Broad-spectrum Combination Research Articles

Combination of AgNPs and Domiphen is Antimicrobial Against Biofilms of Common Pathogens.

PurposeThe aim was to evaluate the antimicrobial potential of AgNPs synthesized with Artemisia argyi leaf extract and investigate the antimicrobial synergistic effects of AgNPs combined with domiphen and provide an efficient and broad-spectrum combination drug strategy.MethodsAgNPs synthesized with Artemisia argyi leaf extract were studied using UV–vis spectroscopy, FTIR spectroscopy and particle size analysis. Then, Artemisia argyi leaf extract-synthesized AgNPs and domiphen were tested against Acinetobacter baumannii (ATCC 19606), Staphylococcus aureus (ATCC 6538), Escherichia coli (8099) and Candida albicans (ATCC 10231), respectively. Then, we explore synergistic antimicrobial effect and synergistic anti-biofilm effect through combined drug susceptibility test and combined drug minimum biofilm eradication concentration (MBEC50) test.ResultsCharacteristic absorption bands of AgNPs were found near 430 nm in the UV–vis spectrum. Particle size analysis results revealed that the average particle size of Artemisia argyi leaf extract-synthesized AgNPs was 77.6 nm. Artemisia argyi leaf extract-synthesized AgNPs showed high antimicrobial activity against the above four strains. Minimum inhibitory concentration (MIC) of Artemisia argyi leaf extract-synthesized AgNPs against strains was 1 μg/mL for Acinetobacter baumannii, 2 μg/mL for Staphylococcus aureus, Escherichia coli and Candida albicans. MBEC50 of Artemisia argyi leaf extract-synthesized AgNPs against strains was 2 μg/mL for Acinetobacter baumannii, 4 μg/mL for Staphylococcus aureus, 1/2 μg/mL for Escherichia coli and 2 μg/mL for Candida albicans. The combination of Artemisia argyi leaf extract-synthesized AgNPs and domiphen has synergistic antimicrobial effect and synergistic anti-biofilm effect. Fractional inhibitory concentration (FIC) was ≤0.5.ConclusionArtemisia argyi leaf extract-synthesized AgNPs had antimicrobial activity against the above four strains. The combination of Artemisia argyi leaf extract-synthesized AgNPs and domiphen has synergistic antimicrobial effects to reduce the dosage of each antimicrobial drugs. Artemisia argyi leaf extract-synthesized AgNPs and domiphen have synergistic anti-biofilm effects.

Development and validation of a simple and sensitive LC-MS/MS method for quantification of ampicillin and sulbactam in human plasma and its application to a clinical pharmacokinetic study

Ampicillin-sulbactam is a broad-spectrum combination antibiotic used for a variety of clinical applications, including as a prophylactic agent to reduce the risk of surgical site infection. The pharmacokinetics of ampicillin-sulbactam after redosing during prolonged surgeries remains incompletely understood. In anticipation of further studying the intra-operative pharmacokinetics of this drug, we have developed a novel liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the quantification of ampicillin and sulbactam. The plasma samples were prepared using a simple protein precipitation method. Gradient chromatographic elution was used to separate analytes, and MS/MS analysis was performed in negative ionization mode for both analytes via multiple reaction monitoring (MRM). All validation parameters were evaluated under a good laboratory practice (GLP) environment. For both ampicillin and sulbactam, the lower limit of quantitation (LLOQ) was established as 0.25 μg/mL. The calibration curve ranged from 0.25 to 200 μg/mL for ampicillin and 0.25–100 μg/mL for sulbactam. Inter- and intra-day precisions for both analytes were ≤11.5 % for quality controls and ≤17.4 % for LLOQ; accuracies ranged from -11.5 to 12.5% for 3 quality control levels and -18.1–18.7% for LLOQ. In addition to sensitivity, accuracy and precision, 13 other parameters were also validated for both analytes, and the results met the acceptance criteria. Our method was successfully applied to quantify ampicillin and sulbactam concentrations in patients undergoing surgery.

New Multidrug Efflux Inhibitors for Gram-Negative Bacteria.

Active efflux of antibiotics preventing their accumulation to toxic intracellular concentrations contributes to clinically relevant multidrug resistance. Inhibition of active efflux potentiates antibiotic activity, indicating that efflux inhibitors could be used in combination with antibiotics to reverse drug resistance. Expression of ramA by Salmonella enterica serovar Typhimurium increases in response to efflux inhibition, irrespective of the mode of inhibition. We hypothesized that measuring ramA promoter activity could act as a reporter of efflux inhibition. A rapid, inexpensive, and high-throughput green fluorescent protein (GFP) screen to identify efflux inhibitors was developed, validated, and implemented. Two chemical compound libraries were screened for compounds that increased GFP production. Fifty of the compounds in the 1,200-compound Prestwick chemical library were identified as potential efflux inhibitors, including the previously characterized efflux inhibitors mefloquine and thioridazine. There were 107 hits from a library of 47,168 proprietary compounds from L. Hoffmann La Roche; 45 were confirmed hits, and a dose response was determined. Dye efflux and accumulation assays showed that 40 Roche and three Prestwick chemical library compounds were efflux inhibitors. Most compounds had specific efflux-inhibitor-antibiotic combinations and/or species-specific synergy in antibiotic disc diffusion and checkerboard assays performed with Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Salmonella Typhimurium. These data indicate that both narrow-spectrum and broad-spectrum combinations of efflux inhibitors with antibiotics can be found. Eleven novel efflux inhibitor compounds potentiated antibiotic activities against at least one species of Gram-negative bacteria, and data revealing an E. coli mutant with loss of AcrB function suggested that these are AcrB inhibitors.IMPORTANCE Multidrug-resistant Gram-negative bacteria pose a serious threat to human and animal health. Molecules that inhibit multidrug efflux offer an alternative approach to resolving the challenges caused by antibiotic resistance, by potentiating the activity of old, licensed, and new antibiotics. We have developed, validated, and implemented a high-throughput screen and used it to identify efflux inhibitors from two compound libraries selected for their high chemical and pharmacological diversity. We found that the new high-throughput screen is a valuable tool to identify efflux inhibitors, as evidenced by the 43 new efflux inhibitors described in this study.

Impact of SEP-1 on broad-spectrum combination antibiotic therapy in the emergency department.

The SEP-1 measures have tied financial reimbursement to the treatment of patients with severe sepsis and septic shock. The purpose of this study was to assess the impact of a SEP-1 initiative on the utilization of broad-spectrum combination therapy (BSCT) in the emergency department (ED). This was an IRB-approved, retrospective evaluation of adult patients who received vancomycin plus an antipseudomonal beta-lactam for a urinary tract infection (UTI) or skin or soft tissue infection (SSTI) in the ED. The primary outcome was the proportion of patients in which use of BSCT was considered appropriate based on clinical criteria. Secondary outcomes included door to antibiotic order time, door to administration time, proportion of patients continued on BSCT upon admission, duration of BSCT, and in-hospital mortality. A total of 400 patients were included in the analysis. Following SEP-1 implementation, appropriate use of BSCT decreased by 12%, with 54% of patients in the pre-SEP-1 group meeting clinical criteria compared to 42% in the post-SEP-1 group (p=0.028). In the subgroup of patients with a suspected UTI the appropriate use of BSCT declined by 25% (40% vs 15%, p=0.005). The median door to first antibiotic administration time was not significantly different between groups (63min vs 61min, p=0.091). The implementation of the SEP-1 mandated measures was associated with an increase in the unnecessary use of BSCT. Additionally, no difference was seen in time to antibiotic administration. The results of this study demonstrate the negative impact that the SEP-1 mandate may have on antimicrobial utilization within the ED.

Inpatients With 'Unexplained' Leukocytosis

BackgroundUnexplained or persistent leukocytosis is an increasing common cause of consultation to infectious disease physicians. Patients appear to be in a state of continued inflammation recently described as the persistent inflammation-immunosuppression and catabolism syndrome (PICS). Hospital course of such patients is frequently prolonged and associated with extensive use of empiric broad-spectrum antibiotics. We wished to determine the associated clinical features and outcome of such patients in anticipation of future specific diagnostic and therapeutic approaches to this syndrome. MethodsWe reviewed all infectious disease consultations from July 1, 2017, to March 31, 2018, for reason for consultation. Of those whose primary reason was “leukocytosis” or “bandemia,” each chart was assessed for demographics, reason for admission, hospital day of consultation, peak white blood cell count, infections and possible microbiological colonization, antibiotic use, and outcome. ResultsA total of 29 patients were identified, constituting 4.5% of consults during the study period. Cause of admission was sepsis in 7, major trauma 6, cerebrovascular accident 5, major elective surgery 4, ischemic leg 3, and 1 each lung mass, acute myocardial infarction, interstitial lung disease, and angioblastic lymphoma. Peak total leukocyte count (WBC) was 26.4K ± 8.8 on mean day 9.6 ± 5.5 days of hospitalization. Mean duration of leukocytosis greater than 11K was 14.5 ± 10.6 days. Peak percentage early myelocytic (“band”) leukocytes was 18.4 ± 13.8 and was of higher than 5% for a duration of 4.5 ± 5.6 days. Total eosinophilia count >500 was observed in 15 patients (range 500-2800) median hospital day 12. All patients received multiple and prolonged courses of broad-spectrum combination empiric antibiotics without apparent benefit either in terms of leukocytosis, signs of sepsis if present, or change in cultures, although those 7 with confirmed sepsis at admission tended to have shorter duration of leukocytosis and hospital course, whereas patients with trauma manifested greatest “bandemia.” Most patients became colonized with resistant opportunistic organisms, the most significant being Clostridium difficile enteritis in 6 patients. Hospitalization was prolonged, and most common disposition was to nursing home or rehabilitation (11 patients, mean day of discharge 21.6 ± 16.8) and home (8 patients, day 16.0 ± 9.3). Three patients died at mean hospital day 35.7 ± 29.7. ConclusionsExcept for 1 person with pelvic abscess post-cystectomy, patients appeared to have extensive tissue damage rather than active infection driving the leukocytosis. Patients appeared to meet clinical criteria for PICS that was substantiated by development of eosinophilia. Future studies should include direct measurements of the CD33CD11b+ myeloid suppressor cells, and the relative contribution of damage-associated molecular patterns (DAMPS) compared with pathogen-associated molecular patterns (PAMPS) such as endotoxin and other microbial products. More prudent and effective use of antibiotics could be possible.

Incidence of Acute Kidney Injury Among Critically Ill Patients With Brief Empiric Use of Antipseudomonal β-Lactams With Vancomycin.

Nephrotoxins contribute to 20%-40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations. The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups. The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85-1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71-1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09). Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.

Nephrotoxicity of piperacillin/tazobactam combined with vancomycin: should it be a concern?

The combination of piperacillin/tazobactam (TZP) and vancomycin (VAN) provides a wide spectrum of activity against many pathogens acquired in healthcare settings. However, there have been reports of increased potential for nephrotoxicity with this combination. The aim of this study was to evaluate the nephrotoxic effect of TZP+VAN and to compare it with that of TZP and VAN monotherapies as well as VAN + meropenem (MEM), another broad-spectrum combination. A total of 402 patients receiving any of the antimicrobial regimens for >48 h were evaluated retrospectively over a 2-year period (2012-2013). Patients admitted to the intensive care unit, those with a baseline serum creatinine >2.0 mg/dL, patients on haemodialysis or peritoneal dialysis, pregnant women and those in septic shock were excluded. The presence and severity of acute kidney injury (AKI) was assessed according to the AKIN criteria. The incidence of AKI was significantly higher in the TZP+VAN group (41.3%) compared with the TZP (16.0%), VAN (15.7%) and VAN+MEM (10.1%) groups (P < 0.001). In the multivariate analysis, the risk of AKI increased 3.5-fold in patients treated with TZP+VAN and 1.7-fold in those who were receiving a potentially nephrotoxic drug when the antibiotic regimen was started compared with patients treated with VAN alone. Combined use of TZP+VAN carries a much higher risk of AKI than either antibiotic monotherapy regimen. Therefore, this broad-spectrum combination should be used cautiously in patients with a high likelihood of developing kidney injury.

Effects of clinical pathway implementation on antibiotic prescriptions for pediatric community-acquired pneumonia.

BackgroundItalian pediatric antimicrobial prescription rates are among the highest in Europe. As a first step in an Antimicrobial Stewardship Program, we implemented a Clinical Pathway (CP) for Community Acquired Pneumonia with the aim of decreasing overall prescription of antibiotics, especially broad-spectrum.Materials and methodsThe CP was implemented on 10/01/2015. We collected antibiotic prescribing and outcomes data from children aged 3 months-15 years diagnosed with CAP from 10/15/2014 to 04/15/2015 (pre-intervention period) and from 10/15/2015 to 04/15/2016 (post-intervention period). We assessed antibiotic prescription differences pre- and post-CP, including rates, breadth of spectrum, and duration of therapy. We also compared length of hospital stay for inpatients and treatment failure for inpatients and outpatients. Chi-square and Fisher’s exact test were used to compare categorical variables and Wilcoxon rank sum test was used to compare quantitative outcomes.Results120 pre- and 86 post-intervention clinic visits were identified with a diagnosis of CAP. In outpatients, we observed a decrease in broad-spectrum regimens (50% pre-CP vs. 26.8% post-CP, p = 0.02), in particular macrolides, and an increase in narrow-spectrum (amoxicillin) post-CP. Post-CP children received fewer antibiotic courses (median DOT from 10 pre-CP to 8 post-CP, p<0.0001) for fewer days (median LOT from 10 pre-CP to 8 post-CP, p<0.0001) than their pre-CP counterparts. Physicians prescribed narrow-spectrum monotherapy more frequently than broad-spectrum combination therapy (DOT/LOT ratio 1.157 pre-CP vs. 1.065 post-CP). No difference in treatment failure was reported before and after implementation (2.3% pre-CP vs. 11.8% post-CP, p = 0.29). Among inpatients we also noted a decrease in broad-spectrum regimens (100% pre-CP vs. 66.7% post-CP, p = 0.02) and the introduction of narrow-spectrum regimens (0% pre-CP vs. 33.3% post-CP, p = 0.02) post-CP. Hospitalized patients received fewer antibiotic courses post-CP (median DOT from 18.5 pre-CP to 10 post-CP, p = 0.004), while there was no statistical difference in length of therapy (median LOT from 11 pre-CP to 10 post-CP, p = 0.06). Days of broad spectrum therapy were notably lower post-CP (median bsDOT from 17 pre-CP to 4.5 post-CP, p <0.0001). No difference in treatment failure was reported before and after CP implementation (16.7% pre-CP vs. 15.4% post-CP, p = 1).ConclusionsIntroduction of a CP for CAP in a Pediatric Emergency Department led to reduction of broad-spectrum antibiotic prescriptions, of combination therapy and of duration of treatment both for outpatients and inpatients.

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies Against Staphylococcus Aureus Exploiting In Vitro Information.

Broad‐spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad‐spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic‐pharmacodynamic (PK‐PD) model mimicking a simplified bacterial life‐cycle of S. aureus was developed upon time‐kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK‐PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK‐PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN‐MER might be favorable over LZD‐MER due to an unfavorable antagonistic interaction between LZD and MER.

Efficacy of a topical combination of fipronil, (S)-methoprene, eprinomectin and praziquantel (Broadline(®)) against naturally acquired infections with cestodes of the genus Joyeuxiella in cats.

Cats are host to dipylidiid cestodes of the genera Diplopylidium, Dipylidium and Joyeuxiella. Broadline(®), a topical broad-spectrum combination parasiticide containing fipronil (8.3% w/v), (S)-methoprene (10% w/v), eprinomectin (0.4% w/v) and the cestocide praziquantel (8.3% w/v), has previously been shown to be efficacious against Dipylidium caninum and Diplopylidium spp. in cats. To evaluate its efficacy against Joyeuxiella species, a blinded clinical efficacy study was conducted according to GCP. All cats had evidence for naturally acquired dipylidiid cestode infection as confirmed by pre-treatment examination. Cats were allocated randomly to two groups of 13 cats each based on bodyweight: Control (untreated) and Broadline(®) at 0.12mL/kg bodyweight administered once topically. Based on the comparison of helminth counts in the treated and untreated cats seven days post treatment, Broadline(®) demonstrated >99% efficacy (p < 0.01) against mature J. fuhrmanni and J. pasqualei, with 11 and 13 of the untreated cats harbouring 1 to 102 or 2 to 95 cestodes, respectively. In addition, parasite counts indicated 95.9% efficacy (p = 0.006) against the rictularoid nematode Pterygodermatites cahirensis.

Diagnosis and Successful Surgical Removal of an Aural Ceruminous Gland Adenocarcinoma in a Domestic Ferret (Mustela putorius furo)

A 4-year-old neutered male albino domestic ferret (Mustela putorius furo) was evaluated for otitis externa of the right ear. A general physical examination revealed severe inflammation of the right external ear canal with large amounts of ceruminous debris. Ear mites (Otodectes cynotis), large numbers of cocci and rod bacteria, and yeast were noted on cytological examination of an ear swab. After treatment with topical selamectin, and 8 days of treatment with a compounded broad-spectrum combination ear cleaner, the inflammation had resolved. On a subsequent otoscopic examination, an 8-mm diameter, painful, multilobed, irregular, fleshy mass was noted to be completely occluding the right ear canal. A lateral ear canal resection was performed to provide exposure to the base of the mass. The mass was found to have a stalk-like origin at the junction of the vertical and horizontal ear canals. The mass was removed at the base using electrocautery. Histopathology identified the mass as a ceruminous gland adenocarcinoma. Follow-up radiation and chemotherapy were declined by the owners. There was no evidence of recurrence of either the mass or otitis 9 months after the operation. This case report demonstrates that a lateral ear canal resection can facilitate removal of a mass from within the ear canal, and that surgical resection alone may provide a desirable disease-free resolution of the problem in ferrets.

46 Broad-spectrum preclinical combination activity of eribulin combined with various anticancer agents in human breast cancer, lung cancer, ovarian cancer, and melanoma xenograft models

and Q-PCR. The status of TP53 in ALL cells was determined by Sanger sequencing. Results: Nine ALL cell lines exhibited different susceptibilities to Aurora kinase inhibitors (AKIs). Cells sensitive to AKIs underwent apoptosis at an IC50 of approximately 10 to 30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC50 more than 10 mM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility was not correlated with the expression level or activation status of Aurora kinases. RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora-A inhibitors. CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to AKIs. Conclusions: Our study suggests that Aurora-A kinase inhibitors may have clinical utility in MLL-AF4-positive ALL. CDKN1A can be used as a biomarker to determine drug responsiveness in MLL-AF4-positive ALL.

Guidelines for hospital-acquired pneumonia and health-care-associated pneumonia: a vulnerability, a pitfall, and a fatal flaw

The 2005 American Thoracic Society and Infectious Disease Society of America's guidelines for pneumonia introduced the new category of health-care-associated pneumonia, which increased the number of people to whom the guidelines for multidrug-resistant pathogens applied. Three fundamental issues inherent in the definition of hospital-acquired pneumonia and health-care-associated pneumonia undermined the credibility of these guidelines and the applicability of their recommendations: a vulnerability, a pitfall, and a fatal flaw. The vulnerability is the extreme heterogeneity of the population of patients. The fatal flaw is the failure to accurately diagnose hospital-acquired pneumonia and ventilator-associated pneumonia; inability to distinguish colonisation from infection in respiratory-tract cultures renders the guidelines inherently unstable. The pitfall is spiralling empiricism of antibiotic use for severely ill patients in whom infection might not be present. A vicious circle of antibiotic overuse leading to emergence of resistant microflora can become established, leading to unnecessary use of empirical broad-spectrum combination antibiotics and increased mortality. Controlled studies now show that administration of broad-spectrum combination antibiotic therapy can lead to increased mortality in uninfected patients. Proposed solutions include the use of individualised assessment of patients. Health-care-associated pneumonia should be broken down into several distinct subgroups so narrow-spectrum antibiotic therapy can be used. Emphasis should be placed on defining the microbial cause of the pneumonia rather than reflex administration of empirical combination therapy.

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 broadspectrum 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 patient’s 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. (Korean J Intern Med 2011;26: 220-252)

Computer-Based Monitoring as a Tool for Antimicrobial De-Escalation

Purpose Multiple studies have found an association between the prompt initiation of empirically-appropriate antimicrobial therapy and improved patient outcomes. Such empiric-antimicrobial therapy is often broad; however, once the patient's infectious syndrome, microbiology, and susceptibilities are more defined, it is important to refine antimicrobial therapy. Despite the potential benefits of an “antimicrobial de-escalation” approach, it may be difficult to enforce in clinical practice. Mayo Clinic's Computer-Based Antimicrobial Monitoring System (CBAM) is a medical-informatics tool that was used to assist in this endeavor. This study evaluates the hypothesis that CBAM can enhance the de-escalation of vancomycin and broad-spectrum combination antimicrobial therapy. Methods Hospitalized patients at the Mayo Clinic were screened from January through June 2006 using rule-based algorithms incorporated by CBAM. Interventions were performed by physicians and pharmacists as pertinent. These patients were compared with a historical group of patients obtained by CBAM reporting capabilities. De-escalation rates and mean duration of antimicrobial therapy were compared between groups. Results Vancomycin de-escalation rates significantly improved from 33% to 68% with intervention ( P = 0.001). In addition, the average duration of therapy was decreased from 10.4 ± 7.3 days to 7.7 ± 2.4 days among patients who underwent vancomycin de-escalation per recommendation ( P = 0.014). Conclusions Utilizing the Mayo Clinic's CBAM system to identify potential patients for de-escalation is a unique approach and was successful at improving adherence to vancomycin de-escalation.

Was gibt es Neues in der Behandlung der ambulant erworbenen Pneumonie?

Community-acquired pneumonia (CAP) is the most important infectious disease in Germany. After 3 years of data recording, the country-wide competence network CAPNETZ presents reliable data on etiology and course of the disease, based on more than 3,500 prospectively observed patients. In the acute phase, lethality is as high as nearly 10%, and in the 6-month follow-up period after the acute infection, lethality is > 15%. A reliable detection of the underlying pathogen is possible in less than half of all patients studied. The most frequent pathogens are Streptococcus pneumoniae (40%), Haemophilus influenzae, and Mycoplasma pneumoniae (8% each). Legionella (3%) and Chlamydia pneumoniae (< 1%) are rarely found, and gram-negative enterobacteriaceae (< 5%) are restricted to high-risk patient groups (nursing home, multimorbidity). CAPs due to pneumococci, legionella or enterobacteriaceae were associated with increased lethality. Problems with resistances had not been found in Germany, except for a decreasing susceptibility of S. pneumoniae to macrolides. Viruses could be detected in nearly 15% of all pneumonia patients. The CRB-65 score allows a reliable discrimination between patients with a high and low risk of dying. The new S3 guideline for diagnosis and treatment of CAP recommends a risk-adapted treatment. Low-risk patients shall receive a monotherapy with, e. g., amoxicillin, high-risk patients should be treated with a broad-spectrum combination therapy (beta-lactam and macrolide).

Was gibt es Neues in der Behandlung der ambulant erworbenen Pneumonie?

Community Acquired Pneumonia (CAP) is the most important infectious disease in Germany. In the acute phase, lethality is almost 10%, and in the six months follow up period following the acute infection, lethality is more than 15%. Problems with resistances had not been found in Germany, except for a decreasing susceptibility of S. pneumoniae against macrolides. The CRB-65 score allows a reliable discrimination between patients with a high and low risk of dying. The new S3 guideline for diagnosis and treatment of community acquired pneumonia recommends a risk adapted treatment. Low risk patients shall receive a monotherapy with e. g. amoxicillin, high risk patients should be treated with a broad spectrum combination therapy (beta-lactam and macrolide).

Single additional dose postpartum therapy for women with chorioamnionitis

Objective To determine whether a short course of antibiotics provides adequate treatment for chorioamnionitis. Methods Women received intravenous ampicillin, 2 g every 6 hours, and gentamicin, 1.5 mg/kg every 8 hours, when clinical chorioamnionitis was diagnosed. After delivery, subjects were randomized to continue this regimen until afebrile and asymptomatic for 24 hours (control group) or to receive only the next scheduled dose of each drug (study group). If delivered via cesarean, patients received clindamycin, 900 mg intravenously, at umbilical cord clamping. The control group continued receiving clindamycin every 8 hours until antibiotics were discontinued. The primary outcome was treatment failure, defined as a single temperature after the first postpartum dose of antibiotics of 39.0C or more, or two temperatures 38.4C or more at least 4 hours apart. To detect a 150% increase in rate of treatment failures from 8% in the control group to 20% in the study group, 292 subjects were needed (α = .05; 1 − β = .80). Results From December 26, 1999, to March 18, 2003, a total of 292 women were enrolled in the study. In the intent-to-treat analysis, treatment failure rate did not differ between the control ( n = 141) and study ( n = 151) groups (3.5% versus 4.6%; P = .639). Conclusion If treated promptly intrapartum, one additional dose of a broad-spectrum combination of antibiotics is sufficient postpartum therapy for immune-competent women with chorioamnionitis.

Evolution of aminoglycoside resistance phenotypes of four Gram-negative bacteria: an 8-year survey in a University Hospital in Greece

In order to determine the resistance patterns and evolution trends of four common Enterobacteriaceae ( Escherichia coli, Proteus spp., Klebsiella spp. and Enterobacter spp.), aminoglycoside resistance phenotypes of 8917 non-repetitive strains, isolated over an 8-year period, were analysed. Phenotypes were defined by examining the susceptibility of the strains to a panel of aminoglycosides, using disk diffusion method. A large diversity of different resistance phenotypes was encountered. A significant progressive increase in the proportions of wild-type E. coli strains was noted. Among resistant strains of Enterobacter spp. and Klebsiella spp., the incidence of phenotype KTANt (kanamycin, tobramycin, amikacin and netilmicin), indicative of AAC(6′)-I production, was very high (66.7 and 46.5%, respectively). Phenotypes indicative for gentamicin-modifying enzymes as well as broad-spectrum combinations (combinations of gentamicin-modifying enzymes with AAC(6′)-I) were infrequent.

Variability of treatment duration for bacteraemia in the critically ill: a multinational survey.

No definitive evidence is available to inform 'best' antibiotic practice for treating bacteraemia in the critically ill patient, either in terms of duration of therapy, or the use of mono- versus combination therapy. We therefore undertook a large-scale international survey to assess the variability of current practice. A questionnaire was sent to membership lists of national and international intensive care societies. Responses from 254 intensive care units in 34 countries revealed a wide variation in antibiotic strategy for all types of bacteraemia, ranging from short course (<or=5 days) therapy with restricted-spectrum antibiotics, to long course (>or=10 days) use of broad-spectrum combinations. Two factors were significantly associated with antibiotic prescribing practice, namely the country of origin (in those with >or=10 responders) and the level of microbiologist and/or infectious diseases specialist input. The greater the specialist input, the shorter the duration of therapy (P < 0.0001). The wide variability in antibiotic prescribing patterns suggests an urgent need to produce high-quality evidence to identify optimal antibiotic prescribing policies for bacteraemia in the critically ill patient.