Wan Beom Park

Bloodstream Infections Caused by Antibiotic-Resistant Gram-Negative Bacilli: Risk Factors for Mortality and Impact of Inappropriate Initial Antimicrobial Therapy on Outcome

ABSTRACT The marked increase in the incidence of infections due to antibiotic-resistant gram-negative bacilli in recent years is of great concern, as patients infected by those isolates might initially receive antibiotics that are inactive against the responsible pathogens. To evaluate the effect of inappropriate initial antimicrobial therapy on survival, a total of 286 patients with antibiotic-resistant gram-negative bacteremia, 61 patients with Escherichia coli bacteremia, 65 with Klebsiella pneumoniae bacteremia, 74 with Pseudomonas aeruginosa bacteremia, and 86 with Enterobacter bacteremia, were analyzed retrospectively. If a patient received at least one antimicrobial agent to which the causative microorganisms were susceptible within 24 h of blood culture collection, the initial antimicrobial therapy was considered to have been appropriate. High-risk sources of bacteremia were defined as the lung, peritoneum, or an unknown source. The main outcome measure was 30-day mortality. Of the 286 patients, 135 (47.2%) received appropriate initial empirical antimicrobial therapy, and the remaining 151 (52.8%) patients received inappropriate therapy. The adequately treated group had a 27.4% mortality rate, whereas the inadequately treated group had a 38.4% mortality rate (P = 0.049). Multivariate analysis showed that the significant independent risk factors of mortality were presentation with septic shock, a high-risk source of bacteremia, P. aeruginosa infection, and an increasing APACHE II score. In the subgroup of patients (n = 132) with a high-risk source of bacteremia, inappropriate initial antimicrobial therapy was independently associated with increased mortality (odds ratio, 3.64; 95% confidence interval, 1.13 to 11.72; P = 0.030). Our data suggest that inappropriate initial antimicrobial therapy is associated with adverse outcome in antibiotic-resistant gram-negative bacteremia, particularly in patients with a high-risk source of bacteremia.

Bloodstream Infections Due to Extended-Spectrum β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae: Risk Factors for Mortality and Treatment Outcome, with Special Emphasis on Antimicrobial Therapy

ABSTRACT This study was conducted to evaluate risk factors for mortality and treatment outcome of bloodstream infections due to extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK). ESBL production in stored K. pneumoniae and E. coli blood isolates from Jan 1998 to Dec 2002 was phenotypically determined according to NCCLS guidelines and/or the double-disk synergy test. A total of 133 patients with ESBL-EK bacteremia, including 66 patients with ESBL-producing K. pneumoniae and 67 with ESBL-producing E. coli, were enrolled. The overall 30-day mortality rate was 25.6% (34 of 133). Independent risk factors for mortality were severe sepsis, peritonitis, neutropenia, increasing Acute Physiology and Chronic Health Evaluation II score, and administration of broad-spectrum cephalosporin as definitive antimicrobial therapy (P < 0.05 for each of these risk factors). In 117 of the 133 patients, excluding 16 patients who died within 3 days after blood culture sample acquisition, the 30-day mortality rates according to definitive antibiotics were as follows: carbapenem, 12.9% (8 of 62); ciprofloxacin, 10.3% (3 of 29); and others, such as cephalosporin or an aminoglycoside, 26.9% (7 of 26). When patients who received appropriate definitive antibiotics, such as carbapenem or ciprofloxacin, were evaluated, mortality in patients receiving inappropriate empirical antimicrobial therapy was found not to be significantly higher than mortality in those receiving appropriate empirical antimicrobial therapy (18.9 versus 15.5%; P = 0.666). Carbapenem and ciprofloxacin were the most effective antibiotics in antimicrobial therapy for ESBL-EK bacteremia. A delay in appropriate definitive antimicrobial therapy was not associated with higher mortality if antimicrobial therapy was adjusted appropriately according to the susceptibility results. Our data suggest that more prudent use of carbapenem as empirical antibiotic may be reasonable.

Epidemiology and Clinical Features of Bloodstream Infections Caused by AmpC-Type-beta-Lactamase-Producing Klebsiella pneumoniae

ABSTRACT Cases of bacteremia caused by AmpC-type-β-lactamase-producing Klebsiella pneumoniae isolates were retrospectively studied to determine the epidemiologic features and clinical outcomes of bloodstream infections. Among 389 blood isolates recovered from 1998 to 2002, 65 isolates (16.7%) were found to be extended-spectrum β-lactamase (ESBL) or AmpC β-lactamase producers. The β-lactamases from 61 of the 65 isolates were characterized; 28 of 61 isolates produced AmpC-type enzymes (14 isolates each produced DHA-1 and CMY-1-like enzymes), 32 isolates produced TEM or SHV-related ESBLs, and 1 isolate produced a CTX-M-14-like enzyme. To compare the clinical features and outcomes of bloodstream infections caused by AmpC producers with those caused by TEM- or SHV-related ESBL producers, 27 patients infected with isolates producing AmpC-type enzymes (AmpC group) and 25 patients infected with isolates producing TEM- or SHV-related enzymes (ESBL group) were analyzed. There was no significant difference between the AmpC and the ESBL groups in terms of risk factors. When the initial response was assessed at 72 h after antimicrobial therapy, the treatment failure rate for the AmpC group was 51.9% (14 of 27 patients) and the 7- and 30-day mortality rates were 14.8 and 29.6%, respectively, which were similar to those for the ESBL group. When the mortality rate for the patients who received extended-spectrum cephalosporins as definitive treatment was assessed, all four patients in the DHA-1 group and one of three patients in the CMY-1-like group died. In summary, the prevalence of AmpC enzyme-producing K. pneumoniae was high at the Seoul National University Hospital, and the clinical features and outcomes for the patients infected with AmpC-producing organisms were similar to those for the patients infected with TEM- or SHV-related ESBL producers.

In Vitro Activities of 28 Antimicrobial Agents against Staphylococcus aureus Isolates from Tertiary-Care Hospitals in Korea: a Nationwide Survey

ABSTRACT Staphylococcus aureus, one of the most frequently isolated pathogens in both hospitals and the community, has been particularly efficient at developing resistance to antimicrobial agents. As methicillin-resistant S. aureus (MRSA) has prevailed and, furthermore, as S. aureus with reduced susceptibility to vancomycin has emerged, the therapeutic options for the treatment of S. aureus infections have become limited. To update the current status of antibiotic resistance, clinical S. aureus isolates were collected from eight university-affiliated hospitals from June 1999 to January 2001. Susceptibility tests with 28 antibiotics were performed by the disk diffusion method. Among a total of 682 isolates, the methicillin resistance rate was 64% (439 of 682), and most of the MRSA isolates were resistant to multiple classes of antibiotics. Although a constitutive macrolide-lincosamide-streptogramin B resistance phenotype was common, no isolates were resistant to quinupristin-dalfopristin or linezolid. Rifampin, fusidic acid, trimethoprim-sulfamethoxazole, and arbekacin showed superior in vitro activity compared with the other antibiotics against the MRSA isolates. No isolates showed reduced susceptibility to vancomycin.

One‐year adherence to clinic visits after highly active antiretroviral therapy: a predictor of clinical progress in HIV patients

Objective.  To determine whether adherence to clinic visits early after initiation of highly active antiretroviral therapy (HAART) is predictive of long‐term clinical outcome.

A survey of community-associated methicillin-resistant Staphylococcus aureus in Korea

Sir, Studies on the molecular epidemiological characteristics of methicillin-resistant Staphylococcus aureus (MRSA) have demonstrated their genetic and geographic diversity in comparisons between the community-associated (CA) and hospitalassociated (HA) strains. In addition, it has been suggested that the CA-MRSA found in Korea is genetically different from those found in other regions of the world. – 3 Recently, Kim et al. reported a nationwide survey of CA-MRSA in Korea. We also published an article on the same subject in Korea. Both studies confirmed the unique features of the Korean MRSA strains. Kim et al. designed a prospective sentinel hospital laboratory-based survey from seven hospitals in Korea. After dividing the strains into CA-MRSA and HA-MRSA, 72 isolates from each group were compared. Pathogens, colonizers and an ‘undetermined’ group were all included in the study. However, we have collected isolates from blood, wounds and pus from six hospitals in an effort to exclude possible colonization and contaminants. The enrolled hospitals did not overlap in the two articles. The definitions of CA-MRSA and multidrug resistance (MDR), and the number of antibiotics used in susceptibility testing, were slightly different in comparisons between the two articles. Kim et al. calculated the resistance rate as the number of intermediate and resistance strains over the total number of strains. In contrast, we did not consider ‘intermediate’ as resistance. Finally, we clustered MRSA isolates into representative groups based on genetic backgrounds, and clonal types were redefined according to staphylococcal chromosome cassette mec (SCCmec) type and susceptibilities. Despite these differences, both articles demonstrated similar features of the MRSA in Korea: SCCmec type IVA/ST72/Panton–Valentine leucocidin (PVL)-negative and SCCmec type II or III/ST5 or ST239/ PVL-negative strains were predominant in CA-MRSA and HA-MRSA, respectively. Kim et al. reported that for CA-MRSA, the prevalence of SCCmec type IVA was 43% and the prevalence of ST72 was 35%, and that for HA-MRSA, the prevalence of SCCmec type II or III was 82% and the prevalence of ST5 or ST239 was 86%. Similarly, our data showed that for CA-MRSA, the prevalence of SCCmec type IVA was 53.1% and the prevalence of ST72 was 27.2%, and that for HA-MRSA, the prevalence of SCCmec type II or III was 73.6% and the prevalence of ST5 or ST239 was 73.7%. PVL toxin was rarely identified in either study. In Korea, SCCmec type II or III /ST5 or ST239 was prevalent in HA-MRSA. The articles by Kim et al. and Park et al. elucidated the characteristics of CAand HA-MRSA in Korea. It is interesting that both studies were nationwide studies performed at the same time and had very similar results. We think the data shown in these articles represent the current features of both CAand HA-MRSA in Korea. However, we would like to recommend caution with regard to the conclusion that MDR in CA-MRSA was high (64%), as suggested by Kim et al. Jung et al. also reported that 60.7% of the CA-MRSA isolates were MDR. However, most of their CA-MRSA (82%) were community-onset HA-MRSA cases based on the definition of Kim et al. Another study in Korea showed that ,50% of the strains, among 20 SCCmec type IVA, were MDR when standardized according to the definition of Kim et al. After conforming to the definitions of Kim et al., we re-analysed our data and found that the overall MDR rate, in CA-MRSA, was 51.9%. However, we grouped the clonal types according to their genetic backgrounds and SCCmec type, and found antibiotic susceptibility patterns more distinctly classified (Table 1; modified from Park et al.). For example, most ST72 belonging to B-I were not MDR. B-I, D-I and E-I corresponded to SCCmec type IVA, and most of B-I and D-I were not MDR either. Therefore, the SCCmec type IVA/ST72/PVL-negative clones, the dominant CA-MRSA strains in Korea, were not MDR at least. The clonal types could have the advantage of demonstrating antibiotic susceptibility patterns more precisely than the groups defined by SCCmec only. We agree with Kim et al. and Jung et al. that there were multiple clones of CA-MRSA circulating in communities in Korea and some clones had MDR characteristics similar to HA-MRSA. Even in the dominant SCCmec type IVA in CA-MRSA, our data showed that there would be at least three different groups; however, only 30.2% were MDR. As commented on by Park et al., isolates classified as ‘undetermined’ (46.4%) were all recovered from patients with chronic otitis media; most of them belonged to ST5 or ST239, which was predominant in the HA-MRSA. These findings may explain why the authors concluded that the MDR rate was high in the CA-MRSA. If the subgroup analysis was performed for the pathogen, colonizer and undetermined groups, or the clonal type was used in the analysis, a different conclusion would be expected. In order to confirm the epidemiological characteristics, standardization of study design, classifications and definitions are required. Further study is required to monitor the current trends and detect changes when they occur both locally and worldwide.

Salvage Treatment for Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Efficacy of Linezolid With or Without Carbapenem

BACKGROUND Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with high mortality rates, but no treatment strategy has yet been established. We performed this study to evaluate the efficacy of linezolid with or without carbapenem in salvage treatment for persistent MRSA bacteremia. METHODS All adult patients with persistent MRSA bacteremia for 7 days from January 2006 through March 2008 who were treated at Seoul National University Hospital were studied. The results of linezolid salvage therapy with or without carbapenem were compared with those of salvage therapy with vancomycin plus aminoglycosides or rifampicin. RESULTS Thirty-five patients with persistent MRSA bacteremia were studied. The early microbiological response (ie, negative results for follow-up blood culture within 72 hours) was significantly higher in the linezolid-based salvage therapy group than the comparison group (75% vs 17%; P =.006). Adding aminoglycosides or rifampicin to vancomycin was not successful in treating any of the patients, whereas linezolid-based therapy gave an 88% salvage success rate P =.001). The S. aureus-related mortality rate was lower for patients treated with a linezolid salvage regimen than for patients continually treated with a vancomycin-based regimen (13% vs 53%; P =.030). CONCLUSIONS Linezolid-based salvage therapy effectively eradicated S. aureus from the blood for patients with persistent MRSA bacteremia. The salvage success rate was higher for linezolid therapy than for vancomycin-based combination therapy.

Is Cefazolin Inferior to Nafcillin for Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia?

ABSTRACT About 20% of methicillin-susceptible Staphylococcus aureus (MSSA) isolates have a substantial inoculum effect with cefazolin, suggesting that cefazolin treatment may be associated with clinical failure for serious MSSA infections. There are no well-matched controlled studies comparing cefazolin with nafcillin for the treatment of MSSA bacteremia. A retrospective propensity-score-matched case-control study was performed from 2004 to 2009 in a tertiary care hospital where nafcillin was unavailable from August 2004 to August 2006. The cefazolin group (n = 49) included MSSA-bacteremic patients treated with cefazolin during the period of nafcillin unavailability, while the nafcillin group (n = 84) comprised those treated with nafcillin. Treatment failure was defined as a composite outcome of a change of antibiotics due to clinical failure, relapse, and mortality. Of 133 patients, 41 patients from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment failure rates were not significantly different at 4 or 12 weeks (10% [4/41] versus 10% [4/41] at 4 weeks [P > 0.99] and 15% [6/41] versus 15% [6/41] at 12 weeks [P > 0.99]). Cefazolin treatment was interrupted less frequently than nafcillin treatment due to drug adverse events (0% versus 17%; P = 0.02). Cefazolin had clinical efficacy similar to that of nafcillin and was more tolerable than nafcillin for the treatment of MSSA bacteremia.

Bloodstream infections caused by Enterobacter species: predictors of 30-day mortality rate and impact of broad-spectrum cephalosporin resistance on outcome.

BACKGROUND Enterobacter species have become increasingly important nosocomial pathogens. However, resistance to cephalosporins often complicates the treatment of Enterobacter infection. This study was conducted to evaluate the predictors of mortality and the impact of cephalosporin resistance on outcome in patients with Enterobacter bacteremia. METHODS A total of 183 patients with Enterobacter bacteremia were retrospectively analyzed. Broad-spectrum cephalosporin resistance was defined as in vitro resistance to cefotaxime or ceftazidime. The main outcome measure was the 30-day mortality rate. RESULTS Of 183 patients, 86 (47%) had bacteremia caused by broad-spectrum cephalosporin-resistant Enterobacter species, and their infections were classified as resistant. The 30-day mortality rate of patients with resistant infections (the resistant group) was significantly higher than that of patients with susceptible infections (the susceptible group) (33.7% vs. 18.6%; P=.021). When the 30-day mortality rates were compared according to the primary sites of infection and underlying conditions, the 30-day mortality rates of the resistant group were significantly higher than those of the susceptible group, in patients with an unknown primary site of infection, or in patients with septic shock. Multivariate analysis showed that broad-spectrum cephalosporin resistance was one of the independent risk factors associated with 30-day mortality (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.01-13.52; P=.049). Presentation with septic shock and an increasing Acute Physiology and Chronic Health Evaluation II score were also independent risk factors for mortality (OR, 59.91 [95% CI, 14.93-240.15; P<.001] and 1.52 [95% CI, 1.24-1.86; P<.001], respectively). CONCLUSIONS Broad-spectrum cephalosporin resistance adversely affects the outcome of patients with Enterobacter bacteremia, especially those with an unknown primary site of infection and those with septic shock.

Evidence-Based Guidelines for Empirical Therapy of Neutropenic Fever in Korea

Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3-5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patients condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers.