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Antimicrobial Agents and Chemotherapy, February 2006, p. 498-504, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.498-504.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Bloodstream Infections Caused by Extended-Spectrum-ß-Lactamase-Producing Klebsiella pneumoniae: Risk Factors, Molecular Epidemiology, and Clinical Outcome

Mario Tumbarello,1* Teresa Spanu,2 Maurizio Sanguinetti,2 Rita Citton,1 Eva Montuori,1 Fiammetta Leone,2 Giovanni Fadda,2 and Roberto Cauda1

Departments of Infectious Diseases,1 Microbiology, Catholic University, Largo A. Gemelli 8, 00168 Rome, Italy2

Received 10 April 2005/ Returned for modification 6 July 2005/ Accepted 31 October 2005


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ABSTRACT
 
Bloodstream infections caused by extended-spectrum-ß-lactamase (ESBL)-producing Klebsiella pneumoniae isolates are a major concern for clinicians, since they markedly increase the rates of treatment failure and death. One hundred forty-seven patients with K. pneumoniae bloodstream infections were identified over a 5-year period (January 1999 to December 2003). The production of ESBLs in bloodstream isolates was evaluated by molecular methods. A retrospective case-case-control study was conducted to identify risk factors for the isolation of ESBL-producing K. pneumoniae or non-ESBL-producing K. pneumoniae isolates in blood cultures. Forty-eight cases infected with ESBL-producing K. pneumoniae isolates and 99 cases infected with non-ESBL-producing K. pneumoniae isolates were compared to controls. Risk factors for isolation of ESBL-producing K. pneumoniae isolates were exposure to antibiotic therapy (odds ratio [OR], 11.81; 95% confidence interval [CI], 2.72 to 51.08), age (OR, 1.14; 95% CI, 1.08 to 1.21), and length of hospitalization (OR, 1.10; 95% CI, 1.04 to 1.16). Independent determinants for isolation of non-ESBL-producing K. pneumoniae were previous urinary tract infection (OR, 8.50; 95% CI, 3.69 to 19.54) and length of hospitalization (OR, 1.07; 95% CI, 1.04 to 1.10). When the initial response was assessed at 72 h after antimicrobial therapy, the treatment failure rate for the ESBL-producing K. pneumoniae-infected group was almost twice as high as that of the non-ESBL-producing K. pneumoniae-infected group (31% versus 17%; OR, 2.19; 95% CI, 0.98 to 4.89). The 21-day mortality rate for all patients was 37% (54 of 147); it was 52% (25 of 48) for patients with ESBL-producing K. pneumoniae bloodstream infections and 29% (29 of 99) for patients with non-ESBL-producing K. pneumoniae bloodstream infections (OR, 2.62; 95% CI, 1.28 to 5.35). In summary, this investigation identifies epidemiological characteristics that distinguish ESBL-producing K. pneumoniae infections from non-ESBL-producing K. pneumoniae ESBL bloodstream infections.


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INTRODUCTION
 
Klebsiella pneumoniae is an important pathogen that causes urinary tract infections (UTIs), pneumonia, and intra-abdominal infections in hospitalized immunocompromised patients with severe underlying diseases (32). Of the gram-negative bacteria implicated in nosocomial bloodstream infections (BSIs), K. pneumoniae is second only to Escherichia coli (32). Community-acquired K. pneumoniae infections have also been reported (32).

The low-level resistance of K. pneumoniae to amino- and carboxypenicillins is due to the production of a chromosomally encoded clavulanate-susceptible penicillinase (SHV-1 type) (32). High-level penicillin resistance and reduced susceptibility to narrow-spectrum cephalosporins are related to the production of plasmid-acquired ß-lactamases, generally of the TEM-1, TEM-2, or SHV-1 type (15), while overproduction of such a penicillinase is responsible for amoxicillin-clavulanate and cephalothin resistance (31).

The broad-spectrum oxyimino-cephalosporins (e.g., ceftazidime and cefotaxime) are widely used to treat infections caused by antibiotic-resistant organisms. The union of the oxyimino chain with the 2-amino-5-thiazolyl nucleus stabilizes these drugs against the effects of the common TEM-1 and SHV-1 ß-lactamases (3, 22, 32). Resistance can develop in K. pneumoniae isolates that produce extended-spectrum ß-lactamases (ESBLs), which hydrolyze all cephalosporins (except cephamycins), penicillins, and monobactams and which are usually inhibited by clavulanic acid, sulbactam, and tazobactam (3, 4, 22). First reported in 1983 (20), ESBL-producing strains of K. pneumoniae are currently found throughout the world, although their phenotypic characteristics and prevalence vary widely from region to region (1, 9, 16, 24, 28, 30, 33, 39, 42). ESBL production is generally the result of point mutations in the blaTEM and blaSHV genes which alter the primary amino sequences of the respective ß-lactamase enzymes (3, 22, 32). Other types have also been identified (3, 4), in particular, the cefotaximase (CTX-M) ESBLs, which are being reported with increasing frequency throughout the world (9, 28).

In Europe and the United States, the number of BSIs caused by ESBL-producing strains of the family Enterobacteriaceae is on the increase, and this trend has a significant impact on mortality rates and hospital costs (2, 7, 8, 10, 17, 23, 29, 34). Although ESBLs have been detected in many gram-negative species, K. pneumoniae is still the most frequently reported producer of these enzymes. Since the ESBL genes are usually found in large plasmids that also contain other antimicrobial resistance genes, ESBL-producing organisms may also be resistant to aminoglycosides, tetracyclines, chloramphenicol, and/or sulfonamides (3, 32); and ESBL-producing K. pneumoniae strains are more likely to be resistant to fluoroquinolones than their non-ESBL-producing counterparts (26, 36). Recently, the isolation of multidrug-resistant strains of ESBL-producing K. pneumoniae has become increasingly common, especially in intensive care units (ICUs) and other high-risk hospital areas (32, 34). ESBL production has an important clinical impact even when cephalosporin MICs are in the susceptible range (17, 27). Carbapenems are the mainstay of therapy for infections caused by multidrug-resistant ESBL-producing organisms, and recent reports of acquired carbapenem resistance among these organisms are thus a cause for serious concern (43).

In 1999, we noted a sharp increase in the number of ESBL-producing K. pneumoniae isolates recovered from blood cultures in our hospital. To identify the factors associated with the isolation of ESBL-producing K. pneumoniae strains, we conducted a case-case-control study, in which patients with BSIs caused by ESBL-producing K. pneumoniae isolates and those caused by non-ESBL-producing K. pneumoniae were both compared with non-BSI control patients. The clinical response to treatment and microbiological characteristics of the ESBL-producing K. pneumoniae isolates were also analyzed.


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MATERIALS AND METHODS
 
Setting and study design. This retrospective study was conducted at the Catholic University Hospital, a 1,900-bed university hospital located in Rome, Italy, which admits approximately 60,000 patients per year.

The computerized database of our microbiology laboratory was used to identify patients hospitalized from 1 January 1999 through 31 December 2003 with K. pneumoniae BSIs, defined as the presence of at least one positive blood culture and clinical features compatible with systemic inflammatory response syndrome. Each patient was included in the study only once, at the time of the initial positive blood culture. A case-case-control study design was used. The first case group was composed of patients from whom ESBL-producing K. pneumoniae strains were isolated (the ESBL-producing K. pneumoniae group); the second case group contained patients from whom non-ESBL-producing K. pneumoniae were isolated (the non-ESBL-producing K. pneumoniae group). The same control group was used for both case groups. The control group was selected from a computer-generated list of patients who (i) had been hospitalized in our center during the same periods of time and in the same wards as the cases and (ii) had no evidence of BSIs during their hospital stay or positivity for K. pneumoniae in cultures of any type. Patients were included as controls only if complete data series could be collected from their medical charts. The distribution of the control admissions throughout the study period was similar to that of the case admissions. As in other case-case-control studies, our control population consisted of patients who were at risk for the development of K. pneumoniae BSIs and not those infected with susceptible (i.e., non-ESBL-producing) strains. It was believed that the case-case-control study design could best be accomplished by comparing and contrasting two multivariate models: risk factors for the isolation of ESBL-producing K. pneumoniae strains and risk factors for the isolation of non-ESBL-producing K. pneumoniae strains (12, 18).

BSIs were classified as nosocomial if the signs and symptoms of infection become evident >48 h after hospital admission and/or if the patient had been hospitalized during the 2 weeks before the current admission (11).

Computerized medical, pharmacy, and microbiological records were retrospectively reviewed to collect patient data. In addition, information on cases was obtained from a database in the microbiology laboratory containing complete profiles on all patients with positive blood cultures for gram-negative bacteria since 1999. The variables explored as possible risk factors included age; sex; the number of hospitalizations during the 12 months preceding BSI onset; the ward in which the infection was diagnosed; the duration of the hospital stay; the duration of the ICU stay prior to the isolation of K. pneumoniae (for controls; the duration of the ICU stay at any point during hospitalization); and the severity of illness at the time of infection, as calculated by the Acute Physiology and Chronic Health Evaluation (APACHE) III score (19). The following comorbid conditions were documented: hepatic dysfunction; malignancy; diabetes mellitus; renal insufficiency (indicated by a creatinine level of >2.0 mg/dl or the current use of dialysis); human immunodeficiency virus infection; neutropenia; prior organ transplantation; a previous UTI (in the 30 days before the onset of the BSI); the use of an immunosuppressive agent, including corticosteroids, in the 30 days before the onset of the BSI; surgery in the 30 days before the onset of the BSI (or, for controls, at any point during hospitalization); invasive procedures during the 72 h before the onset of the BSI (insertion of a central venous catheter, endoscopy, endoscopic retrograde cholangiopancreatography, insertion of a nasogastric tube, bronchoscopy, and parenteral nutrition); mechanical ventilation and urinary catheterization during the 72 h before the onset of the BSI; and exposure to antibiotics in the 30 days before the onset of the BSI (or, for controls, at any point during hospitalization) (18). The Charlson score was used to provide a composite score of comorbid conditions (6). Empirical antibiotic treatment was that prescribed before in vitro susceptibility test results were available; it was considered "inadequate" if the drug used showed no in vitro activity against the strain responsible for the BSI or if the treatment with an active drug was started more than 48 h after the onset of BSI. Treatment outcomes and factors associated with mortality were also evaluated. The main outcomes measured were the initial response to treatment (assessed after the first 72 h of antimicrobial therapy) and the mortality rates 7 and 21 days after the initiation of treatment (calculated as the total number of deaths/total number of cases). The initial response was classified as "treatment failure" if signs of the infection were unchanged or worsened or if death occurred.

Microbiological analysis. K. pneumoniae isolates from each enrolled case were subjected to in vitro antimicrobial susceptibility testing with a gradient diffusion method (Epsilometer test [Etest]; AB Biodisc, Solna, Sweden), as described previously (37, 40). Escherichia coli ATCC 25922, E. coli ATCC 35218, K. pneumoniae ATCC 700603, and Pseudomonas aeruginosa ATCC 25783 were included as quality-control strains in all sessions. MICs were classified according to the criteria of the Clinical Laboratory Standards Institute (CLSI; formerly the National Committee for Clinical Laboratory Standards (25).

Isolates with MICs of ≥2 mg/liter for cefotaxime, aztreonam, ceftazidime, and/or cefepime were checked for ESBL production by the double-disk synergy test and the Etest (AB Biodisc), as described previously (37, 40). For these assays, E. coli ATCC 25922 and K. pneumoniae ATCC 700603 were included as quality-control strains in all sessions.

Isoelectric focusing was used for the preliminary characterization of the ß-lactamases (37). Bands with pIs in the range of 5.2 to 6.5 were considered suggestive of TEM, while those with pIs in the range of 7.0 to 8.2 were suggestive of SHV (http://www.lahey.org/studies/webt.htm). The ESBL type was then verified by PCR amplification of the blaTEM and blaSHV genes, as described previously (37). The following primers were used: primers 5'-ATGAGTATTCAACATTTCCGTG (nucleotides [nt] 1 to 23, from the start of the enzyme-coding region) and 5'-TTACCAATGCTTAATCAGTGAG (nt 861 to 840) for blaTEM and primers 5'-ATGCGTTATATTCGCCTGTG (nt 1 to 20) and 5'-TTAGCGTTGCCAGTGCTC(nt 864 to 847) for blaSHV. Isolates were also subjected to PCR amplification of the blaOXA, blaCTX-M, blaOXY, and ampC-type genes, as described elsewhere (37). ESBL-producing K. pneumoniae strains were genotypically compared by repetitive extragenic palindromic sequence-based PCR (REP-PCR) assay, as described previously (38). Strains with a similarity coefficient of 0.9 or greater were considered identical.

Statistical analysis. Contingency data were analyzed by the two-tailed {chi}2 test or Fisher's exact test, and continuous data were analyzed by Student's t test. The significance of differences in proportions was assessed by the {chi}2 test. The 95% test-based confidence intervals (95% CIs) were calculated to determine the significance of the odds ratios (OR). Multivariate analysis was performed by means of multiple logistic regression, including all variables with alpha values of <0.1 in univariate analysis. Two-tailed tests of significance at the level of a P value of <0.05 were used to determine statistical significance. All statistical analyses were performed with Intercooled Stata software, version 8, for Windows (Stata Corporation).


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RESULTS
 
Population characteristics. K. pneumoniae BSIs were diagnosed in 147 of the 310,480 patients hospitalized in our center between 1999 and 2003 (overall incidence, 0.47 per 1,000 admissions). Complete medical records were available for review for 132 of 147 (89%) patients with K. pneumoniae BSIs. In the other 15 cases, complete data series were collected through review of partial medical records and other data sources (e.g., microbiology laboratory reports and infection control records).

ESBL-producing strains were identified in 48 of 147 cases (33%). The percentage of ESBL-producing K. pneumoniae infections remained fairly constant (about 17 to 20%) in 2000, 2002, and 2003, while peaks of 56% and 43% were recorded in 1999 and 2001, respectively. ESBL-producing K. pneumoniae BSIs were significantly more common in the ICU (19 of 34 cases; 56%) than in surgical wards (56% versus 35%; 12 of 34 cases) (relative risk [RR], 1.54; 95% CI, 0.91 to 2.72; P = 0.08) or medical wards (56% versus 21%; 17 of 79 cases) (RR, 2.59; 95% CI, 1.54 to 4.35; P < 0.001). Descriptive characteristics of the patients with BSIs are shown in Table 1.


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  		TABLE 1. Clinical characteristics of patients with bloodstream infection caused by ESBL-producing and non-ESBL-producing strains of K. pneumoniae

Microbiological data. As shown in Table 2, almost all of the ESBL-producing K. pneumoniae isolates were susceptible to imipenem, meropenem, and amikacin; roughly two-thirds were susceptible to amoxicillin-clavulanic acid, cefoxitin, gentamicin, and co-trimoxazole; and about one-half were susceptible to fluoroquinolones and piperacillin-tazobactam. In contrast, very few non-ESBL-producing K. pneumoniae isolates displayed resistance to any of the antimicrobials tested (P < 0.001).


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  		TABLE 2. In vitro antimicrobial susceptibilities of 147 bloodstream K. pneumoniae isolates

Molecular analysis revealed that all 48 ESBL-producing K. pneumoniae isolates produced blaSHV-type enzymes: SHV-2a (n = 8), SHV-5 (n = 5), SHV-8 (n = 6), SHV-11 (n = 10), and SHV-12 (n = 19). Twelve of these also had genes encoding TEM-type enzymes: TEM wild type (n = 1); TEM-24 (n = 1); TEM-93 (n = 3); and the recently described TEM-116 variant, which was detected in seven isolates recovered in the ICU in 1999, all seven of which carried blaSHV-2a genes. SHV-11 and SHV-12 producers were present throughout the entire survey period. The first SHV-12 strain was initially recovered from a surgical patient and, subsequently, from patients in the ICU and medical wards. The distribution of the SHV-11 producers was restricted exclusively to the medical wards. Strains carrying ESBLs such as SHV-2a, SHV-5, SHV-8, and TEM-type ß-lactamases were found during more limited periods of time.

Among the 48 ESBL-producing K. pneumoniae isolates, 13 unique REP-PCR profiles were found: 5 in isolates expressing SHV-12, 4 in those carrying SHV-11 genes, and 4 others in SHV-8-positive isolates. Four major episodes of clonal dissemination were detected. Two were observed in 1999: the first, involving isolates producing SHV-5, occurred in the ICU, while the second was caused by TEM-116 and SHV-2a producers in surgical wards. The remaining two episodes (one in the ICU and one in a medical ward) occurred in 2001, and both involved SHV-12 strains showing two different profiles.

Risk factors for ESBL-producing K. pneumoniae and non-ESBL-producing K. pneumoniae BSIs. The results of a comparison of the case groups with the controls by univariate analysis are shown in Table 3. ESBL-producing K. pneumoniae cases were significantly older than controls, and long hospital stays and previous hospitalization were more common in this group. Compared with controls, the ESBL-producing K. pneumoniae group had higher rates of previous UTIs and malignancy; and the patients were more likely to have undergone invasive procedures, mechanical ventilation, urinary catheterization, and previous treatment with antimicrobials.


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  		TABLE 3. Univariate analysis of risk factors for isolation of ESBL-producing and non-ESBL-producing strains of K. pneumoniae

The non-ESBL-producing K. pneumoniae cases were also significantly older than the controls and were more likely to be male. Isolation of non-ESBL-producing K. pneumoniae was also associated with long hospitalization, urinary catheterization, steroid use, and previous UTIs.

Logistic regression analysis revealed that three variables were independently associated with the isolation of ESBL-producing K. pneumoniae strains: age (OR, 1.14; 95% CI, 1.08 to 1.21), length of hospitalization (OR, 1.10; 95% CI, 1.04 to 1.16), and previous antibiotic therapy (OR, 11.81; 95% CI, 2.72 to 51.08) (Table 4).


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  		TABLE 4. Logistic regression analysis of risk factors for bloodstream infections caused by ESBL-producing K. pneumoniae and non-ESBL-producing K. pneumoniae

Significant risk factors for the isolation of non-ESBL-producing K. pneumoniae strains were length of hospitalization (OR, 1.07; 95% CI, 1.04 to 1.10) and previous UTI (OR, 8.50; 95% CI, 3.69 to 19.54).

Treatment and outcome. Patients infected by ESBL-producing K. pneumoniae strains were empirically treated with the following antimicrobials: oxymino-cephalosporins (n = 17), ß-lactam-ß-lactamase inhibitor combinations (n = 8), carbapenems (n = 8), aminoglycosides (n = 5) fluoroquinolones (n = 8), or other antimicrobials (n = 2). Patients infected by non-ESBL-producing K. pneumoniae strains were treated with oxymino-cephalosporins (n = 33), ß-lactam-ß-lactamase inhibitor combinations (n = 20), carbapenems (n = 10), aminoglycosides (n = 14), fluoroquinolones (n = 18), or other antimicrobials (n = 4).

The results of in vitro susceptibility testing indicated that empirical therapy was inadequate in 24 (50%) patients with ESBL-producing K. pneumoniae BSIs. Seventeen of these patients received oxymino-cephalosporins, five were treated with fluoroquinolones, and two were treated with ß-lactam-ß-lactamase inhibitor combinations. In contrast, only two (2%) patients with non-ESBL-producing K. pneumoniae BSIs received inadequate therapy (P < 0.001). After these results were reported, therapy was changed in 18 patients with ESBL-producing K. pneumoniae infections. Six of these 18 patients (33%) were changed to carbapenem, 5 (28%) were changed to ß-lactams-ß-lactamase inhibitors, 4 (22%) were changed to an aminoglycoside, and 3 (17%) were changed to a fluoroquinolone.

As shown in Table 5, after 72 h of treatment, the rate of therapeutic failure in the ESBL-producing K. pneumoniae group was almost twice as high as that in the non-ESBL-producing K. pneumoniae group (31% versus 17%; OR, 2.19; 95% CI, 0.98 to 4.89). The overall 21-day mortality rate of all patients was 36.7% (54 of 147 cases). The mortality rate was significantly higher in the ESBL-producing K. pneumoniae group than in the non-ESBL-producing K. pneumoniae group both at the 7th day (OR, 2.66; 95% CI, 1.07 to 6.59) and the 21st day (OR, 2.62; 95% CI, 1.28 to 5.35). The mortality rate among the 24 ESBL-producing K. pneumoniae isolate-infected patients whose initial antibiotic regimen was inadequate was 67% (16 of 24), while that among the patients in the subgroup treated appropriately from the start was 37% (9 of 24) (P = 0.04).


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  		TABLE 5. Clinical outcomes for patients with BSIs caused by ESBL-producing K. pneumoniae isolates versus those for patients with BSIs caused by non-ESBL-producing K. pneumoniae isolates

The mean length of hospitalization after the diagnosis of BSI was 22 ± 11 days for ESBL-producing K. pneumoniae-infected cases and 16 ± 5 days for the others (P = 0.03).


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DISCUSSION
 
Our 5-year surveillance clearly confirmed that BSIs caused by ESBL-producing K. pneumoniae isolates are an important clinical problem. About 30% of the isolates that we examined were ESBL producers. Many ESBLs are mutant forms of the ß-lactamases encoded by the TEM-1, TEM-2, or SHV-1 genes, although CTX-M enzymes are being reported with increasing frequency. We identified five different SHV-type and four different TEM-type ß-lactamase sequences. These findings are consistent with those from previous reports from Italy and other countries (16, 28, 30). SHV-12 was the most common type found, while SHV-5-type ESBL-producing K. pneumoniae, which is more common in the United States and other countries (28, 33), was responsible for a clonal dissemination observed in 1999 in the ICU. Interestingly, TEM-116-type ESBL-producing K. pneumoniae, which has recently been isolated in Korean hospitals (16), was recovered from our ICU during the first outbreak in 1999. The emergence of the same ESBL variant in geographically and temporally distant settings has been attributed to convergent evolutionary events (13). It is noteworthy that, in contrast to the findings presented in previous reports (9, 28), none of our ESBL-producing K. pneumoniae isolates produced CTX-M enzymes, although they were quite common among the ESBL-producing strains of E. coli isolated in our hospital during the same period of time (data not shown).

ESBL genes are usually carried on plasmids; and some of them are located within various transposable elements, which strongly facilitate their spread among bacterial strains, even those of different species. Therefore, various epidemiological situations have been identified, ranging from sporadic cases to large outbreaks. Our molecular analysis indicates that the dissemination of ESBL-producing K. pneumoniae strains in our hospital probably involved the simultaneous spread of several clones, although horizontal transfer of the resistance determinant could also have played a role. This possibility is supported by the finding of multiple clones (from four to five) with same genes (e.g., SHV-12, SHV-11, or SHV-8) or strains with the same REP-PCR profile but different ESBLs. An endemic-epidemic distribution of ESBL-producing K. pneumoniae strains was observed. The rate of isolation of ESBL-producing K. pneumoniae peaked in 1999, when up to four different types of ESBLs were detected, and again in 2001. That year, both outbreaks involved only SHV-12-type ESBL-producing K. pneumoniae strains, and blaSHV-11 was found in only a few strains. The SHV-12- and SHV-11 ESBLs appear to be resident enzymes in our institution, while other types, e.g., SHV-2a and SHV-5, were responsible only for brief outbreaks in 1999. Outbreaks of ESBL-producing K. pneumoniae infections may be the result of intrinsic contamination of medical equipment and/or the environment or contact with patients. These outbreaks often occur in ICUs (32, 34, 41), presumably because patients in these areas often have a relatively high number of risk factors for colonization or infection with these organisms. Factors such as severe clinical status, advanced age, misuse or abuse (or even appropriate use) of antimicrobial agents, the high frequency of invasive procedures, and the high workloads in ICUs can all reduce patients' resistance to exogenous bacteria, increasing the risk for cross-infection (2, 5, 8, 10, 21, 23) and creating an ideal reservoir for multiple-drug-resistant K. pneumoniae. The reported prevalence of ESBL-producing K. pneumoniae among isolates recovered from ICU patients varies from 9% to 59% (34, 41). Geographic variations in these figures are thought to be related to local antimicrobial prescribing practices and infection control policies, but they may also reflect the diligence of the microbiologists in identifying isolates with these enzymes. In this study, over half (56%) of the K. pneumoniae isolates from the ICU produced ESBLs.

We used a case-control approach to identify factors associated with the isolation of ESBL-producing K. pneumoniae strains. The fact that length of hospitalization was identified as a risk factor for the isolation of both ESBL-producing K. pneumoniae strains and non-ESBL-producing K. pneumoniae strains is not surprising. As opportunistic pathogen, K. pneumoniae primarily attacks immunocompromised individuals who are hospitalized for severe underlying diseases. Patients of this type often require prolonged hospitalization and invasive procedures, which breach the normal host defenses and increase the risk of bacterial colonization and infection (32). Many of our ESBL-producing K. pneumoniae-infected patients had undergone invasive procedures, mechanical ventilation, and urinary catheterization; and the last factor was also common in the non-ESBL-producing K. pneumoniae group.

When the two case groups were compared, the most striking difference noted was the fact that previous antimicrobial treatment and older age were associated only with ESBL-producing K. pneumoniae BSIs. Advanced age is a well-known risk factor for nosocomial infections, and it is probably a marker of relatively severe disease that is more likely to require aggressive diagnostic and therapeutic procedures. Another possible explanation is that the rate of colonization by antibiotic-resistant bacteria may be high in older hospitalized patients. Vulnerability to infection with a resistant bacterial strain is also increased by previous antimicrobial therapy, which is also more likely in older patients and during long hospitalizations.

Antimicrobial use has historically been associated with the emergence of ESBL-producing strains of the family Enterobacteriaceae (5, 7, 10), and this finding is confirmed by our multivariate analysis. Antibiotic therapy promotes the colonization or infection of the treated patient by resistant organisms by eradicating susceptible strains and modifying the host's resistance to colonization. Eradication or reduction of drug-susceptible normal flora can also increase one's vulnerability to the acquisition of new strains. This effect can increase the risk of colonization by resistant organisms if exposure occurs during or shortly after antibiotic treatment. In addition, an organism that is resistant to multiple drugs may be more subject to selection by the use of any one of those drugs. Over half of our ESBL-producing K. pneumoniae isolates were coresistant to fluoroquinolones. This type of resistance reduces the therapeutic options for infections caused by ESBL producers, and careful monitoring of their spread is thus extremely important.

ESBL-producing K. pneumoniae BSIs are a major concern for clinicians (17, 27), since they markedly increase the rates of treatment failure and death. The mortality rate among our patients was even higher than that recently reported by Kang et al. (17), and death occurred much more frequently in patients who had received inadequate empirical therapy. It is perhaps worth noting that analysis of our ESBL-producing K. pneumoniae-infected cases revealed better outcomes when carbapenems were included in the initial therapy (data not shown). Recently, Hyle and colleagues (14) reported that inadequate initial antimicrobial therapy is an independent risk factor for mortality in non-UTIs caused by ESBL-producing strains of E. coli and K. pneumoniae. It has been shown that delays in the start of the appropriate therapy have no significant effect on the therapeutic outcomes of BSIs caused by ESBL-producing K. pneumoniae strains if therapy is promptly adjusted in accordance with in vitro susceptibility data (17, 21). Therefore, in cases characterized by a high risk of death, these data must be reported to the physician as soon as possible. However, the prognosis of BSIs also depends on other factors, such as the site of infection, the presence of underlying diseases and their severity at the time of administration of antibiotics, or the infecting pathogen. Of particular interest are reports on the association between ESBL production and expression of pathogenicity factors (35).

In conclusion, BSIs caused by ESBL-producing strains of K. pneumoniae represent a serious clinical problem associated with a high mortality rate. This investigation identifies epidemiological characteristics that distinguish ESBL-producing K. pneumoniae BSIs and non-ESBL-producing K. pneumoniae BSIs. Almost half of our ESBL-producing K. pneumoniae isolates were also resistant to fluoroquinolones, which some authors still regard as valid alternatives to carbapenems for the treatment of ESBL-producing K. pneumoniae BSIs (17). Further investigation will increase our understanding of these serious infections and allow us to elaborate sounder and more effective policies and practice guidelines for reducing their frequency and the morbidity and mortality that they cause.


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ACKNOWLEDGMENTS
 
This work was partially supported by grants from the Italian Ministry for the University and Scientific Research (MIUR 2004).

We thank Manuela Di Chio for her technical assistance in the molecular typing of K. pneumoniae strains.


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FOOTNOTES
 
* Corresponding author. Mailing address: Istituto Malattie Infettive, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy. Phone: 39-06-30155373. Fax: 39-06-3054519. E-mail: tumbarello{at}rm.unicatt.it. Back


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Antimicrobial Agents and Chemotherapy, February 2006, p. 498-504, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.498-504.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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