Increased resistance of gram-negative urinary pathogens after kidney transplantation

Urinary tract infection (UTI) is the most common infection after kidney transplantation [1‐3]. It is also one of the most common causes for allograft failure, sepsis and mortality after transplantation. The risk for UTI after kidney transplantation is highest during the first year of transplantation with up to 60% [4]. Other risk factors are advanced age, female sex, diabetes mellitus and vesicoureteral reflux [5].

The incidence of drug resistant urinary pathogens seems to be increasing and has become a rising therapeutic challenge for clinicians. Drug resistant strains seem to have significant negative impact on the clinical course [6‐9]. The rising incidence of resistant strains may be due to high antibiotic exposure. Antibiotic exposure could be identified as a risk factor for emerging resistance in gram-negative bacteria in other settings [10]. The antibiotic exposure after kidney transplantation is elevated due to treatment of asymptomatic bacteriuria (ASB) and pneumocystis pneumonia (PCP) prophylaxis.

The current treatment strategies of UTI after kidney transplantation are not defined or standardized. Most transplant center strategies include antibiotic treatment of ASB [11, 12]. The local UTI treatment strategy of the University Hospital Essen contains treatment of ASB as well [13].

This study investigates the prevalence of urinary pathogens and the resistance patterns in a cohort of kidney transplant patients during a period of 4 years (2009–2012) [14‐16].

From 2009 to 2012 a large number of 15.741 urine samples were obtained from 859 patients (324 (38%) male, 535 (62%) female). The average age of the patients was 54 years. Bacterial growth was detected in 2985 of 15.741 (19%) samples. In 2009 911/3931 (23%), in 2010 667/4310 (16%), in 2011 652/3566 (18%), and in 2012 755/3934 (19%) were tested positive.

In the present study, we found that the species-specific prevalence of urinary tract infections remained stable between 2009 and 2012 in our cohort of renal transplant patients. Interestingly, the resistance pattern of E.coli and P. aeruginosa did not significantly shift over time. In contrast, the prevalence of ESBL producing and chinolone-resistant Klebsiella spp. increased steadily between 2009 and 2012.

In the literature E.coli is the most detected gram negative pathogen causing UTI with up to 38% [19, 20]. This can be confirmed with our present data. In addition no difference of the species distribution was detected from 2009 to 2012. The most frequent prescription of trimethoprim-sulfamethoxazole, ciprofloxacin and cefuroxime reflects the adherence to local guidelines for i. Pneumocystis pneumonia prophylaxis and ii. UTI. The lesser prescription of trimethoprim-sulfamethoxazole in 2012 compared to 2010 (−11%) is based on its primary use for Pneumocystis pneumonia prophylaxis in our center. It reflects the deceasing number of renal transplantations in Germany from 2010 to 2012 with −12,8% [21]. The high rate of nitrofurantoin ddd in 2012 shows the influence of clinical (practice) guidelines for uncomplicated UTI published in 2011 by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases which recommends nitrofurantoin for uncomplicated UTI [22]. Furthermore nitrofurantoin may represent the use for ESBL-producing E. coli, as it shows to be an efficacious agent for UTI caused by ESBL-producing E. coli [23].

Resistance of gram-negative strains increased during the last decades. Pathogens with distinct resistance against multiple groups of antibiotics are associated with increased mortality, longer hospital stays, and higher hospital costs [24, 25]. In our cohort, the prevalence of multi-resistant Klebsiella spp. increased steadily whereas E.coli as well as P. aeruginosa showed no significant change in resistance pattern. The increase of multi-resistant Klebsiella spp. isolates did not seem to have an impact on the number of urosepsis cases per year in our cohort, although the amount of Klebsiella spp. isolated in urosepsis cases increased steadily. Interestingly, increasing resistance of gram negative isolates has been observed in other cohorts, too [6, 16, 26‐28]. In general, previous antibiotic exposure and increased broad-spectrum antibiotic consumption could be identified as risk factors for increasing resistance. After solid organ transplantation (SOT) additional risk factors are delayed graft function, diabetes mellitus and relapsing UTI [26, 29, 30]. Therefore we hypothesize that rising antimicrobial resistance of gram negative pathogens could be influenced by the present UTI treatment strategy.

In contrast to other reports, the shift of resistance pattern was limited to Klebsiella spp. in our cohort; the resistance pattern of other gram-negative pathogens remained unchanged over time. The reason why increased antibiotic resistance was limited to Klebsiella spp. isolates in our cohort remains unknown.

In our cohort, recurrent pathogen detection was linked to a higher rate of antimicrobial resistant E.coli and Klebsiella spp. detection. Recurrent detection of resistant pathogens may be due to insufficient first-line treatment, since quinolones and cephalosporins are included in the local UTI treatment guideline. Further more in literature MDR pathogens are frequent in kidney recipients with recurrent UTI [19]. This could be another explanation for the association of resistant pathogen detection in multiple urinary cultures, because renal transplant patients with recurrent or persistent UTI receive intensive follow up monitoring including repeated urinary cultures.

To challenge pathogen resistance, the reduction of antibiotic exposure is currently under discussion. The impact of the rational use of antibiotics on antimicrobial susceptibility remains controversial. A swedish study could not show an influence of rational antibiotic use on penicillin-resistant Streptococcus pneumoniae, although reduction of antibiotic use could be observed [31]. One prospective study of kidney transplant recipients with ASB showed no greater incidence of multi-drug resistant pathogens in patients receiving treatment for ASB compared to patients remaining untreated [32]. However, this study was limited to 115 patients and a follow up of 24 months.

Though, the majority of studies showed that resistance can be reduced by introducing antimicrobial stewardship programs [33, 34]. The stewardship programs recommend the use of the antibiotics with the narrowest spectrum possible. In addition limitation of the therapy duration is recommended.

However, in patients after SOT, reduction of antibiotic exposure is challenging. Trimethoprim-sulfamethoxazole prophylaxis is used for Pneumocystis pneumonia prophylaxis. The prophylaxis is crucial for survival after SOT [35]. Therefore it cannot be suspended, although it is associated with increased amoxicillin and trimethoprim-sulfamethoxazole resistance in gram-negative bacteria [36]. Even in our study, resistance of Klebsiella spp. isolates to trimethoprim-sulfamethoxazole increased significantly.

There are additional strategies to reduce antibiotic exposure and to strengthen rational antibiotic treatment. The differentiation between UTI and ASB should be implemented in future strategies. UTI after renal transplantation has a great impact on the transplant outcome. Gołębiewska et al. evaluated the influence of UTIs on renal graft function in a cohort of 209 adult renal transplant recipients. They observed 322 UTI episodes in 111 patients, including asymptomatic bacteriuria, lower and upper UTIs and urosepsis. Graft function was significantly worse in patients suffering from UTI [37]. Furthermore Pelle et al. investigated in a cohort of 177 renal transplant recipients that patients with upper UTIs (acute pyelonephritis) exhibited a decrease in creatinine clearance compared to patients with uncomplicated UTI 1 year after transplantation, which was still persistent 4 years after transplantation [18]. In addition Dharnidharka et al. investigated that the risk for graft loss after early UTI was elevated in a cohort of under aged renal transplant patients [38]. Therefore treatment for UTI is warrantable. In the context of “choosing wisely”, the antibiotic treatment of ASB is controversial [39]. A Cochrane Renal Group’s Specialized Register analysis could not find a clinical benefit of ASB treatment [40]. Even in the cohort of kidney transplant patients, treatment strategies for ASB are currently changing. However, untreated ASB within the first 3 months of transplantation has been identified as an independent risk factor for acute cellular rejection. [41]. In contrast ASB is not associated with short-term graft function impairment [42]. Therefore, treatment should be considered early after transplantation but maybe obsolete at a later time point [43]. Alternatively, patients with ASB could be monitored. Treatment should be initiated in case of decreasing kidney function or UTI symptoms [41]. This strategy may prevent unnecessary antibiotic exposure.