Definitive Antimicrobial Therapy Research Articles

Inappropriate empirical antimicrobial therapy for multidrug-resistant organisms in critically ill patients with pneumonia is not an independent risk factor for mortality: Results of a prospective observational study of 758 patients.

The benefits of broad-spectrum initial empirical antibiotic therapy for all patients in intensive care units (ICUs) with high rates of multidrug-resistant organisms (MDROs) have not been critically evaluated. In this study, 758 ICU patients with pneumonia were prospectively evaluated. Of 349 positive respiratory cultures, 119 (34.1%) were with MDRO isolates. These were associated with increased mortality [adjusted hazard ratio (HR)=1.65, 95% confidence interval (CI) 1.01-2.68; P=0.04] as was increasing age and Acute Physiology and Chronic Health Evaluation (APACHE) II score. Among the patients with MDRO-associated pneumonia, increasing age, APACHE II score and inappropriate definitive antimicrobial therapy (IDAT) were found to be significant risk factors for mortality (in-ICU mortality, adjusted HR=2.8, 95% CI 1.3-5.8; P=0.007), but inappropriate empirical antimicrobial therapy (IEAT) was not (in-ICU mortality, unadjusted HR=1.6, 95% CI 0.7-3.6; P=0.3). In conclusion, we found that among critically ill patients with MDRO-associated pneumonia, IEAT is not an independent risk factor for ICU mortality. Hence, we do not recommend the use of broad-spectrum initial empirical antimicrobial therapy for all patients, as its benefits may not outweigh the potential risks. Early microbiological diagnosis to facilitate implementation of early definitive antimicrobial therapy through use of novel technologies is likely to have a major impact.

Impact of multidrug resistance on Pseudomonas aeruginosa ventilator-associated pneumonia outcome: predictors of early and crude mortality

The prevalence of multidrug-resistant (MDR) Pseudomonas aeruginosa has increased over the past decade and a significant rise in these isolates in ventilator-associated pneumonia (VAP) has been observed. However, the impact of MDR on VAP outcome has not been analysed in depth. We investigated the risk factors for early and crude mortality in a retrospective study of microbiologically and clinically documented VAP. Ninety-one VAP episodes in 83 patients were included, 31 caused by susceptible P. aeruginosa and 60 by MDR strains, of which 42 (70 %) were extensively drug-resistant (XDR) P. aeruginosa. Thirteen episodes concomitantly presented P. aeruginosa bacteraemia, in seven of which the origin was the respiratory tract. Whereas susceptible P. aeruginosa episodes were more likely than MDR episodes to receive adequate empirical (68 % vs. 30 %; p < 0.001) and definitive antimicrobial therapy (96 % vs. 50 %; p < 0.001), susceptible P. aeruginosa VAP presented a trend towards early mortality (29 % vs. 15 %; p = 0.06). A logistic regression model with early mortality as the dependent variable identified multiorgan dysfunction syndrome (MODS) [odds ratio (OR) 10.4; 95 % confidence interval (CI) 1.7-63.5; p = 0.01] and inadequate antibiotic therapy (OR 4.27; 95 % CI 0.98-18.4; p = 0.052) as independent risk factors for early mortality. A similar analysis identified MODS (OR 4.31; 95 % CI 1.14-16.2; p = 0.03) as the only independent predictor of crude mortality. The severity of acute illness clinical presentation was the main predictor of mortality. Despite adequate antibiotic therapy, susceptible P. aeruginosa seems to cause major early mortality. Although adequate therapy is essential to treat VAP, the severity of acute illness is a more important factor than drug resistance.

Clinical impact of inappropriate initial antimicrobial therapy on outcome in bacteremic biliary tract infections

The marked increase in the incidence of biliary tract infections due to antimicrobial-resistant pathogens in recent years is of great concern, as patients infected by these isolates might initially receive antibiotics ineffective against the responsible pathogens. A retrospective cohort study including 556 episodes of bacteremic biliary tract infection was designed to evaluate the impact of inappropriate initial antimicrobial therapy on the clinical outcomes of patients with biliary tract infections. Of 556 episodes, 257 (46.2%) received inappropriate initial antimicrobial therapy. Although Escherichia coli and Klebsiella species are the most common pathogens, the pathogens that were most frequently associated with inappropriate therapy were Pseudomonas aeruginosa and Enterococcus spp. In multivariable analysis, inappropriate initial antimicrobial therapy was found to be independently associated with increased mortality (odds ratio (OR) 2.25, 95% confidence interval (CI) 1.13-4.48; p = 0.021), along with pancreaticobiliary tract cancer, liver cirrhosis, Enterobacter infection, and a high Pitt bacteremia score (All p < 0.05). Subgroup multivariate analyses showed that inappropriate initial therapy was not a significant factor associated with mortality in cases where therapeutic decompression or drainage procedures were employed (OR 1.24, 95% CI 0.43-3.54; p = 0.691) or in cases with appropriate definitive antimicrobial therapy (OR 1.61, 95% CI 0.69-3.72; p = 0.270) after adjustment for other variables. Our findings suggest that the administration of inappropriate initial antimicrobial therapy might be associated with an adverse outcome in patients experiencing bacteremic biliary tract infections, and that the impact of inappropriate therapy on the outcome may be dependent on therapeutic drainage and appropriate definitive antimicrobial therapy.

Ertapenem in the treatment of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli: a propensity score analysis

This study assessed the impact of ertapenem and other carbapenems on mortality in patients with monomicrobial extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) bacteremia. This non-concurrent prospective study included adult patients with ESBL-EC bacteremia during a 2.5-year period at a 2200-bed teaching hospital. We used a multivariate logistic regression model and Cox's proportional hazards model including propensity score analysis to assess variables associated with 30-day mortality. Of 71 patients who met the study criteria, nine died within 3 days. Among the 62 remaining patients who received definitive antimicrobial therapy, 13 died within 30 days. Male gender, ICU stay, solid tumor, and primary bacteremia were independent predictors of 30-day mortality, whereas definitive antimicrobial therapy using either ertapenem or imipenem/meropenem was protective (p<0.001 and p=0.002, respectively). Adjustment by propensity score found that ertapenem appeared to exhibit more favorable outcomes, but the difference fell short of statistical significance (hazard ratio 0.02, p=0.06). Inappropriate initial therapy was not a significant predictor of mortality. ICU stay, but not initial choice of empirical antimicrobial therapy, was a major predictor of mortality. Using a carbapenem as definitive therapy was a protective factor for 30-day mortality. The choice of ertapenem is reasonable for less severely-ill patients who are at risk of ESBL-EC bacteremia and unlikely to have infection due to Pseudomonas aeruginosa.

Clinical manifestations and prognostic factors in cancer patients with bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli or Klebsiella pneumoniae

Clinical information about bacteremia due to extended-spectrum β-lactamase (ESBL)-producing pathogens in cancer patients was limited. The study was aimed to identify the clinical manifestations and risk factors for mortality in ESBL-producer bacteremia in cancer patients. A retrospective study of bacteremia caused by ESBL-producing Escherichia coli or Klebsiella pneumoniae in adults with cancer in National Cheng Kung University Hospital and National Taiwan University Hospital from July 2002 to August 2007 was conducted. Clinical characteristics, initial manifestations, and antimicrobial therapy were analyzed for their association with crude mortality at 14 days after bacteremia onset. A total 113 episodes of bacteremia caused by E coli (59.3%), K pneumoniae (39.8%) or both (0.9%) were included. Patients with hematological malignancy were younger (55 ± 22 vs. 69 ± 14 years, p < 0.003) and had less co-morbidity, but were more likely to have neutropenia (73.1% vs. 4.6%, p < 0.001) than those with solid tumor. By the univariate analysis in 113 episodes of ESBL-producer bacteremia, several risk factors, including pneumonia or soft-tissue infection as the bacteremia source, initial manifestations with high Pitt bacteremia scores, shock, respiratory failure or severe sepsis, and inappropriate definitive therapy were associated with 14-day crude mortality. By multivariate analysis, only pneumonia [adjusted odds ratio (AOR), 5.2; 95% confident interval (CI), 1.3-21.0; p = 0.021], severe sepsis (AOR, 24.3; 95% CI, 5.6-105.0; p < 0.001), and inappropriate definitive therapy (AOR, 11.3; 95% CI, 1.7-72.8; p = 0.011) were independently associated with a fatal outcome. The presence of neutropenia or underlying hematological malignancy in cancer patients with ESBL-producer bacteremia was not associated with an increase in the mortality rate. Appropriate definitive antimicrobial therapy will be beneficial in improving clinical outcome.

Clinical manifestations, antimicrobial therapy, and prognostic factors of monomicrobial Acinetobacter baumannii complex bacteremia

Bacteremia due to Acinetobacter baumannii complex (ABC), which composed of four genomic species (gen. sp.), is a serious and potentially fatal condition. The epidemiology and outcome of such infections due to individual gen. sp. remain undefined. A retrospective study of patients with monomicrobial ABC bacteremia over six years was conducted at a medical center to determine the association of gen. sp. with clinical outcome. Included were 291 patients with monomicrobial ABC bacteremia. Of them, 222 (76.3%) patients had bacteremia caused by gen. sp. 2, i.e. A. baumannii. The presence of multidrug-resistant phenotype was the only independent predictor of Acinetobacter gen. sp. 2 bacteremia (adjusted odd ratio, 7.5; 95% confidence interval, 3.8-14.7; P < 0.001). Patients with Acinetobacter gen. sp. 2 bacteremia had a higher sepsis-related (P = 0.006) and 30 day (P = 0.028) mortality rates than the non-Acinetobacter gen. sp. 2 group. The fatal outcome was independently associated with high SPAS II scores (P = 0.002), rapidly fatal underlying diseases (P = 0.002), bacteremia caused by Acinetobacter gen. sp. 2 (P = 0.01), inappropriate definitive antimicrobial therapy (P < 0.001), and severe sepsis (P < 0.001). Acinetobacter gen. sp. 2 bacteremia heralded a worse clinical outcome, and therefore the gen. sp. identification of ABC bacteremic isolates is justified.

Impact of inappropriate antimicrobial therapy on outcome in patients with hospital-acquired pneumonia caused by Acinetobacter baumannii

The purpose of this study was to evaluate the impact of inappropriate antimicrobial therapy on the outcome of patients with hospital-acquired pneumonia (HAP) caused by Acinetobacter baumannii. All cases of HAP caused by A. baumannii from January 2000 to March 2006 at the Samsung Medical Center (Seoul, Korea) were analyzed retrospectively. A total of 116 patients with clinically significant Acinetobacter HAP were enrolled. Among the A. baumannii isolates, 60.3% showed multi-drug resistance (MDR), 16.4% were found to have imipenem resistance, and 15.5% had pan-drug resistance (PDR). The mean APACHE II score of the patients was 22.3 +/- 7.9. The overall in-hospital and pneumonia-related mortality rates were 47.4% and 37.9%, respectively. The univariate analysis showed that the factors associated with pneumonia-related mortality were: MDR, PDR, high APACHE II score, inappropriate empirical antimicrobial therapy, and inappropriate definitive antimicrobial treatment (All p < 0.05). Among these, a high APACHE II score and inappropriate definitive antimicrobial therapy were found to be independent factors associated with a high mortality, after adjustment for other variables. The appropriate definitive antimicrobial therapy should be provided in patients with HAP caused by A. baumannii.

The Utility of Rapid Microbiological and Molecular Techniques in Optimizing Antimicrobial Therapy

Early treatment of bloodstream infections with appropriate, definitive antimicrobial therapy has proven to reduce mortality, length of hospital stay, and healthcare costs. Culture-based testing methods require up to five days for final pathogen identification and susceptibility reporting, forcing use of broad spectrum empiric therapy. Recently, multiple rapid microbiological and molecular testing methods have been developed that reduce the time to identify the pathogen and susceptibility, allowing optimal antimicrobial therapy to be prescribed earlier. Real-time polymerase chain reaction and gene microarray have been described in literature, yet only peptide nucleic acid fluorescent in-situ hybridization has published data justifying its use based on clinical outcomes and cost savings. Target enriched multiplex polymerase chain reaction was developed to identify both the pathogen and multiple genes associated with resistance from blood within 6 hours and this methodology was studied in our hospital to assess effectiveness at optimizing antimicrobials in staphylococcal bloodstream infections.

Detection of pbp2b and ermB genes in clinical isolates of Streptococcus pneumoniae

Streptococcus pneumoniae is a major human pathogen. The emergence of penicillin resistant strains since the 1970s has been life threatening and the evolution of the bacteria have enabled itself to develop resistance to many other antibiotics such as the macrolides and the fluoroquinolones. This study aims to characterize S. pneumoniae isolates for the presence of penicillin and macrolide resistance genes. One hundred and twenty clinical isolates of S. pneumoniae were obtained from patients of University Malaya Medical Centre (UMMC). The strains were screened using a multiplex real-time PCR method for the presence of alterations in the genes encoding the penicillin binding proteins: pbp2b, macrolide resistance determinant ermB and the pneumolysin gene, ply. Dual-labelled Taqman probes were used in the real-time detection method comprising three different genes labeled with individual fluorophores at different wavelengths. One hundred and twenty isolates from bacterial cultures and isolates directly from blood cultures samples were analyzed using this assay. A multiplex PCR comprising the antibiotic resistance genes, ermB and and pneumolysin gene (ply), a S. pneumoniae species specific gene, was developed to characterize strains of S. pneumoniae. Out of the 120 pneumococcal isolates, 58 strains were categorized as Penicillin Sensitive Streptococcus pneumoniae (PSSP), 36 as Penicillin Intermediate Streptococcus pneumoniae (PISP) and 26 as Penicillin Resistant Streptococcus pneumoniae (PRSP). All the 58 PSSP strains harboured the pbp2b gene while the 36 PISP and 26 PRSP strains did not harbour this gene, thus suggesting reduced susceptibility to penicillin. Resistance to erythromycin was observed in 47 of the pneumococcal strains while 15 and 58 were intermediate and sensitive to this drug respectively. Susceptibility testing to other beta-lactams (CTX and CRO) also showed reduced susceptibility among the strains within the PISP and PRSP groups but most PSSP strains were sensitive to other antibiotics. The characterization of pneumococcal isolates for penicillin and erythromycin resistance genes could be useful to predict the susceptibility of these isolates to other antibiotics, especially beta-lactams drugs. We have developed an assay with a shorter turnaround time to determine the species and resistance profile of Streptococcus pneumoniae with respect to penicillin and macrolides using the Real Time PCR format with fluorescent labeled Taqman probes, hence facilitating earlier and more definitive antimicrobial therapy which may lead to better patient management.

Ceftobiprole: A Novel Broad-Spectrum Antiinfective

Objective: To review the efficacy, safety, pharmacology, pharmacokinetics, pharmacodynamics, and in vitro microbiology susceptibilities of ceftobiprole, a new broad-spectrum cephalosporin. Data Sources: A PubMed and Internet search (2000–September 2007) was conducted, using the key words ceftobiprole, Ro 63–9141, BAL5788, and BAL9141. Cochrane Library and International Pharmaceutical Abstracts (2000–September 2007) were accessed and reference citations from publications identified were reviewed. Study Selection and Data Extraction: All English-language articles identified from the data sources were reviewed. Phase 3 studies were included in the evaluation. Data Synthesis: Two multinational, double-blind, pivotal Phase 3 studies involving more than 1,600 patients have shown ceftobiprole to have in vitro activity against penicillin-resistant Streptococcus pneumoniae, Pseudomonas spp., and methicillin-resistant Staphylococcus aureus (MRSA). In addition, the cure rates associated with ceftobiprole for complicated skin and skin structure infections (cSSSI) were comparable with those of a single drug or a 2-drug comparator combination. Adverse effects included nausea, vomiting, taste disturbance, headache, and diarrhea. Conclusions: Ceftobiprole is an essential addition to the antimicrobial armamentarium for use against MRSA and/or multidrug-resistant gram-negative infections. Ceftobiprole is approved for the treatment of cSSSI, including diabetic foot infections; however, studies related to the treatment of hospital-acquired and community-acquired pneumonia requiring hospitalization are ongoing. The safety profile is consistent with that of the cephalosporin class of antibiotics. Ceftobiprole will serve as empiric or definitive antimicrobial therapy for resistant gram-negative and gram-positive pathogens. The challenge will be to maintain judicious use through antibiotic stewardship programs and deescalation strategies.

Diagnosing Cutaneous Leishmaniasis: The Advantage of Forward Deployed Histology in Avoiding a Surgical Pitfall

Military surgeons are often consulted for excisional debridement of skin lesions that fail to respond to medical therapy among soldiers who have been operating in areas of Afghanistan where cutaneous leishmaniasis is endemic. Wide surgical excision without knowledge of the primary etiology can lead to a surgical pitfall. Failure to properly treat cutaneous leishmaniasis, however, can lead to medical pitfalls of permanent disfigurement, deformity, and disability. Forward deployed surgeons should be supported by a laboratory that can confirm the presence of atypical organisms in biopsies of these lesions. With a x 100 microscope and Wright-Giemsa stains, a medical treatment facility is able to confirm cutaneous leishmaniasis, which allows for rapid transfer of soldiers for definitive antimicrobial therapy.

Staphylococcus aureus infective endocarditis: diagnosis and management guidelines

S. aureus infective endocarditis (SAIE) is a serious infection associated with considerable morbidity and mortality. There is evidence that the incidence of SAIE is increasing. As its clinical features are non-specific, SAIE must be suspected in every case of S. aureus bacteraemia, whether it is associated with an obvious source or not. The optimal antimicrobial agent(s) and duration of treatment for SAIE are currently not known, but on the basis of present evidence, a minimum of 2 weeks of antimicrobial therapy is recommended for 'right-sided' SAIE, a minimum of 4 weeks for uncomplicated 'left-sided' SAIE, and a minimum of 6 weeks for complicated 'leftsided' or prosthetic valve SAIE. Although there is no evidence to suggest that combination therapy with a cell-wall active agent (e.g. flucloxacillin) and an aminoglycoside decreases mortality in SAIE, combination therapy should be considered during the initial 3-5 days of therapy as it can shorten the duration of bacteraemia. In complicated or prosthetic valve SAIE, early and close liaison with cardiology and cardiothoracic surgery services is essential. Rapid identification and susceptibility testing of the infecting organism are important in determining the choice of definitive antimicrobial therapy.

Mortality risk factors of Acinetobacter baumannii bacteraemia

Acinetobacter baumannii is one of the most important nosocomial pathogens, and its multiple antibiotic resistance has emerged as an obstacle in the treatment of these infections worldwide. To identify risk factors of mortality for A. baumannii bacteraemia. A retrospective cohort study of 72 patients with significant A. baumannii bacteraemia was conducted to evaluate risk factors for mortality. The median age of the 72 enrolled patients was 48 years, 96% of the cases were hospital-acquired, and the bacteraemia-related mortality rate was 29% (21 of 72 patients). Univariate analysis revealed that the risk factors for mortality included: an elevated acute physiology and chronic health evaluation (APACHE II) score, receipt of in vitro ineffective definitive antimicrobial therapy, in vitro A. baumannii resistance to cefoperazone/ sulbactam, neutropenia, and presentation with septic shock. Multivariate analysis reveals that the independent risk factors for mortality are neutropenia and elevated APACHE II scores. Risk factors such as neutropenia and elevated APACHE II scores are found to be associated with higher mortality rates of A. baumannii bacteraemia. Further study is necessary for the determination of optimal strategies for both the prevention and treatment of these infections.

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

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.

Single versus combination antimicrobial therapy for ventilator-associated pneumonia

The appropriate selection of definitive antimicrobial therapy is a necessary component of the overall treatment for ventilator-associated pneumonia. When possible, single-agent therapy is preferable. A combination of antibiotics is necessary to treat multiple organisms not susceptible to a single appropriate antibiotic and when antibiotic-resistant gram-negative bacteria are present. Treatment failure is more commonly the result of persistent pneumonia and the development of antibiotic resistance than to recurrence after successful antimicrobial therapy. The duration of treatment will vary depending on the severity of the underlying illness and the pneumonic process.

INFECTIONS OF THE NERVOUS SYSTEM

Epidemiologic trends causing infections of the nervous system remain a significant source of morbidity and mortality one half-century after the introduction of penicillin. This article outlines common causes of bacterial meningitis, aseptic meningitis syndrome, encephalitis, abscess, spinal cord syndromes, and cranial and peripheral nerve problems. Recommendations for diagnostic evaluation and both empiric and definitive antimicrobial therapy are offered; controversial management issues are also discussed. The protean manifestations of varicella-zoster virus and Lyme diseases are outlined. In addition, special considerations in the immunocompromised host, including organ transplant recipients, cancer patients, and HIV-positive persons are explained, and antimicrobial therapy is discussed.