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Article

Urinary Tract Infections with Carbapenem-Resistant Klebsiella pneumoniae in a Urology Clinic—A Case-Control Study

by
Viorel Dragos Radu
1,2,
Radu Cristian Costache
1,2,
Pavel Onofrei
3,4,*,
Adelina Miron
1,2,
Carina-Alexandra Bandac
2,
Daniel Arseni
2,
Mihaela Mironescu
2,
Radu-Stefan Miftode
5,
Lucian Vasile Boiculese
6 and
Ionela-Larisa Miftode
7
1
Department of Urology, Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania
2
Department of Urology and Renal Transplantation, “C.I. Parhon” University Hospital, 700115 Iasi, Romania
3
Department of Morpho-Functional Sciences II, Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania
4
Department of Urology, Elytis Hope Hospital, 700010 Iasi, Romania
5
Department of Internal Medicine I, Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania
6
Department of Preventive and Interdisciplinarity, Medical Informatics and Biostatistics, Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania
7
Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, University of Medicine and Pharmacy “Gr. T. Popa”, 700115 Iasi, Romania
*
Author to whom correspondence should be addressed.
Antibiotics 2024, 13(7), 583; https://doi.org/10.3390/antibiotics13070583
Submission received: 27 May 2024 / Revised: 19 June 2024 / Accepted: 20 June 2024 / Published: 24 June 2024
Review Reports Versions Notes

Abstract

:
Background: The aim of our study was to analyze the factors associated with the increased risk of urinary tract infection (UTI) with carbapenem-resistant (CR) Klebsiella pneumoniae (Kpn) and the antibiotic resistance spectrum of the strains in patients. As secondary objectives, we elaborated the profile of these patients and the incidence of different types of carbapenemases. Methods: We conducted a retrospective case-control study in which we compared a group of 62 patients with urinary tract infections with CR Kpn with a control group consisting of 136 patients with urinary tract infections with multidrug-resistant (MDR), but carbapenem-sensitive (CS), Kpn, who were hospitalized between 1 January 2022 and 31 March 2024. Results: Compared to patients with urinary tract infections with CS Kpn, patients with urinary tract infections with CR Kpn were preponderant in rural areas (62.9% vs. 47.1%, p = 0.038) and more frequently had an upper urinary tract infection (69.4% vs. 36.8%, p < 0.01). Among the risk factors examined, patients in the study group had a higher presence of urinary catheters inserted for up to one month (50% vs. 34.6%, p = 0.03), rate of hospitalization in the last 180 days (96.8% vs. 69.9%, p < 0.01) and incidence of antibiotic therapy in the last 180 days (100% vs. 64.7%, p < 0.01). They also had a higher rate of carbapenem treatment in the last 180 days (8.1% vs. 0%, p < 0.01). Patients in the study group had a broader spectrum of resistance to all antibiotics tested (p < 0.01), with the exception of sulfamethoxazole–trimethoprim, where the resistance rate was similar in both groups (80.6% vs. 67.6%, p = 0.059). In the multivariate analysis, transfer from other hospitals (OR = 3.51, 95% and CI: 1.430–8.629) and treatment with carbapenems in the last 180 days (OR = 11.779 and 95% CI: 1.274–108.952) were factors associated with an increased risk of disease compared to the control group. The presence of carbapenemases was observed in all patients with CR Kpn, in the order of frequency New Delhi metallo-ß-lactamase (NDM) (52.2%), Klebsiella pneumoniae carbapenemase (KPC) (32.6%), and carbapenem-hydrolyzing oxacillinase (Oxa-48) (15.2%). Conclusions: The environment of origin and previous treatment with carbapenems appear to be the factors associated with an increased risk of urinary tract infection with CR Kpn compared to patients with urinary tract infections with CS Kpn. CR Kpn exhibits a broad spectrum of antibiotic resistance, among which is resistance to carbapenem antibiotics.

1. Introduction

In recent decades, more and more cases of CR Enterobacteriaceae infections have been reported worldwide [1,2]. The production of enzymes called carbapenemases is the main cause of resistance of Enterobacteriaceae to carbapenem antibiotics [3,4]. The majority of infections with Enterobacteriaceae that are CR are found in the urinary tract [5]. Kpn is one of the most common Gram-negative bacteria that are CR and cause urinary tract infections [2,6,7,8], although the reason for its prevalence compared to other Enterobacteriaceae is not known [9]. In South-Eastern Europe, Kpn is the most common CR Enterobacteriaceae, more common than E. coli, and thus plays an important role in the spread of antibiotic resistance [10].
These MDR infections are most commonly hospital-acquired infections associated with medical procedures [11,12]. Kpn is a commensal pathogen that occurs in the gastrointestinal tract, oral cavity, and nasopharynx [13], and causes 10% of nosocomial infections [14]. Kpn, including CR Kpn, can also be found in non-clinical environments, such as meat, seafood and vegetable samples [15]. In recent years, most extraintestinal infections with Kpn are multidrug-resistant [16]. Numerous risk factors for the occurrence of urinary tract infections with CR Kpn have been investigated, many of which are consistent with the risk factors for MDR urinary tract infections with Enterobacteriaceae. These include previous hospitalization, prolonged antibiotic treatment [4,17], comorbidities and invasive procedures [18,19,20], previous carbapenem use, number of patients admitted in the intensive care units (ICU) [20,21,22], presence of urinary catheters [19,23], previous colonization [23,24,25], and the formation of a bacterial biofilm on both the urothelial mucosa and abiotic surfaces such as urinary catheters [26,27,28,29].
Urinary tract infections with CR Kpn require prolonged antibiotic therapy and have a slow evolution and increased mortality [4,7]. However, to our knowledge, no study of this infection has been conducted in a urology clinic, where there are likely to be many patients with this disease. Most studies have been conducted in general hospitals or intensive care units [4,6,22,30,31]. It is not known what the patient profile and risk factors are for the occurrence of urinary tract infections with CR Kpn compared to urinary tract infections with MDR Kpn sensitive to carbapenems in a urology clinic. There are no current studies on the type of surgical procedures that favor the occurrence of urinary tract infections with CR Kpn in a urology clinic. Also, the sensitivity spectrum of germs is constantly changing and there are no recent studies in our geographic area that have analyzed this.
In recent years, we have observed an increase in the frequency of urinary tract infections with CR Kpn in our clinic. Therefore, we conducted a case-control study in which we analyzed the risk factors for the occurrence of urinary tract infections with CR Kpn compared to urinary tract infections with MDR Kpn sensitive to carbapenems and the resistance spectrum of the bacterium. We also analyzed the profile of patients in the two groups, the sensitivity spectrum of Kpn in the two groups, and the presence of enzymes conferring resistance to carbapenems in the case of the study group.
Our study is of interest not only to urologists, but also to infectious disease doctors, internal medicine doctors, and intensive care doctors, who treat this type of patient, and it is also a contribution to a better understanding of the worldwide spread of this type of germ, known for its wide distribution. It also helps in understanding of circulation of Kpn bacteria that possess enzymes that confer resistance to carbapenems.

2. Results

Between 1 January 2022 and 31 March 2024, there were 198 patients with urinary tract infections with MDR Kpn who met the inclusion criteria. Among them, 62 patients with UTIs with CR Kpn formed the study group, and the remaining 136 patients had UTIs with MDR Kpn that was carbapenem-sensitive. Table 1 shows the demographics of the patients in the two groups, the presence of comorbidities, urosepsis on admission, mortality rate, and transfer from other hospitals.
Patients in both groups had an average age of over 60 years, with the same frequency in men (59.7% vs. 53.7%, p = 0.43) and women (40.3% vs. 46.3% p = 0.52). Patients in the study group had a statistically significantly higher incidence of rural origin (62.9% vs. 47.1%, p = 0.038) and urinary tract infection at the renal level (69.4% vs. 36.8%, p < 0.01), compared to the control group. Regarding comorbidities, both groups had an increased incidence of DM (33.9% vs. 26.5%, p = 0.28), neoplasia (46.8% vs. 36%, p = 0.15), anemia (60.7% vs. 58.1%, p = 0.73), and obesity (24.2% vs. 20.6%, p = 0.56), but without significant statistical differences. Instead, we observed an increased incidence in favor of the study group in terms of the presence of renal failure (67.7% vs. 50.7%, p = 0.025) and neurological disorders (19.4% vs. 7.4%, p = 0.013). In the control group, the proportion of patients with arterial hypertension was higher (69.1% vs. 50%, p = 0.01).
Although the rate of presence of urosepsis on admission and mortality was higher in percentage terms in the study group, there were no statistically significant differences between these variables. We also note that there was a higher incidence of cases transferred from other hospitals in the study group (24.2% vs. 8.8%, p < 0.01).
Table 2 shows the presence of urinary catheters at the time of diagnosis, according to the type and duration of their presence until the time of diagnosis of urinary tract infection with Kpn in the two groups.
We observed a very high percentage of patients with catheters at the time of diagnosis in the two groups (88.71% vs. 83.1%, p = 0.26), most frequently double-J catheters (46.8% vs. 36.8%, p = 0.18) and Foley urethral catheters (29% vs. 25.7%, p = 0.62), but also nephrostomy catheters, cystostomy catheters, and cutaneous ureterostomy catheters, with no statistically significant differences between the two groups. Instead, patients in the study group had a higher incidence of catheters inserted earlier than one month compared to the control group (50% vs. 34.6%, p = 0.03).
Table 3 shows the comparisons of the frequency of occurrence of the investigated risk factors.
Patients with urinary tract infections with CR Kpn had a higher rate of hospitalization and antibiotic therapy in the last 180 days compared to the control group (p < 0.01). They also had more days of hospitalization (p = 0.034). Regarding the type of urological procedures, patients in the study group had more insertions/replacements of nephrostomy catheters (p < 0.01), but fewer insertions/replacements of Foley urethral catheters (p < 0.01) and percutaneous nephrolithotomies (p = 0.037).
Moreover, all types of interventions, including the insertion and replacement of ureteral double-J catheters occurred in similar, statistically insignificant percentages. However, it should be noted that almost half of the patients in both groups had a history of double-J catheter insertion or replacement (46.8% and 38.2%, respectively, p = 0.25).
Multivariate analysis showed that for patients, transfer from other hospitals and previous carbapenem treatment were factors associated with an increased risk of CR Kpn UTI compared to CS Kpn UTI: OR = 3.512 (95% CI: 1.430–8.629) and OR = 11.779 (95% CI: 1.274–108.952). On the other hand, patients wearing a Foley urethral catheter had a lower risk of CR Kpn UTI (OR = 0.164).
Table 4 shows the frequency of antibiotic resistance in the two groups. The first 14 antibiotics were tested in all patients enrolled in the study.
We note that in addition to resistance to carbapenems, patients in the study group had a urinary tract infection with Kpn with an extended spectrum of resistance (statistically significant) to all commonly used antibiotics compared to the control group, with the exception of sulfamethoxazole–trimethoprim, where resistance occurred in approximately the same percentage (80.6% vs. 67.6% p = 0.059).
All patients in the study group showed resistance to meropenem, and 55 of 62 patients (90.3%) showed resistance to imipenem. Colistin was tested in 43 patients, of whom 13 (30%) showed resistance. Tigecycline was tested in four patients, all with resistance. Aztreonam was tested in six patients, and four showed resistance. Ceftazidime/avibactam was tested in five patients, and four showed resistance. Cefpozolam/tazobactam was tested in five patients, all with resistance. Imipenem/cilastatin/relebactam was tested in five patients, three of whom showed resistance. Four patients showed resistance to all 14 commonly tested antibiotics, including colistin. One case showed resistance to all 14 routinely tested antibiotics, including colistin, tigecycline, and aztreonam.
Table 5 shows the type of enzymes that confer Kpn resistance to carbapenems for the isolates of 30 patients examined.
Of the five enzymes tested, three were highlighted, and all isolates of the 30 patients presented one or two enzymes. The most common was NDM (38.7%), followed by KPC (24.2%) and Oxa-48 (11.3%). In 25.8% of patients, i.e., more than a quarter, Kpn with two enzymes was detected.

3. Discussions

Patients with CR Kpn had a higher incidence of upper urinary tract infections and a higher rate of patients transferred from other hospitals than patients with CS Kpn. Patients from both groups had a high incidence of the presence of urinary catheters of any type, but in patients with CR Kpn, catheters inserted earlier than one month predominated. Patients with CR Kpn had a history of urologic procedures; many of them remained with permanent urinary catheters, had a higher rate of carbapenem treatment, and more hospital days compared to patients from the control group. Patients in both groups showed increased resistance to the antibiotics commonly used in urology. The resistance to carbapenems is due to the presence of NDM, KPC, and Oxa-48 enzymes.
To our knowledge, there are few internation and local studies in the literature that analyze the profile of patients with CR Kpn UTIs in a urology clinic, as well as the risk factors and spectrum of bacterial sensitivity in this particular group of patients [32,33,34]. The main limitation of the study is its retrospective nature. Another limitation of our study is that we analyzed the presence of enzymes conferring resistance to carbapenems in only 30 of the 62 patients in the study group. In addition, some patients who underwent surgery in our clinic were monitored in other departments, and it is likely that those diagnosed with CR Kpn UTIs were treated in other urology or infectious disease departments. Conversely, a significant percentage of patients with CR Kpn UTIs were transferred from other departments, making it difficult to accurately determine the incidence of this infection in our clinic. However, this does not affect the identification of patient profiles, factors associated with increased risk, and the spectrum of sensitivity. Another potential bias is that we could not determine the number of previous hospitalizations for each patient, although we know that each hospitalization can increase the risk of MDR-UTI.
As expected, the profile of the CR Kpn UTI patients is similar to that of the control group. The predominant age is over 60 years with a higher mortality potential [35,36], as most patients requiring urological interventions are elderly. Although women are in principle more susceptible to urinary tract infections, we did not find any difference between genders in our study. The localization of urinary tract infections in the upper urinary tract is explained by the higher incidence of double-J ureteral catheters and nephrostomy catheters in the study group patients, while in the control group there was a greater number of patients with a permanent urethral catheter. The presence of a large number of comorbidities indicates the sensitivity of these patients to develop UTIs by lowering the body’s immunity. DM, neoplasia, and anemia are known factors for reducing host defenses against infection, but they did not appear to be factors that increased the incidence of CR Kpn UTI. The fact that there were a greater number of patients with renal failure in the study group is explained by the likely high incidence of patients with sepsis and secondary organ failure. We mention that we could not determine whether the patients had normal renal function before the UTI, so we could not assess whether the renal failure was pre-existing or secondary to sepsis, so we cannot conclude that renal failure could increase the risk of UTI with CR Kpn. Neurological disorders were the only comorbidities that occurred more frequently in the study group compared to the control group. The fact that patients in both groups had a high rate of urosepsis on admission, as in other studies [37], demonstrates the aggressiveness of MDR Kpn. However, mortality was lower, demonstrating the better prognosis of urosepsis of urinary origin.
An interesting result of our study was the higher incidence of patients transferred from other hospitals in the study group in multivariate analysis. These findings can be explained by the aggressiveness of the infection and perhaps the limited possibilities of antibiotic treatment in other hospitals, as well as the need for urgent urological intervention, which is not possible in other hospitals. However, the occurrence of CR Kpn in other secondary hospitals in the north-eastern region of Romania indicates a wide distribution and the fact that this resistance to carbapenems may occur in several regions probably after similar treatments with antibiotics.
As in other studies [18,19,20,38,39,40], as expected, antibiotic therapy and previous hospitalization together with urological procedures were predominant in both groups of patients, showing a high probability that these infections were nosocomial hospital infections, especially since colonization in the general population with CR Kpn has not been reported in our country. However, the statistically significant higher rate in the study group shows that these factors intervene to a greater extent in the occurrence of urinary tract infections with CR Kpn. The ICU admissions were similar in both groups, occurring in patients previously diagnosed with CR Kpn and CS Kpn UTIs, so we could not prove that ICU admissions were risk factors in the case of our group, as in other studies [17,22]. Although we did not have the opportunity to find out how many previously operated patients were hospitalized in the ICU, most of the patients described in our study who underwent this type of surgery were not routinely hospitalized in the ICU.
Previous treatment with carbapenems has been shown to be associated with an increased risk of urinary tract infection with CR Kpn, even in multivariate analysis. However, in percentage terms, this factor occurred in less than 10% of patients, which indicates that other factors are also involved in the occurrence of resistance to carbapenems.
The insertion/replacement of double-J catheters were the most common operations performed in both groups before the occurrence of MDR-UTI although these procedures were frequently performed as emergencies in our clinic. Percutaneous nephrostomy was performed more frequently in the study group, an operation that was also predominantly performed as an emergency, as was the insertion of double-J catheters for obstructive pyelonephritis, i.e., in patients who already had a urinary tract infection and who were administered antibiotics, most frequently injectable cephalosporins, sometimes over long periods of prolonged hospitalization, which probably contributed to the emergence of bacterial resistance. On the other hand, in patients with CS Kpn UTIs, Foley urethral catheters were inserted and changed more frequently, resulting in a higher lower tract UTI incidence, thus explaining the lower number of hospital days and shorter duration of antibiotic treatment. At the same time, only a few of these patients were admitted to hospital, as this procedure was performed on an outpatient basis. This explains the lower incidence of urinary tract infections in these patients with CR Kpn due to the lower rate of hospitalization, the less frequent antibiotic therapy, and the shorter duration of antibiotic treatment. Although we observed a higher rate of percutaneous nephrolithotomy in the control group, we cannot say that this type of surgery has a lower risk for the subsequent occurrence of urinary tract infections with CR Kpn, probably because the shorter hospital stay and antibiotic therapy as well as the rapid extraction of the nephrostomy tube after surgery explain this.
As in other local studies [34,41,42] showing the presence of urinary catheters in association with Kpn UTIs, the current study also found a high presence of patients with urinary catheters at the time of diagnosis. Numerous studies have demonstrated bacterial colonization of catheters, including with Kpn through its ability to bind to biotic and abiotic surfaces via fimbriae [43]. After fixation, the germs form a bacterial biofilm [26,29,37,44], an element of bacterial persistence and the development of resistance to carbapenems [27]. We have shown that not only does the presence of Foley urethral catheters confer a risk of urinary tract infection with CR Kpn [6], but also the presence of double-J ureteral catheters, nephrostomy, cystostomy, or ureterostomy double-J catheters, as in other studies [26,27,29].
The actual incidence of patients with permanent urethral catheters and urinary tract infections with CR Kpn is therefore likely to be higher. The fact that patients with UTIs with CR Kpn were more likely to have catheters installed for less than one month indicates that infection is likely to occur more rapidly and perhaps more frequently than in patients with urinary catheters but colonized with CS Kpn, even if they are also MDR, due to increased aggressiveness after colonization. Our results suggest that all measures should be taken to reduce the indication of chronic wear of urinary catheters, especially double-J ureteral catheters, and to shorten the time to their removal if they do need to be inserted. CR Kpn UTI was obviously a nosocomial infection, even if the diagnosis was made at the time of readmission. In patients discharged without indwelling urinary catheters, the infection rate was low, although patients were exposed to the same risk of infection in hospital as patients with urinary catheters. In other local studies, we have not reported the occurrence of MDR UTIs in patients discharged without urinary catheters [45]. It is likely that a normal urinary system without a urinary catheter does not develop UTIs despite possible contamination with CR Kpn, which is why we do not suggest screening all discharged patients for MDR UTIs as in other studies [46], but only those patients discharged with urinary catheters, especially if their removal is not expected for a long time.
Regarding antibiotic resistance, we note that in addition to the presence of resistance to carbapenems, the study group also had a higher rate of resistance to quinolones and cephalosporins, and frequently to almost all antibiotics tested from these two groups, suggesting that the occurrence of carbapenem resistance depends on the same favorable factors as the occurrence of resistance to other antibiotics. The only exception was sulfamethoxazole–trimethoprim, to which resistance was similar in both study groups. We note that, in contrast to other studies that reported increased resistance to imipenem as well as the presence of the enzyme imipenem-hydrolyzing metallo-beta-lactamases (IMPs) [47], in our study group all patients had resistance to meronem and not all patients to imipenem, without objectifying the presence of IMPs.
This can be explained by the predominant use of meronem for the treatment of carbapenem-sensitive MDR UTIs in our clinic, whereby the increased use led to the occurrence of resistance [48]. Antibiotic resistance was very different in the two groups, indicating the simultaneous presence of numerous serotypes of Kpn in the clinic. A favorable element for treatment options was the fact that a relatively high percentage of patients in the study group had a urinary tract infection with Kpn with preserved sensitivity to gentamicin, amikacin, fosfomycin i.v., or trimethoprim/sulfamethoxazole. Although it is considered a second-line drug [49], colistin had a high resistance rate, which is explained by the fact that it was frequently used in our clinic to treat urinary tract infections with CR Enterobacteriaceae and that resistance to this antibiotic occurs relatively quickly [46]. Of concern is the presence of resistance to last-generation antibiotics that were not as commonly used in the clinic, such as ceftozolan/tazobactam, ceftazidime/avibactam, or imipenem/cilastatin/relebactam, demonstrating the broad resistance of CR Kpn to multiple antibiotics. Despite the aggressiveness of the germs, however, mortality was low, which indicates a mostly favorable evolution of the infection with CR Kpn at the urinary tract level.
Regarding the mechanism by which Kpn acquires resistance to carbapenems, we were able to demonstrate that the most important mechanism is the secretion of carbapenemases. The enzymes we identified are NDM, KPC, and Oxa-48, with some germs even presenting two enzymes. Although the presence of KPC was first reported in the United States and the presence of NDM in Asia [47], their identification in our country demonstrates the virtually worldwide distribution of Kpn genes resistant to carbapenems.
CR Kpn is constantly on the rise in hospitals and in the north-eastern region of Romania, and the occurrence of pan-drug resistant germs will pose serious problems for the public health system in our country. Therefore, the prudent use of antibiotics by shortening the duration of administration and the fastest possible removal of urinary catheters, as well as the shortening of waiting times of patients with indwelling urinary catheters until definitive endoscopic urological treatment, are proposals to limit the transmission of these germs, including carbapenem-sensitive MDR germs, and further directions of study.

4. Materials and Methods

4.1. Patient Selection and Data Collection

We conducted a retrospective case-control study in patients diagnosed with MDR UTIs with Kpn between 1 January 2022 and 31 March 2024 at the urology clinic of the Teaching Hospital “Dr. C.I. Parhon” in Iasi, Romania. The patient data were retrieved from the electronic documents of the hospital using the ICD-10 code from the International Classification of Diseases, 10th edition. We identified all patients who had the code B96.1 (Klebsiella pneumoniae, the cause of some diseases classified in other chapters). It should be mentioned that all identified patients had a urinary tract infection. There was a single case associated with a urinary tract infection and colonization with Kpn in the tracheal aspirate, with the bacteria having the same sensitivity spectrum. As they did not have an antibiogram in the electronic data, 4 patients were excluded from the study. The 214 identified patients were divided into two groups based on the antibiogram prepared in the hospital’s microbiology laboratory, depending on whether resistance to carbapenems was present. The study group consisted of all patients with Kpn urinary tract infections resistant to at least one carbapenem, defined as CR [50], and the rest of the patients had Kpn urinary tract infections sensitive to all tested carbapenems.
Among the latter, there were 14 patients with a urinary tract infection with multidrug-sensitive Kpn who were excluded from the study, as well as two cases with a urinary tract infection with MDR Kpn and an infection associated with COVID-19, as we were unable to determine whether the infection with Kpn occurred before that with COVID-19 so we could consider the COVID-19 infection as a risk factor. The remaining patients with urinary tract infections with MDR Kpn who showed preserved sensitivity to carbapenems formed the control group. We defined MDR as all germs that showed resistance to at least one antibiotic from at least 3 different classes [51]. For the diagnosis of urosepsis, we used the definition from the third international consensus definitions for sepsis and septic shock (Sepsis 3) [52].

4.2. Microbiology Methods

A urinary tract infection was diagnosed in the presence of a positive urine culture and clinical and paraclinical phenomena suggestive of a urinary tract infection (pollakiuria, urinary urge, pyuria or cloudy urine due to leukocytes, dysuria, febrile syndrome, lower back pain, and leukocytosis). We defined a positive urine culture if it was above 105 UFC/mL. Antimicrobial susceptibility testing was performed by the disk diffusion method using the EUCAST clinical breakpoint for interpretation of minimum inhibitory concentrations and zone diameters.
The following antibiotic discs (producer: MAST GROUP LTD, Mast House, UK) were used: ampicillin (10 µg), amoxicillin–clavulanic acid (10–20 µg), cefuroxime (30 µg), ceftriaxone (30 µg), ceftazidime (10 µg), cefepime (30 µg), piperacillin–tazobactam (6–30 µg), ciprofloxacin (5 µg), levofloxacin (5 µg), imipenem (10 µg), meropenem (10 µg), gentamicin (10 µg), amikacin (30 µg), fosfomycin (200 µg), aztreonam (30 µg), nitrofurantoin (100 µg), trimethoprim–sulfamethoxazole (1.25–23.75 µg), ceftazidime–avibactam (4–10 µg)—ZAFICEFTA®, ceftozolan-tazobactam (10–30 µg)—ZERBAXA®, and imipenem/cilastatin/relebactam (10–25 µg)—RECARBIO®.
The results for sensitivity to tigecycline and colistin were reported after testing with the Microscan WalkAway DxM 1040 device (Beckman Coulter, Indianapolis, IN, USA) and we obtained the minimum inhibitory concentration (MIC) according to the EUCAST criteria; for tigecycline MIC < 0.5 mg/L sensitive and for colistin, MIC < 2 mg/L sensitive.
If the result of the antibiogram showed partial (intermediate) resistance, we considered resistance to this antibiotic. It should be mentioned that we did not have a single patient with a positive urine culture who did not have at least one clinical or paraclinical sign of a UTI. We did not have a single patient with Kpn in whom the urine culture was <105 UFC/mL. Urine cultures were obtained in the first hours after admission, before initiation of empirical antibiotic therapy and during hospitalization for suspected UTI. In 3 patients from the study group who had negative urine cultures on admission, the diagnosis of CR Kpn UTI was established by repeat urine cultures on days 9, 12, and 14.
All other patients in the study group were diagnosed by urine culture performed at the time of admission. In the control group, urinary tract infection with CS Kpn was diagnosed in 4 patients by urine cultures performed on days 5, 7, 12, and 15 after admission. The remaining patients in the control group were diagnosed by urine culture performed at the time of admission. The antibiogram was used to test for resistance to a range of 14 antibiotics in all patients in the study. In the study group, if resistance to carbapenems was detected or suspected, resistance to other antibiotics was also tested for at least one of the following antibiotics for each patient: colistin, aztreonam, tigecycline, ceftazidime/avibactam, cefpozolam/tazobactam, and imipenem/cilastatin/relebactam.
Isolates resistant to at least one carbapenem (according to the EUCAST criteria) were tested for the production of carbapenemases using the immunochromatographic test NG-Test CARBA5 (NG Biotech, Guipry, France), a rapid test that can detect 5 types of carbapenemases simultaneously: KPC (Kpn carbapenemase), NDM (New Delhi metallo-beta-lactamase), OXA-48 (oxacillinase), VIM (Verona integron-encoded metallo-beta-lactamase), and IMP (imipenemase, or IMP metallo-beta-lactamase). The last 30 patients with CR Kpn urinary tract infections enrolled in the study were tested for the presence of carbapenemases. We mention that we had no pregnant women and patients under the age of 18 in either group.

4.3. Outcome Measures

We compared the two patient groups in terms of gender, age, residence, type of urinary tract infection—upper or lower urinary tract—and comorbidities: presence of diabetes, neoplasia, renal and heart failure, anemia, neurological disease, hypertension, and obesity. We also analyzed the presence of urosepsis on admission, the number of patients transferred from other hospitals, and mortality in the two groups. All comorbidities considered in the study favor the occurrence of UTIs by lowering the body’s defense mechanisms or favoring the occurrence of some urological diseases that predispose to UTIs, such as the occurrence of renal lithiasis in immobilized patients with neurological diseases. As our hospital is a teaching hospital, it receives complex cases from other hospitals. For this reason, we analyzed the presence of urinary tract infections with Kpn before transferring from other hospitals in order to have a perspective on this infection at the level of the entire north-eastern region of Romania. The presence of urosepsis and mortality gives us information about the severity of urinary tract infection with Kpn in comparison of the two groups.
With regard to potential risk factors, we analyzed the presence of urinary catheters at the time of diagnosis, a recognized factor for increasing the incidence of MDR UTI [53], such as urethral catheters, double-J ureteral catheters, percutaneous nephrostomy catheters, cystostomy catheters, and percutaneous ureterostomy catheters. Regarding the presence of urinary catheters, we analyzed patients with catheters inserted earlier than one month ago and over one month separately in the two groups, knowing that the presence of catheters is a risk factor for bacterial colonization and the subsequent occurrence of infections. Other risk factors that were analyzed were hospitalization in the last 180 days, antibiotic therapy in the last 180 days, the percentage of patients who required hospitalization in the ICU, carbapenem therapy in the last 180 days, and the types of surgical procedures that preceded the UTI with Kpn and were performed up to 180 days before the UTI was diagnosed. All of these factors are recognized to promote the emergence of bacterial resistance, including the occurrence of UTIs with CR Enterobacteriaceae. We analyzed the resistance spectrum of Kpn in the two groups and the presence of the enzymes responsible for the resistance of Kpn to carbapenems in the last 30 patients of the study group.

4.4. Statistical Analysis

To describe the data statistically, we computed absolute and relative frequencies for categorical variables, while the mean and standard deviation were used for numerical variables. To compare the groups (univariate analysis) on the basis of statistical hypothesis, the t-test was used for the mean and the chi-square test for the frequencies. Fisher’s exact test (superscript F) was only used if chi-square consistency was not met. For primary data collection, we used Microsoft Excel version 2016 (Microsoft Corporation, Redmond, WA, USA), while data analysis was performed using SPSS version 24 (IBM, Armonk, NY USA).

5. Conclusions

The patients with CR Kpn UTIs were over 60 years of age and had multiple comorbidities, particularly neoplasia, DM and anemia. All patients with CR Kpn UTIs admitted to the urology clinic underwent urologic surgery, predominantly endoscopic, and had a history of antibiotics, with the most common surgeries being those in which patients remained urinary catheter carriers. Transfer from other hospitals and previous treatment with carbapenems appear to be factors associated with an increased risk of CR Kpn UTIs compared to patients with CS Kpn UTIs. Compared to the control group, the patients in the study group have an extended resistance spectrum that is not limited to resistance to carbapenems. The main pathway of Kpn resistance to carbapenems in the urologic clinic is the presence of carbapenemases and probably the formation of a bacterial biofilm on the surface of urinary catheters. Future prospective studies are needed to validate our results.

Author Contributions

Conceptualization, V.D.R., P.O. and I.-L.M.; methodology, V.D.R., P.O., M.M. and I.-L.M.; software, L.V.B.; validation, V.D.R., R.C.C. and A.M.; formal analysis, C.-A.B. and D.A.; investigation, C.-A.B. and D.A.; resources, M.M.; data curation, C.-A.B., D.A. and R.-S.M.; writing—original draft preparation, V.D.R. and P.O.; writing—review and editing, P.O., R.C.C. and I.-L.M.; visualization, R.-S.M. and L.V.B.; supervision, V.D.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Teaching Hospital “Dr. C.I. Parhon”, Iasi, Romania, protocol code 9679 of 24 November 2023. All the results were kept confidential, and all patients signed the hospital’s standard informed consent prior to any medical procedure, agreeing to the processing and publication of data for scientific purposes.

Informed Consent Statement

Patient consent was waived due to the retrospective nature of the study. However, all the patients signed a standard consent at admission in a university clinic, all the data being anonymously processed.

Data Availability Statement

Data are contained within the article.

Acknowledgments

We would like to thank Radu Mihaita Ouatu and Theodor Florin Pantilimonescu for the technical support in data curation, medical residents of the Teaching Hospital “Dr. C.I. Parhon”, Iasi, Romania, Urology Department.

Conflicts of Interest

The authors declare no conflicts of interest.

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Table 1. Characteristics of the patients in the two groups.
Table 1. Characteristics of the patients in the two groups.
Study Group (n = 62)Control Group (n = 136)p-Value for Chi-Square Test
Male37 (59.7%)73 (53.7%)0.43
Female25 (40.3%)63 (46.3%)
Age (mean ± SD)Male65.84 ± 14.0967.56 ± 12.980.52 t
Female64 ± 16.9760.95 ± 16.250.46 t
Residence area (U)23 (37.1%)72 (52.9%)0.038
Localization of UTIUpper UTI43 (69.4%)50 (36.8%)<0.01
Lower UTI19 (30.6%)86 (63.2%)
Comorbidities
Type 2 diabetes (DM)21 (33.9%)36 (26.5%)0.28
Neoplasia29 (46.8%)49 (36%)0.15
Kidney failure42 (67.7%)69 (50.7%)0.025
Heart failure12 (19.4%)36 (26.5%)0.27
Anemia37 (60.7%)79 (58.1%)0.73
Stroke sequelae (neurological disorders)12 (19.4%)10 (7.4%)0.013
Hypertension31 (50%)94 (69.1%)0.01
Obesity15 (24.2%)28 (20.6%)0.56
Urosepsis at the moment of admission32 (51.6%)57 (41.9%)0.20
Mortality5 (8.1%)4 (2.9%)0.14 F
Transfer from other hospitals15 (24.2%)12 (8.8%)<0.01
t—Student’s t-test; SD—standard deviation; F—Fisher’s exact test.
Table 2. Urinary catheters at the time of diagnosis.
Table 2. Urinary catheters at the time of diagnosis.
Study Group (n = 62)Control Group (n = 136) p-Value for
Chi-Square Test
Permanent urethral catheter18 (29%)35 (25.7%)0.62
Permanent double-J ureteral catheter29 (46.8%)50 (36.8%)0.18
Permanent nephrostomy catheter8 (12.9%)25 (18.4%)0.33
Permanent ureterostomy double-J catheter1 (1.6%)1 (0.7%)0.56 F
Permanent cystostomy catheter 2 (3.2%)5 (3.7%)0.99 F
Total permanent urinary catheters58 (3 patients had 2 urinary catheters) 93.5%116 (3 patients had 2 urinary catheters) 85.2%0.09
Total number of patients with permanent urinary catheters<1 month31 (50%)47 (34.6%)0.03
>1 month24 (38.71%)66 (48.5%)0.23
Total number of patients with permanent urinary catheters55 (88.71%)113 (83.1%)0.26
Total number of patients without urinary catheter at the time of hospitalization7 (11.29%)23 (16.9%)0.26
F—Fisher’s exact test.
Table 3. Risk factors of CR Kpn UTI.
Table 3. Risk factors of CR Kpn UTI.
Study Group (n = 62)Control Group (n = 136)p-Value for
Chi-Square Test
Hospitalization in the past 180 days60 (96.8%)95 (69.9%)<0.01
Antibiotherapy in the past 180 days62 (100%)88 (64.7%)<0.01
Hospitalization days (mean ± standard deviation)10.34 ± 9.737.48 ± 5.590.034
ICU stay (number of patients)7 (11.3%)8 (5.9%)0.18
Previous history of carbapenems treatment5 (8.1%)0 (0%)<0.01 F
Types of urological interventions performed before the diagnosis of MDR infections
TURP (+/− lithotripsy)2 (3.2%)5 (%)1 F
TURBT7 (11.3%)8(5.8%)0.18
Percutaneous nephrostomy tube insertion/replacement8 (12.9%)2 (1.4%)<0.01
Urethral catheter insertion/replacement4 (6.5%)38 (27.9%)<0.01
Percutaneous nephrolithotomy (PCNL)5 (8.1%)27 (19.9%)0.037
Double-J catheter insertion/replacement29 (46.8%)52 (38.2%)0.25
Open surgery4 (6.5%)4 (2.9%)0.26 F
Ureterostomy double-J catheter replacement10
Cystostomy2 (3.23%)0 (0%)0.09
Total patients with urological maneouvers, before the occurrence of MDR62136
F—Fisher’s exact test.
Table 4. Antibiotic resistance in the 2 groups.
Table 4. Antibiotic resistance in the 2 groups.
Study Group (n = 62)Control Group (n = 142)p-Value for Chi-Square Test
Ampicillin62 (100%)126 (92.6%)<0.01
Amoxicillin/acid clavulanic 62 (100%)102 (75%)<0.01
Trimethoprim/sulfamethoxazole 50 (80.6%)92 (67.6%)0.059
Nitrofurantoin60 (96.8%)81 (59.6%)<0.01
Ciprofloxacin62 (100%)106 (77.9%)<0.01
Levofloxacin62 (100%)91 (66.9%)<0.01
Cefuroxime62 (100%)89 (65.4%)<0.01
Ceftriaxone62 (100%)81 (59.6%)<0.01
Ceftazidime62 (100%)80 (58.8%)<0.01
Cefepime62 (100%)75 (55.1%)<0.01
Piperacillin/Tazobactam 59 (95.2%)24 (17.6%)<0.01
Imipenem56 (90.3%)0 (0%)<0.01
Meropenem62 (100%)0 (0%)<0.01
Gentamicin52 (83.9%)58 (42.6%)<0.01
Colistin (tested for 43 patients)13 (30%)Not tested
Fosfomycin53 (85.5%)Not tested
Amikacin51 (82.3%)Not tested
Nr. of cases resistant to one carbapenem 6 (9.67%)0 (0%)
Nr. of cases resistant to all carbapenem 56 (90.33%)0 (0%)
Table 5. Types of carbapenemases observed in the isolated specimens.
Table 5. Types of carbapenemases observed in the isolated specimens.
Isolates Tested (n = 30)Incidence (%)
Kpn enzymes
Isolates with KPC1524.2%
Isolates with Oxa-48711.3%
Isolates with NDM2438.7%
Isolates with 2 enzymes1625.8%
Total number of KPC, Oxa-48 and NDM detected46
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Radu, V.D.; Costache, R.C.; Onofrei, P.; Miron, A.; Bandac, C.-A.; Arseni, D.; Mironescu, M.; Miftode, R.-S.; Boiculese, L.V.; Miftode, I.-L. Urinary Tract Infections with Carbapenem-Resistant Klebsiella pneumoniae in a Urology Clinic—A Case-Control Study. Antibiotics 2024, 13, 583. https://doi.org/10.3390/antibiotics13070583

AMA Style

Radu VD, Costache RC, Onofrei P, Miron A, Bandac C-A, Arseni D, Mironescu M, Miftode R-S, Boiculese LV, Miftode I-L. Urinary Tract Infections with Carbapenem-Resistant Klebsiella pneumoniae in a Urology Clinic—A Case-Control Study. Antibiotics. 2024; 13(7):583. https://doi.org/10.3390/antibiotics13070583

Chicago/Turabian Style

Radu, Viorel Dragos, Radu Cristian Costache, Pavel Onofrei, Adelina Miron, Carina-Alexandra Bandac, Daniel Arseni, Mihaela Mironescu, Radu-Stefan Miftode, Lucian Vasile Boiculese, and Ionela-Larisa Miftode. 2024. "Urinary Tract Infections with Carbapenem-Resistant Klebsiella pneumoniae in a Urology Clinic—A Case-Control Study" Antibiotics 13, no. 7: 583. https://doi.org/10.3390/antibiotics13070583

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