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

Abstract

Multidrug-resistant (MDR) bacterial infections are a major cause of morbidity, mortality, and graft loss in kidney transplant recipients, who are particularly vulnerable due to intensive immunosuppression, frequent healthcare exposure, and recurrent antibiotic use. The rising prevalence of resistance among key uropathogens and bloodstream isolates has outpaced the development and uptake of transplant-specific diagnostic and therapeutic strategies. This mini-review synthesizes contemporary evidence on MDR gram-negative and gram-positive infections in kidney allograft recipients, focusing on extended-spectrum beta-lactamase-producing Enterobacterales, carbapenem-resistant Enterobacterales, difficult-to-treat Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii, vancomycin-resistant Enterococci, methicillin-resistant Staphylococcus aureus, and Clostridioides difficile infection. We outline epidemiology, risk factors, and clinical impacts on patient and graft outcomes, including the association of recurrent urinary tract infection and MDR bloodstream infection with reduced estimated glomerular filtration rate, increased hospitalization, and higher death-censored graft failure. The article highlights advances in rapid molecular diagnostics (such as polymerase chain reaction, matrix-assisted laser desorption/ionization-time of flight, and syndromic panels) that shorten time to organism and resistance detection, enabling earlier optimization and de-escalation of antimicrobial therapy. Emerging agents - including novel beta-lactam/beta-lactamase inhibitor combinations, siderophore cephalosporins, and investigational boronate beta-lactamase inhibitors - are discussed, emphasizing nephrotoxicity profiles, drug-drug interactions with calcineurin inhibitors, and evidence gaps in transplant populations. We also review the evolving roles of phage therapy, monoclonal antibodies, vaccines, and therapeutic drug monitoring (including area under the curve/minimum inhibitory concentration-guided vancomycin dosing and cautious reuse of aminoglycosides) in this high-risk cohort. Finally, we propose a pragmatic stewardship framework tailored to kidney transplant units, integrating individualized perioperative prophylaxis, avoidance of unnecessary treatment of asymptomatic bacteriuria, early device removal, and minimization of broad-spectrum exposure to limit MDR selection and Clostridioides difficile infection. A transplant-specific approach that combines rapid diagnostics, rational deployment of new antimicrobials, and rigorous stewardship is essential to improve survival and preserve allograft function in the era of MDR infections after kidney transplantation.

Key Words: Kidney transplantation; Multidrug-resistant bacterial infections; Kidney allograft recipients; Urinary tract infection; Bloodstream infection; Antimicrobial stewardship; Novel antimicrobial agents; Molecular rapid diagnostics; Therapeutic drug monitoring

Core Tip: Multidrug-resistant bacterial infections are now a leading threat to survival and long-term graft function after kidney transplantation. This mini-review synthesizes current data on multidrug-resistant epidemiology, risk factors, and outcomes in kidney transplant recipients, and highlights emerging tools, such as rapid molecular diagnostics, novel β-lactam/β-lactamase inhibitor combinations, siderophore cephalosporins, and individualized perioperative antibiotic strategies. A kidney transplant-specific antimicrobial stewardship framework is proposed to balance timely, effective therapy with preservation of allograft function and containment of resistance.

INTRODUCTION

Kidney transplantation is the optimal therapy for end-stage renal disease[1]. It prolongs survival in individuals with kidney failure across all candidate ages and waiting times[2]. It is cost-effective across all donor types despite higher costs associated with marginal organs and innovative living donor practices[3].

For kidney transplant (KT) recipients, infections are an inherent risk associated with the immunosuppression required to maintain the graft. Increasingly potent immunosuppression, older recipient age, and transplantation following desensitization in ABO-incompatible or human leukocyte antigen-mismatched donors further increase the risk of infectious complications. Infections are a major cause of increased morbidity and mortality following KT[4,5], with a cumulative incidence of 78% 5 years after transplantation. KT recipients who develop an infection have a 2.22-fold higher risk of death and a 1.92-fold higher risk of death-censored graft loss[5]. Infections are the second most common cause of death in KT recipients, accounting for 15%-21% of all deaths[6-8]. Although both conventional and opportunistic pathogens are important causes of infection, 54%-85% of deaths in KT recipients are due to bacterial infections[8,9].

The World Health Organization has declared antimicrobial resistance a priority public health threat[10]. Therapeutic options for patients with multidrug-resistant (MDR) organism infections are limited, and mortality rates are disproportionately higher than in infections caused by susceptible bacteria[11]. The six leading pathogens responsible for resistance-associated death (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) accounted for 929000 deaths attributable to antimicrobial resistance and 3.57 million deaths associated with antimicrobial resistance in 2019[12]. KT recipients may be particularly prone to develop urinary tract infections (UTIs) with extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales because of the antimicrobial selection pressure induced by antibiotic prophylaxis and early empiric treatment for suspected infection[13]. This mini-review focuses on MDR bacterial infections in kidney allograft recipients, with particular emphasis on urinary and bloodstream infections (BSIs), and highlights emerging diagnostics and novel therapeutics.

MDR INFECTION-ASSOCIATED ORGANISMS

Key multidrug-resistant phenotypes in KT recipients, including their epidemiology, risk factors and clinical outcomes, are summarized in Table 1.

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

ESBL-producing Enterobacteriaceae

As causative pathogens, Enterobacterales play a major role and are responsible for 50%-80% of UTIs in KT recipients, most commonly due to Escherichia coli and Klebsiella species[13]. A high incidence of ESBL-related UTI is observed in the post-transplant period, accounting for 18%-31% of all UTIs[13,14]. ESBL-producing Enterobacteriaceae (ESBL-E) are characterized by resistance to most beta-lactams, with frequent co-resistance to aminoglycosides and fluoroquinolones, thereby requiring carbapenems for optimal treatment[15]. Diabetes mellitus, prior antibiotic prophylaxis or treatment, previous UTI, relapsing infection, and delayed graft function after transplantation are important risk factors for infection with ESBL-positive Enterobacteriaceae in recipients[16].

These patients have nearly a threefold higher risk of recurrent UTI and an increased need for hospitalization[13,15]. Recurrent UTIs are associated with a lower 1-year epidermal growth factor receptor and reduced long-term death-censored allograft survival[17].

Up to one in six KT recipients may develop gram-negative bloodstream infection (BSI) within the first year after transplantation, of which 29%-71% are caused by ESBL-E[18,19]. The genitourinary tract is the predominant source of BSIs, and second kidney transplantation and receipt of induction therapy are associated with an increased risk of BSI[18]. Perianal ESBL carriage, detected by preoperative swabs, may be a risk factor for subsequent bacteremia and other serious infections in KT recipients[20]. Bacteremia caused by ESBL-E is associated with high mortality and a high risk of recurrence[21].

ESBL- Escherichia coli colonization and asymptomatic bacteriuria (ASB) in KT recipients complicate clinical decision-making because of concerns about progression to symptomatic infection and sepsis. Current evidence does not support routine screening for or treatment of post-transplant ASB in these patients, and such strategies increase antibiotic use and promote the emergence of resistant organisms[22].

Treatment: Trimethoprim-sulfamethoxazole (TMP-SMX), ciprofloxacin, or levofloxacin are preferred treatment options for pyelonephritis or complicated UTIs (cUTIs) caused by ESBL-E, provided in vitro susceptibility is demonstrated[23]. Ertapenem, meropenem, and imipenem-cilastatin are preferred when resistance or toxicity prevents the use of TMP-SMX or fluoroquinolones[23]. Aminoglycosides are alternative options for ESBL-E pyelonephritis or cUTI, but their use is limited by potential nephrotoxicity[23]. For ESBL-E infections outside the urinary tract, meropenem, imipenem-cilastatin, or ertapenem are the preferred agents[23]. Lack of oral step-down options, due to frequent co-resistance to fluoroquinolones and TMP-SMX, is a major barrier to shortening the duration of intravenous antibiotic therapy.

Although a landmark trial demonstrated that 7 days of antibiotics is noninferior to 14 days for gram-negative bacteremia, solid organ transplant recipients were excluded from the study[24]. In KT recipients treated for cUTI, short-course (6-10 days) vs longer-course (11-21 days) antibiotic therapy was associated with similar outcomes[25]. A multicenter randomized trial (SHORTCUT) comparing 7 days vs 14 days of antibiotic therapy for acute pyelonephritis in KT recipients is ongoing[26].

Carbapenem-resistant Enterobacteriaceae

Infections due to carbapenem-resistant Enterobacteriaceae (CRE) represent a global public health threat because of limited therapeutic options and rapid global dissemination. Solid organ transplant recipients experience up to five times higher CRE infection rates than those in the general population. Among KT recipients, the most common CRE organisms are Klebsiella and Enterobacter species[27].

CRE infection-associated mortality in KT recipients can be as high as 42% and is higher than that observed with infections caused by carbapenem-susceptible Enterobacteriaceae[28]. Colonization with CRE is the most significant risk factor for subsequent CRE infection, with 21%-38% of colonized patients developing clinical infection[29,30]. Other reported risk factors include recipient age > 50 years at the time of CRE acquisition, a median lymphocyte count of 700 cells/mm³, prior carbapenem exposure, and colonization by polymyxin-resistant strains[29,30]. UTI is the most common clinical manifestation of CRE infection in KT recipients, followed by surgical site infection and catheter-related BSI[29].

Because patients colonized with CRE constitute the primary reservoir for subsequent infection, strategies to improve their identification are crucial for preventing CRE dissemination in the hospital setting[30]. Selective culture and real-time polymerase chain reaction (PCR) performed directly on rectal swabs are complementary methods and may be useful for detecting CRE colonization in KT recipients[30].

Treatment: Treatment of CRE infections in KT recipients is complex and often requires the use of potentially nephrotoxic antimicrobials[31]. TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for CRE-induced pyelonephritis when in vitro susceptibility is confirmed. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are also preferred options for treating pyelonephritis. Aminoglycosides are alternative agents for the treatment of CRE-induced pyelonephritis or cUTI, although their use is limited by the risk of nephrotoxicity.

Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred treatment options for infections caused by Klebsiella pneumoniae carbapenemase-producing Enterobacterales, with cefiderocol serving as an alternative agent[23]. For infections due to New Delhi metallo-β-lactamase and other metallo-β-lactamase (MBL)-producing Enterobacterales, ceftazidime-avibactam in combination with aztreonam, or cefiderocol as monotherapy, are preferred treatment options[23].

Polymyxins and aminoglycosides were the backbone of CRE therapy before the advent of novel beta-lactams, but their use in KT recipients have been limited by nephrotoxicity[31]. Ceftazidime-avibactam represents the first major breakthrough because it carries a relatively low risk of nephrotoxicity compared with these older agents. Meropenem-vaborbactam, imipenem-relebactam, and cefiderocol are likewise characterized by a low risk of nephrotoxicity and have minimal interaction with tacrolimus[31]. However, a pharmacodynamic interaction between cyclosporine and imipenem/cilastatin-relebactam has been associated with an increased risk of neurotoxicity, warranting particular caution when these drugs are co-administered[31].

Difficult-to-treat resistant Pseudomonas aeruginosa

Pseudomonas aeruginosa accounts for up to 15% of all BSIs in solid organ transplant recipients[32]. MDR Pseudomonas aeruginosa is defined as isolates that are not susceptible to at least one agent in at least three antimicrobial classes in which susceptibility is typically expected, including penicillins, cephalosporins, fluoroquinolones, aminoglycosides, and carbapenems[33]. Difficult-to-treat resistance (DTR) is defined as Pseudomonas aeruginosa exhibiting non-susceptibility to all of the following agents: Piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin[34].

MDR- or DTR- Pseudomonas aeruginosa typically emerges through the interplay of multiple resistance mechanisms, including decreased expression of outer membrane porins (e.g., OprD), increased production of or amino acid substitutions in Pseudomonas-derived cephalosporinases, upregulation of efflux pumps, mutations in penicillin-binding protein targets, carbapenemase production, and acquisition of extended-spectrum β-lactamases[35].

Transplant recipients are at increased risk of MDR Pseudomonas aeruginosa BSI, with up to 43% of isolates in this population being MDR strains[36]. Previous carbapenem therapy, prior intensive care unit admission, and nosocomial acquisition are independently associated with an increased risk of carbapenem-resistant Pseudomonas aeruginosa infection[37].

Age, the presence of a urinary catheter, a high-risk source of infection, bacteremia due to carbapenem-resistant strains, and greater infection severity are independently associated with higher mortality[37]. Appropriate empirical antimicrobial therapy is associated with reduced mortality in patients with Pseudomonas aeruginosa BSI[37].

Treatment: When Pseudomonas aeruginosa isolates are susceptible to both traditional non-carbapenem β-lactam agents (piperacillin-tazobactam, ceftazidime, cefepime, aztreonam) and carbapenems, the former are preferred over carbapenem therapy[35].

For infections caused by Pseudomonas aeruginosa isolates that are not susceptible to all carbapenems but remain susceptible to traditional β-lactams, high-dose extended-infusion therapy with a traditional β-lactam is suggested[35]. In critically ill patients or those with poor source control who have Pseudomonas aeruginosa isolates resistant to carbapenems but susceptible to traditional β-lactams, use of a susceptible novel β-lactam agent (such asceftolozane-tazobactam, ceftazidime-avibactam, orimipenem-cilastatin-relebactam) is also a reasonable approach[35].

If the isolate is resistant to both traditional agents and carbapenems (e.g., extensively drug-resistant or DTR strains), carbapenemase testing becomes essential. If carbapenemase testing is negative, ceftolozane-tazobactam is considered the drug of choice when in vitro activity is confirmed[35]. For carbapenem-resistant Pseudomonas aeruginosa in which resistance is mediated by a non-MBL carbapenemase, ceftazidime-avibactam or imipenem-relebactam may be used; cefiderocol is an alternative option[35]. Therapeutic options are limited for carbapenem-resistant Pseudomonas aeruginosa isolates with documented MBL production. Cefiderocol or polymyxins are generally the only agents retaining in vitro activity, although clinical efficacy data for cefiderocol are mixed and outcomes with polymyxins/colistin are generally poor because of toxicity[38]. The combination of ceftazidime-avibactam and aztreonam may be considered, although clinical experience is limited, and cefepime-zidebactam has been reported as a salvage option in such cases[38]. Patients with Pseudomonas aeruginosa infection should be monitored closely for clinical response, as this organism has a marked ability to develop additional resistance mechanisms during antibiotic therapy.

CARBAPENEM-RESISTANT ACINETOBACTER BAUMANNII

Acinetobacter baumannii is almost exclusively a nosocomial pathogen and is associated with soft tissue infections, UTIs, catheter-associated BSI, and ventilator-associated pneumonia in critically ill patients[39]. Acinetobacter baumannii has intrinsic resistance to aminopenicillins and first- and second-generation cephalosporins and has increasingly acquired resistance to broad-spectrum antibiotics, including β-lactams, aminoglycosides, fluoroquinolones, and tetracyclines[40]. Most notably, carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged through the acquisition of enzymes such as MBL and oxacillinases capable of hydrolyzing imipenem[40]. CRAB infection mortality rates are the highest among MDR organism infections in solid organ transplant recipients and often exceed 40%[38].

Treatment

Combination therapy with at least two agents, whenever possible, is suggested for the treatment of CRAB infections because of limited clinical data supporting any single antibiotic agent[23]. A regimen that includes a sulbactam-containing agent is recommended. The preferred regimen is sulbactam-durlobactam in combination with a carbapenem (imipenem-cilastatin or meropenem). If sulbactam-durlobactam is not available, an alternative regimen is high-dose ampicillin-sulbactam (total daily dose of 9 g sulbactam) in combination with at least one other agent (polymyxin B, minocycline > tigecycline, or cefiderocol)[23].

DRUG-RESISTANT GRAM-POSITIVE ORGANISM INFECTIONS

Enterococcus faecalis infections

Enterococcus faecalis is a common cause of UTI in transplant recipients, accounting for up to 19% of cases, with Escherichia faecalis representing 76% of isolates[41]. It is the most frequent cause of UTI in the first month after kidney transplantation[42]. Perioperative antibiotic prophylaxis targeting Gram-negative bacilli may promote selection of Enterococcus faecalis, leading to ureteral stent colonization and subsequent infection[43]. In addition, TMP-SMX prophylaxis for UTI does not protect against enterococcal infection. In a Brazilian study of KT recipients, the prevalence of vancomycin-resistant Enterococcus (VRE) fecal colonization was approximately 14%, and prior vancomycin use was identified as a risk factor for VRE colonization, although colonization was not associated with an increased rate of VRE infection[44]. Differentiating true infection from colonization is essential to guide appropriate treatment decisions and avoid unnecessary antimicrobial use[41].

Enterococcus faecalis exhibits consistently low resistance rates to ampicillin, vancomycin, and linezolid[41]. Interestingly, in a single-center 10-year survey from Germany, levofloxacin resistance in Escherichia faecalis markedly decreased from 100% in 2014-2017 to just 2% in 2022[41]. Enterococcus faecium demonstrates very low resistance rates to linezolid; however, vancomycin resistance was reported to be approximately 14% in 2022[41].

In an in vitro study of vancomycin-resistant Enterococcus faecium isolates from renal transplant patients with infected urinary stents, combination therapy with fosfomycin and either daptomycin or amoxicillin demonstrated strong synergy and enhanced bactericidal activity against VRE, suggesting that these combinations warrant further clinical evaluation[45]. Daptomycin monotherapy has been shown to be effective for VRE faecium UTI in KT recipients and may represent a useful alternative treatment option[46]. Furthermore, combination therapy with daptomycin and ampicillin has been reported as an effective aminoglycoside-sparing regimen for VRE endocarditis in KT recipients and may be a preferred initial choice in this setting[47]. Eliminating vancomycin prophylaxis in renal transplant patients may be a reasonable component of a broader strategy to limit vancomycin use[48].

Clostridioides difficile infection

Clostridioides difficile (CD) is a gram-positive, endospore-forming anaerobe that can colonize the intestinal microbiome[49]. It is one of the leading causes of diarrhea following kidney transplantation[50]. Among hospitalized patients in the United States with a history of kidney transplantation, the prevalence of CD infection (CDI) is 2.4%, and CDI is associated with worse outcomes in this population, including higher risks of acute kidney injury, intensive care unit admission, and mortality[51].

Antimicrobial exposure, the number of agents received, duration of antibiotic use, and specific drugs such as third-generation cephalosporins, clindamycin, and imipenem are recognized risk factors for both VRE colonization/infection and CDI[52]. Nosocomial CDI has become an increasing problem with the emergence of the hypervirulent NAP1/BI/027 (binary toxin-producing) strain[53]. CDI is a clinical diagnosis supported by laboratory evidence of free CD toxin or toxigenic CD in the stool of a patient with unexplained, new-onset, clinically significant diarrhea[53].

Differentiating true CDI from colonization is essential for appropriate management[54]. PCR-based assays, although highly sensitive, may yield false-positive results in colonized individuals, as a positive PCR stool test for CD can reflect either active CDI or asymptomatic colonization depending on the clinical context[54].

Treatment: Oral vancomycin, given at a dose of 125 mg four times daily, achieves higher cure rates for CDI than oral metronidazole, particularly in more severe disease[55]. Fidaxomicin, a macrolide-like antibiotic with minimal systemic absorption, high colonic concentrations, and limited disruption of the normal gut microbiota, has emerged as an alternative first-line option, offering similar initial cure rates to vancomycin but with a significantly lower risk of recurrence[55,56].

The use of fecal microbiota transplantation for CDI-associated diarrhea after renal transplantation remains in the exploratory phase because of concerns about infectious complications; however, retrospective series suggest that its efficacy and safety in solid organ transplant recipients with recurrent CDI are comparable to those observed in immunocompetent patients[57]. Surgery is a therapeutic option for patients with fulminant colitis or those who fail to respond to optimized medical therapy.

Methicillin-resistant Staphylococcus aureus

Approximately 20% of the general population are persistent nasal carriers of Staphylococcus aureus, and about 1.5% are asymptomatic carriers of methicillin-resistant Staphylococcus aureus (MRSA). Among KT recipients, 1.9% are MRSA carriers, and preoperative MRSA colonization is an independent predictor of renal allograft failure at 5 years[58]. Short-term complications of MRSA colonization in transplant recipients include skin and soft tissue infection, pneumonia, UTI, intra-abdominal collections, disseminated bacteremia, and wound dehiscence[59].

Most MRSA infections occur within the first few months following kidney transplantation, suggesting that they arise from preoperative or perioperative factors such as central venous catheters, hemodialysis, peritoneal dialysis, and early postoperative exposures[60].

Treatment: Vancomycin remains the preferred agent for most infections caused by MRSA[61]. In this setting, dosing should traditionally target a serum trough concentration between 15 μg/mL and 20 μg/mL, with close monitoring of trough levels to reduce the risk of nephrotoxicity[62].

When administered as a continuous infusion, vancomycin is associated with a 53% reduction in the odds of acute kidney injury and a 2.6-fold higher likelihood of achieving pharmacokinetic (PK) targets compared with intermittent infusion, without affecting overall mortality[63]. In cases of vancomycin intolerance, persistent bacteremia, or a high vancomycin minimum inhibitory concentration (> 1 μg/mL), daptomycin is an appropriate alternative, but it requires monitoring of serum creatine kinase levels due to the risk of myopathy[64]. Teicoplanin is a lipoglycopeptide with a spectrum of activity similar to vancomycin, and studies support its use as an effective and safe alternative to vancomycin for the treatment of healthcare-associated MRSA bacteremia[65].

The fifth-generation cephalosporins ceftaroline and ceftobiprole are active against MRSA and have been approved for serious MRSA infections, including MRSA bacteremia in the case of ceftobiprole[66]. Although kidney transplant recipients were excluded from pivotal phase 3 trials, both agents are considered viable options in this population, supported by real-world observational data (such as the RETRACE and related cohort studies), established renal dose-adjustment guidance, and a generally favorable safety profile with minimal interaction with calcineurin inhibitors[66].

PREVENTION, STEWARDSHIP, AND FUTURE DIRECTIONS

Antimicrobial stewardship in KT units

Antimicrobial stewardship in the KT unit is essential to combat the rising incidence of MDR infections. Diagnostic uncertainty, atypical clinical presentations, and the risk of rapid progression of sepsis under immunosuppression complicate stewardship efforts in KT recipients, making a “one-size-fits-all” approach impractical. Therefore, individualized risk assessment is central to stewardship in this population. Preferred and alternative agents for major multidrug-resistant pathogens in kidney transplant recipients, along with dosing considerations and transplant-specific caveats, are detailed in Table 2.

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.

Strategies to safely minimize perioperative antibiotic use should be prioritized. A randomized controlled trial in non-diabetic, non-obese KT recipients demonstrated that a single, appropriately timed preoperative dose of a long-acting antibiotic was as effective as multiple-dose prophylaxis in preventing postoperative infections, including UTIs, and was associated with lower emergence of MDR infections[67]. These results are supported by retrospective data from centers worldwide, which have shown that single-dose perioperative prophylaxis is acceptable and that broader or prolonged regimens do not clearly improve outcomes but may drive resistance[68,69].

Furthermore, a retrospective study of KT recipients managed with contemporary triple immunosuppression found no increase in perioperative infectious complications, even in the absence of routine perioperative antibiotic prophylaxis, suggesting that prophylaxis may be safely omitted in carefully selected, standard-risk patients[70]. In light of these findings, perioperative antibiotic prophylaxis should be individualized, with single-dose prophylaxis considered sufficient for most KT recipients, and broader or prolonged regimens reserved for those with clearly defined high-risk features.

Differentiating colonization from true infection is essential to avoid unnecessary antibiotic exposure in KT recipients. Pretransplant screening for bacterial colonization is useful, but subsequent antibiotic use should be driven by the clinical context, local resistance patterns, and the patient’s known colonization status rather than by positive cultures alone.

There is a growing body of evidence from clinical trials and meta-analyses showing that routine screening for and treatment of ASB is not beneficial for most KT recipients, particularly beyond the first 1-2 months after transplant[71,72]. Even short courses of antimicrobials can select for resistant organisms, and cumulative antibiotic exposure is directly associated with adverse outcomes such as CDI, MDR infections, graft dysfunction, and increased mortality in this population[73]. Therefore, early de-escalation of broad-spectrum antibiotics to the narrowest effective agent once microbiological data and clinical stability allow is recommended as a core stewardship strategy.

Trials evaluating the adequacy of shorter antibiotic courses for treating infections in KT recipients are limited. One such study, the French “SHORTCUT” trial, is designed to address the optimal duration of antibiotic therapy for acute pyelonephritis in KT recipients[74]. This randomized, multicenter, non-inferiority, open-label trial plans to enroll 470 KT recipients with febrile pyelonephritis and will compare 7 days vs 14 days of antibiotic therapy[74].

The results of this and similar trials are expected to guide future practice by supporting the use of the shortest effective duration of antibiotic therapy in KT recipients, thereby helping to reduce antimicrobial exposure and resistance while maintaining clinical efficacy[74].

UROLOGIC DEVICE MANAGEMENT

Early removal of ureteric stents and urinary catheters after renal transplantation should be considered a potential strategy to reduce catheter-associated UTIs, although the benefits must be balanced against the risk of urological complications. Early ureteric stent removal at 1-3 weeks post-KT can lower UTI incidence without increasing rates of urine leak or ureteric obstruction[75,76].

Although current evidence on early urinary catheter removal is largely based on retrospective observational studies with methodological limitations, early removal does not appear to increase urinary leaks or other major urological complications after kidney transplantation[77,78]. The upcoming ELUCATR randomized controlled trial (“early vs late urinary catheter removal after renal transplantation”), comparing catheter removal at 24 hours vs 72 hours post-surgery, is expected to provide more definitive data to guide practice in this area[79].

FUTURE DIRECTIONS

Novel antibiotics

Novel β-lactam/β-lactamase inhibitor combinations: Several novel β-lactam/β-lactamase inhibitor combinations have recently completed phase 3 trials with encouraging results. Sulbactam-durlobactam was shown to be non-inferior to colistin for the treatment of serious infections caused by CRAB-calcoaceticus complex, with similar or lower 28-day mortality and a more favorable safety profile[80].

Cefepime-taniborbactam was superior to meropenem in adults with cUTI, including acute pyelonephritis, achieving higher composite rates of clinical and microbiological cure; importantly, efficacy was also observed in infections due to meropenem-resistant Enterobacterales and Pseudomonas aeruginosa[81]. Aztreonam-avibactam has likewise demonstrated promising phase 3 data for serious infections caused by MBL-producing Enterobacterales, with favorable clinical and microbiological responses and an acceptable safety profile.

Cefepime-zidebactam and xeruborbactam, an ultra-broad-spectrum boronic acid β-lactamase inhibitor, are currently being evaluated in trials for the treatment of MDR infections. Ceftibuten-xeruborbactam (S-743229) is an investigational oral antibiotic combination with potential application in clinical settings where intravenous therapy is not feasible or desirable.

Siderophore cephalosporins: Cefiderocolis is currently the only Food and Drug Administration-approved siderophore cephalosporin, and it exhibits potent activity against carbapenem-resistant Gram-negative organisms[82]. For infections caused by DTR Pseudomonas aeruginosa isolates that produce MBLs, cefiderocol is the preferred treatment option[23].

A novel siderophore cephalosporin, LCB10-0200 (GT-1), is in preclinical and early clinical development, with in vitro data demonstrating activity against a range of MDR carbapenem-resistant Enterobacterales and non-fermenters[83]. In addition, combinations of cefiderocol with β-lactamase inhibitors, such as cefiderocol/sulbactam and cefiderocol/tazobactam, are being explored in preclinical studies, where they have shown synergistic activity against carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii[83].

Phage therapy

Phage therapy is the use of viruses that infect bacteria, called bacteriophages, to treat bacterial infections in patients. When a lytic phage invades a bacterium, it hijacks its machinery and uses the bacterium’s resources to make copies of itself. A single phage can be replicated into hundreds of copies within one bacterium, which then burst out of the cell (lysis), causing the bacterium to die[84].

This approach is in the nascent stages of evaluation as a therapeutic option in the context of ever-increasing MDR infections. Schooley et al[85] reported the successful use of a personalized bacteriophage-based therapeutic cocktail to treat a patient with a disseminated, resistant Acinetobacter baumannii infection. Animal studies of phage cocktails and phage-antibiotic synergy against MDR infections are promising[86]. Further preclinical and clinical trials and standardization of phage cocktails are required before phage therapy can be added to the treatment arsenal. In the context of MDR infections in KT recipients, the safety of phage therapy needs to be proven conclusively before clinical application.

Monoclonal antibodies

Monoclonal antibodies (mAbs) offer a strategy of passive immunization, providing immediate, pathogen-specific immunity. mAbs act as precision tools that spare the host microbiome. Bezlotoxumab, a human monoclonal antibody against CD toxin B, has been shown to be effective in preventing recurrent CDI[87]. However, clinical trials evaluating mAbs targeting infections caused by MRSA and Pseudomonas aeruginosa have failed to demonstrate clear clinical benefit[88].

Vaccines

Vaccination represents a critical yet underutilized pillar of antimicrobial stewardship. By preventing infections before they occur, vaccines can substantially reduce antibiotic consumption and the resulting selection pressure for antimicrobial resistance. Clinical trials of vaccines targeting Staphylococcus aureus and Escherichia coli have so far failed to demonstrate efficacy in preventing infections[89].

Despite the high burden of infectious complications in KT recipients, clinical management remains largely empirical. Treatment decisions are often extrapolated from data in non-immunocompromised populations rather than grounded in transplant-specific evidence. This gap arises from multiple factors, including the paucity of randomized controlled trials in KT recipients, limited precision PK data for novel antimicrobials in this cohort, ongoing controversy surrounding MDR decolonization strategies, and the still nascent integration of artificial intelligence into predictive infection modeling for this population.

MOLECULAR RAPID DIAGNOSTIC TECHNIQUES

Delayed administration of effective antibiotics increases mortality risk, making early, appropriate antibiotic selection paramount. Molecular rapid diagnostic testing - including PCR, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and peptide nucleic acid fluorescent in situ hybridization - has improved upon conventional microbiologic methods by shortening time to organism identification, optimizing antimicrobial therapy, and improving clinical outcomes, including mortality[90].

Use of molecular rapid diagnostic testing in conjunction with a structured antibiotic stewardship program has been shown, in a systematic review and meta-analysis by Timbrook et al[91] to reduce mortality, shorten hospital length of stay, and decrease time to effective therapy. This shift from traditional phenotypic methods requiring 48-72 hours to rapid molecular or phenotypic assays that deliver results within 1-4 hours represents a paradigm shift in the management of drug-resistant bacterial infections, particularly in KT recipients, in whom unnecessary exposure to broad-spectrum and potentially nephrotoxic antibiotics can be avoided without compromising clinical outcomes.

THERAPEUTIC DRUG MONITORING AND DRUG INTERACTIONS

The PK profile of antibiotics in KT recipients is highly variable because of fluctuating allograft function, altered volumes of distribution, and complex drug-drug interactions with maintenance immunosuppression. Therapeutic drug monitoring is standard practice for calcineurin inhibitors, but its application to antimicrobials in KT recipients remains underutilized. Recent pharmacokinetic/pharmacodynamic and toxicodynamic studies have shown that vancomycin area under the curve/minimum inhibitory concentration-guided monitoring significantly reduces overall drug exposure and nephrotoxicity compared with traditional trough-based monitoring, without compromising clinical outcomes[92].

Trough level monitoring of linezolid is recommended in the setting of graft dysfunction to avoid dose-limiting thrombocytopenia, with emerging data suggesting that trough concentrations above approximately 6-7 μg/mL are associated with a higher risk of hematologic toxicity. Aminoglycosides have historically been avoided in KT recipients because of their potent nephrotoxicity; however, their use is resurging in the context of rising MDR pathogens such as CRE and ESBL producers. High-dose, extended-interval (once-daily) dosing is preferred, as it optimizes concentration-dependent killing while reducing the risk of nephrotoxicity compared with multiple daily dosing schedules. Finally, potential interactions between antibiotics and the metabolism of calcineurin inhibitors should always be considered when selecting antimicrobial regimens for KT recipients, to avoid toxic or subtherapeutic immunosuppressant levels.

CONCLUSION

MDR bacterial infections now represent a central threat to survival and long-term allograft function after kidney transplantation, yet management remains constrained by limited transplant-specific evidence. By integrating rapid molecular diagnostics, rational use of novel and traditional antimicrobials, individualized perioperative prophylaxis, and vigilant stewardship to minimize unnecessary exposure, clinicians can begin to curb resistance while preserving nephron mass. Future priorities include adequately powered trials in KT recipients, pharmacokinetic and pharmacodynamic studies of new agents in this population, and incorporation of predictive analytics to better stratify risk and personalize anti-infective strategies.