Klebsiella pneumoniae carbapenemases in Enterobacteriaceae: history, evolution, and microbiology concerns.

Since the discovery of penicillin 80 years ago, gram-negative bacteria have become proficient at evading the lethal activity of ß-lactam antibiotics, principally through the production of ß-lactamases. The rapid emergence of penicillinases in both gram-positive and gram-negative bacteria led to the development of cephalosporin ß-lactam antibiotics, but production of plasmid-mediated extended-spectrum cephalosporinases (or extended-spectrum ß-lactamases) and AmpC enzymes resulted in resistance to this drug class. Because carbapenems were the only ß-lactam agents active against such extended-spectrum ß-lactamase-producing strains, appropriate and inappropriate use soon resulted in Enterobacteriaceae resistance. As a result, two distinct types of carbapenemases-the metallo-ß-lactamases and Klebsiella pneumoniae carbapenemases (KPCs)-were soon identified. The KPCs comprise 10 variants that differ from one another by one to three amino acid substitutions (KPC-2 to KPC-11). The KPC-producing Enterobacteriaceae are not only multidrug resistant but are also difficult to detect routinely in the clinical microbiology laboratory. Tigecycline, polymyxins (colistin and polymyxin B), and aminoglycosides are possible candidate therapies for infections caused by KPC-producing organisms, although well-conducted clinical trials are required to fully define their roles in patient management. The shortage of new antimicrobial agents on the immediate horizon suggests that enhanced adherence with infection prevention procedures and antimicrobial stewardship programs are needed to curb patient-to-patient transmission and to reduce the selection of multidrug-resistant bacteria.

Candidemia incidence in recipients of parenteral nutrition.

BACKGROUND: The purpose of this study was to assess the incidence of candidemia in recipients of parenteral nutrition (PN) in a tertiary medical center with disease-specific guidelines for appropriate PN use. METHODS: A retrospective, medical record/database review was conducted for adult patients who received PN in a 473-bed medical center from January 2006 to October 2008. Patients receiving PN >72 hours with no recent history of fungemia or concomitant antifungal therapy were evaluated for candidemia incidence with special interest in intensive care unit (ICU) patients. Epidemiological and clinical factors promoting candidemia development, pattern of systemic antifungal therapy use, and patient outcomes were investigated. RESULTS: Of 286 PN recipients, 14 (4.9%) patients were diagnosed with new-onset candidemia, with an incidence rate of 1.6 episodes per 1000 hospital-days. In the subgroup of 177 ICU patients, 11 (6.2%) patients developed candidemia, with an incidence rate of 2.4 episodes per 1000 ICU-days. PN duration was significantly longer in the candidemia group, with a median of 17 (4-53) days compared with 8 (4-124) days in the noncandidemia group (P = .013). Severity of illness was defined as major to extreme in 83.5% of patients. Hospital mortality in the candidemia group was greater than in the noncandidemia group (35.7% vs 16.2%, P = .058). CONCLUSIONS: Guidelines for PN therapy appropriately limit unnecessary use of PN but also select out severely ill patients who are at high risk for the development of candidemia. This study generates questions for future studies, including the benefits of empirical antifungal therapy in high-risk PN recipients.

Trimethoprim-sulfamethoxazole exposure alters ex vivo function of B lymphocytes isolated from human immunodeficiency virus-infected patients receiving Zidovudine.

STUDY OBJECTIVE: To determine if exposure to trimethoprim-sulfamethoxazole (TMP-SMX) causes a defect in peripheral B-cell function among patients with the human immunodeficiency virus (HIV) who are receiving zidovudine antiretroviral therapy. DESIGN: Prospective, single-center, single-group, case-crossover design with a 4-week exposure period. SETTING: University-affiliated infectious diseases outpatient clinic. PATIENTS: Fourteen HIV-infected adult men receiving zidovudine, who had CD4(+) cell counts above 350 cells/mm(3) and undetectable viral loads. INTERVENTION: Patients were administered a 28-day course of TMP 160 mg-SMX 800 mg/day (one double-strength tablet/day). Peripheral blood mononuclear cells (PBMCs) were obtained and isolated before and after exposure to TMP-SMX. Cells were cultured ex vivo with three mitogens of differing immunologic properties: pokeweed mitogen ([PWM] T-cell-dependent B-cell mitogen), Staphylococcus aureus Cowan ([SAC] T-cell-independent B-cell mitogen), and phytohemagglutinin A ([PHA] T-cell mitogen). Functionality of the B and T lymphocytes was then assessed. MEASUREMENTS AND MAIN RESULTS: Proliferative capacity, cytokine secretion, and antibody production were measured and compared before and after TMP-SMX exposure. Reduced proliferative capacities of both PBMC and B cells stimulated with mitogens were observed at the 3-day culture time point in response to PWM, PHA, and SAC (p=0.029, 0.028, and 0.026, respectively). Proliferative capacity at day 7 of culture was not significantly different for any condition examined. Cytokine production was not altered by combination drug exposure after 10 days of culture when cells were stimulated with either PWM or PHA. Although antibody responses to PWM and PHA were similar, total immunoglobulin G concentration was lower in cells stimulated with SAC in samples obtained after TMP-SMX regimen completion compared with those obtained before exposure (p=0.005). CONCLUSION: Although these data were affected by limitations in power and study design, they suggest that peripheral B-lymphocyte function is altered as a result of TMP-SMX exposure in HIV-infected patients concurrently receiving zidovudine. Further study of this effect is warranted.

Bugs versus drugs: addressing the pharmacist's challenge.

PURPOSE: To address how the high endemic levels of antimicrobial resistance and multidrug resistance in hospitals have challenged clinicians to select appropriate therapy for effectively treating bacterial infections among seriously ill patients. SUMMARY: Among gram-positive bacterial infections, differentiating between healthcare-associated and community-associated methicillin-resistant Staphylococcus aureus infections is becoming more difficult and can seriously impact therapeutic strategies and hence outcomes. Furthermore, the rising prevalence of multidrug-resistant gram-negative bacterial infections is increasing the pressure on proper antimicrobial selection given the dearth of new antimicrobial agents under development. Optimized dosing strategies will be instrumental in minimizing emergence of resistance and preserving the utility of currently available agents. Antimicrobial stewardship programs in conjunction with stringent infection control policies will be critical in improving the appropriate use of antimicrobials while reducing the spread of nosocomial pathogens. CONCLUSION: Addressing the challenges of antimicrobial resistance in hospitals will require a multidisciplinary approach, with clinical pharmacists taking a proactive role in ensuring the appropriate use of antimicrobials.

Characterization of community-acquired Staphylococcus aureus infections in children.

BACKGROUND: Limited data exist concerning characteristics of community-acquired Staphylococcus aureus infections (CA-SAI) in central and eastern Kentucky. OBJECTIVE: To describe the incidence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections from January 1, 2004 through December 31, 2005, compare the number of CA-MRSA infections between years, and contrast treatment interventions and antibiotic susceptibility patterns of CA-SAI. METHODS: A concurrent and retrospective study was conducted in 125 patients less than 18 years of age with CA-SAI admitted to the hospital/clinic based on criteria from the Centers for Disease Control and Prevention. Data on demographics, length of stay, antibiotic therapy, and antibiotic susceptibilities were collected. RESULTS: Seventy patients were included for analysis (CA-MRSA, n = 51; community-acquired methicillin-susceptible S. aureus [CA-MSSA], n = 19). No statistically significant differences were noted between the number of CA-MRSA infections and the total CA-SAI (9/15 in 2004 vs 42/55 in 2005; p = 0.15). Approximately 75% of patients with CA-SAI were admitted to the hospital with no significant difference in length of stay. Ninety percent of CA-SAI were skin and soft tissue infections. There was a significant difference between groups with cutaneous abscesses (CA-MRSA, n = 37 vs CA-MSSA, n = 6; p = 0.002). Greater than 95% of all isolates were susceptible to vancomycin and trimethoprim/sulfamethoxazole. Half of CA-MRSA patients received inappropriate antibiotic therapy with beta-lactam antibiotics or clindamycin without confirmatory disk diffusion test. Twenty-five (49%) patients with CA-MRSA received surgical debridement (S/D) and/or incision and drainage (I/D) with concomitant antibiotic therapy. Four patients with CA-MRSA were rehospitalized for subsequent infections; all 4 received appropriate antibiotic therapy. CONCLUSIONS: A noticeable increase in CA-MRSA infections with cutaneous abscess between 2004 and 2005 was noted. In patients receiving inappropriate antibiotic therapy, treatment success was attributed to concomitant S/D and I/D. Further analysis should focus on the impact of antibiotic therapy alone or in combination with S/D and I/D on the incidence of subsequent CA-MRSA infections.

Blunted humoral response to influenza vaccination in patients exposed to zidovudine plus trimethoprim-sulfamethoxazole.

STUDY OBJECTIVES: To determine as proof of principle the effect of combination exposure to zidovudine plus trimethoprim-sulfamethoxazole (TMP-SMX) on humoral immune responses to influenza vaccination in patients with human immunodeficiency virus (HIV). DESIGN: Prospective, open-label trial. SETTING: University-affiliated infectious diseases outpatient clinic. PATIENTS: Twenty-three HIV-infected adults receiving antiretroviral therapy, with CD4+ cell counts greater than 350 cells/mm3 and undetectable viral loads. INTERVENTION: Patients were assigned to one of four treatment groups: zidovudine (6 patients), TMP-SMX (7), zidovudine plus TMP-SMX (5), or neither drug (5); TMP-SMX was given as a 28-day course. Patients were subsequently immunized with the yearly influenza vaccine, and humoral responses were compared among groups 20-24 days after vaccination. MEASUREMENTS AND MAIN RESULTS: Antibody responses to influenza A and B were measured, and total and activated T and B cell percentages in the peripheral blood were determined. Mean influenza B-specific serum immunoglobulin (Ig)G titers were significantly lower in patients receiving TMP-SMX alone (0.98 +/- 0.60 reference value, p=0.010) or the combination of zidovudine plus TMP-SMX (0.73 +/- 0.29 reference value, p=0.003) compared with those receiving neither drug (1.95 +/- 0.38 reference value). This corresponded to a significantly lower percentage of patients in the combination group that achieved immunoprotective titers to influenza B compared with the group who received neither drug (control group; 20% vs 100%, p=0.048). In addition, the relationship between serum IgG titer and CD4+ cell count was statistically significantly different for patients exposed to zidovudine plus TMP-SMX versus control patients for both influenza A and B (F statistics 8.72 and 11.70, respectively, compared with critical F value 7.26 for p<0.025). Likewise, the relationship between influenza B serum IgG and CD4+ cell count was different among patients who received TMP-SMX versus those who did not receive TMP-SMX (F statistic 5.95 compared with critical F value 4.56 for p<0.025). No significant differences were observed among T and B cell percentages in the blood. CONCLUSION: Combination exposure to zidovudine plus TMP-SMX causes a clinically significant suppression of humoral immune responses to influenza vaccination in HIV-infected patients.

Utilizing Pharmacy Records to Assess Antibiotic Prescribing Patterns on the Incidence of Community-Acquired Methicillin-Resistant Staphylococcus aureus Infections in Children.

OBJECTIVE: To assess the effect of prior antibiotic therapy on the incidence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections in children. METHODS: This was a concurrent and retrospective review of antibiotic records for children < 18 years of age with documented CA-MRSA infection identified between January 1, 2004, and December 31, 2005. Antibiotic records were compared against a control group. The primary outcome was the incidence of CA-MRSA using linear regression as a function of age and prior antibiotic therapy (i.e., 3 months prior to admission). Secondary objectives included a comparison of antibiotic courses and classes and a description of antibiotic susceptibilities in patients with CA-MRSA RESULTS: Data from 26 patients were included. Nine out of 51 patients (18%) with CA-MRSA were included. Another 17 children were enrolled in the control group. The median age was approximately 1.75 years (0.08-14 years) in the CA-MRSA group versus 2.75 years (0.005-15 years) in the control group. A statistical difference was noted in the number of patients with prior antibiotic exposure between the CA-MRSA and control group, 8 (88.9%) versus 6 (35.3%), respectively (P = .01). Antibiotic exposure was found to be a significant independent risk factor (P = .005; 95% CI, 0.167-0.846) for the development of CA-MRSA. The interaction between antibiotic exposure and age < 3 was the most significant predictor of CA-MRSA (P = .019; 95% CI, 0.139-1.40). CONCLUSIONS: Prior antibiotic therapy in patients < 3 years of age was associated with a significant risk of developing CA-MRSA. A comprehensive assessment of CA-MRSA patients should include objective methods of measuring prior antibiotic exposure such as pharmacy records.

Why is the microbiology lab calling about an extended-spectrum beta-lactamase bacterium from a wound culture?

As more and more gram-negative bacteria produce extended-spectrum beta-lactamases, it is important that physicians know what to do when these bacteria cause postoperative infections in patients.

Trimethoprim-sulfamethoxazole as a viable treatment option for infections caused by methicillin-resistant Staphylococcus aureus.

OBJECTIVE: To review available data regarding the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). DATA SOURCES: A MEDLINE search was performed (January 1966-December 2003) using the search terms Staphylococcus aureus , sulfamethoxazole, trimethoprim, co-trimoxazole, and methicillin resistance. Abstracts from infectious diseases meetings also were reviewed. DATA SYNTHESIS: The reported rate of TMP-SMX resistance in S. aureus is highly variable. From a mechanistic standpoint, TMP-SMX resistance among MRSA appears to be distinct from multidrug resistance, although some anecdotal reports suggest otherwise. Clonal outbreaks of MRSA resistant to TMP-SMX have been described; of these, the Brazilian clone has more often been resistant to TMP-SMX than the Iberian clone. Rates of TMP-SMX resistance are particularly high in institutions serving large numbers of patients infected by the human immunodeficiency virus, due to increased exposure for Pneumocystis prophylaxis. Limited studies and case reports have found TMP-SMX useful against infections caused by MRSA. CONCLUSIONS: A large body of anecdotal data, but only one randomized clinical trial, indicates the effectiveness of TMP-SMX as a treatment for MRSA infections. Double-blind, randomized controlled trials are needed to compare the two available oral agents-TMP-SMX and linezolid-against MRSA.

Use of macrolides and tetracyclines for chronic inflammatory diseases.

OBJECTIVE: To review the efficacy of macrolides and tetracyclines in several chronic inflammatory conditions. DATA SOURCES: Searches of MEDLINE (1966-March 2004) and an extensive bibliography search were undertaken. Key terms included acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis. STUDY SELECTION AND DATA EXTRACTION: Data were obtained primarily from randomized placebo-controlled trials upon which key recommendations are based. DATA SYNTHESIS: Antibiotics are often prescribed for months or even years for treatment of chronic inflammatory conditions such as acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis. Randomized controlled trials have shown that azithromycin is useful in the management of cystic fibrosis and the tetracyclines are beneficial in the management of rheumatoid arthritis, acne, blepharitis, and periodontitis. Several large, randomized controlled trials have failed to show any benefit of macrolides in the secondary prevention of cardiovascular disease. No randomized placebo-controlled clinical trials have been performed to assess the efficacy of macrolides or tetracyclines in patients with rosacea. CONCLUSIONS: The use of tetracyclines and macrolides for rosacea is based primarily on anecdotal reports or open-label trials. Limited clinical trials support the use of tetracyclines or macrolides in acne, blepharitis, periodontitis, rheumatoid arthritis, and cystic fibrosis. Trials to date do not support the use of antibiotics for secondary prevention of cardiovascular disease.