance) impedes shortening intravenous duration
Carbapenem-resistant Enterobacterales	Pyelonephritis: Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefiderocol. Klebsiella pneumoniae carbapenemase-producers: Meropenem-vaborbactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam. MBL-producers (e.g., new Delhi metallo-β-lactamase): Ceftazidime-avibactam + aztreonam or cefiderocol (monotherapy)	Pyelonephritis/complicated urinary tract infections: Aminoglycosides. Klebsiella pneumoniae carbapenemase. Alternative: Cefiderocol		Nephrotoxicity: Polymyxins and aminoglycosides limited by nephrotoxicity. Novel agents (ceftazidime-avibactam, etc.) have low nephrotoxicity risk. Calcineurin inhibitor interactions: Novel agents have limited interaction with tacrolimus, but imipenem-relebactam + cyclosporine increases neurotoxicity risk
DTR Pseudomonas aeruginosa	Beta-lactam susceptible (non-carbapenem): Piperacillin-tazobactam, ceftazidime, cefepime, or aztreonam (preferred over carbapenems). Carbapenem-resistant (non-MBL): Ceftolozane-tazobactam (drug of choice if carbapenemase negative), ceftazidime-avibactam, imipenem-relebactam. MBL-producers: Cefiderocol	MBL-producers: Ceftazidime-avibactam + aztreonam; polymyxins (poor efficacy/toxicity); cefepime-zidebactam (salvage)	Traditional beta-lactams: High-dose extended-infusion suggested	Resistance: Pseudomonas aeruginosa can develop resistance during therapy; close monitoring required. Polymyxins: Poor data due to toxicity
Carbapenem-resistant Acinetobacter baumannii	Combination therapy: Sulbactam-durlobactam + carbapenem (imipenem-cilastatin or meropenem)	Alternative combination: High-dose ampicillin-sulbactam + at least one other agent (polymyxin B, minocycline, tigecycline, or cefiderocol)	Ampicillin-sulbactam: High-dose (total daily dose of 9 g sulbactam component)	Strategy: Combination therapy suggested due to limited single-agent data
Vancomycin-resistant Enterococci	Vancomycin-resistant Enterococci faecium urinary tract infection: Daptomycin monotherapy. Vancomycin-resistant Enterococci endocarditis: Daptomycin + ampicillin	In-vitro synergy (clinical efficacy to be explored): Fosfomycin + daptomycin or amoxicillin		Renal preservation: Daptomycin + ampicillin is an aminoglycoside-sparing therapy to protect renal function
Clostridioides difficile	Preferred: Oral vancomycin or fidaxomicin	Recurrent Clostridioides difficile infection: Fecal microbiota transplantation	Oral vancomycin: 125 mg four times daily	Fidaxomicin: Lower recurrence rate than vancomycin. Fecal microbiota transplantation: Efficacy/safety in solid organ transplant comparable to immunocompetent individuals
Methicillin-resistant Staphylococcus aureus	Preferred: Vancomycin	Alternatives: Daptomycin (if intolerance, persistent bacteremia, or minimum inhibitory concentration > 1 μg/mL); teicoplanin; ceftaroline; ceftobiprole	Vancomycin: Target serum trough 15-20 μg/mL. Continuous infusion preferred	Vancomycin: Continuous infusion reduces odds of acute kidney injury by 53%. Monitor area under the curve/minimum inhibitory concentration to reduce nephrotoxicity. Daptomycin: Monitor creatine kinase (myopathy risk). Novels: Ceftaroline/ceftobiprole have minimal interactions with calcineurin inhibitors

MBL: Metallo-β-lactamase.