Aristine Cheng

Comparative in vitro antimicrobial susceptibilities and synergistic activities of antimicrobial combinations against carbapenem-resistant Acinetobacter species: Acinetobacter baumannii versus Acinetobacter genospecies 3 and 13TU

Therapeutic options for the treatment of infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are limited. In vitro activity of amikacin, ciprofloxacin, colistin (polymyxin E), ampicillin-sulbactam, and tigecycline alone and in combination with imipenem against CRAB and carbapenem-resistant Acinetobacter genospecies 3 and 13TU was investigated. Colistin (97% susceptible) and tigecycline (88% and 44% susceptible by US Food and Drug Administration [FDA] and European Committee on Antimicrobial Susceptibility Testing [EUCAST] breakpoints for Enterobacteriaceae, respectively) were the 2 most active agents against CRAB, followed by minocycline (66%), ampicillin/sulbactam (16%), and amikacin (13%). Compared with CRAB isolates, carbapenem-resistant Acinetobacter genospecies 3 and 13TU isolates had higher antimicrobial susceptible rates to ciprofloxacin (88%), amikacin (63%), tigecycline (100% by FDA breakpoint and 88% by EUCAST breakpoint for Enterobacteriaceae, respectively), minocycline (100%), and ampicillin/sulbactam (75%). For the 12 tested CRAB isolates, the checkerboard titration method demonstrated synergy between imipenem and colistin (42%), tigecycline (25%), amikacin (16%), and ampicillin/sulbactam (16%). Time-kill assays revealed antimicrobial synergism for imipenem in combination with colistin (75%), tigecycline (50%), ampicillin/sulbactam (42%), amikacin (42%), and ciprofloxacin (16%). However, antimicrobial synergism between imipenem and combined agents was not present among CRAB isolates with an imipenem MIC ≥ 32 mg/L. The combination of tigecycline and colistin showed good in vitro synergy for CRAB with high imipenem resistance. Our results demonstrate accurate identification of prevalent Acinetobacter species and highlight their different antimicrobial susceptibilities. This knowledge will enable clinicians to select appropriate regimens for treating these infections.

A Phase I, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine

BACKGROUND Large-scale outbreaks of enterovirus 71 (EV71) infections have occurred in Asia-Pacific regions. Severe complications include encephalitis and poliomyelitis-like paralysis, cardiopulmonary collapse, and death, necessitating an effective vaccine against EV71. METHODS In this randomized Phase I study, we evaluated the safety and immunogenicity of an inactivated alum-adjuvanted EV71 whole-virus vaccine produced on Vero cell cultures. Sixty healthy volunteers aged 20-60 years received two doses of vaccine, administered 21 days apart. Each dose contained either 5 μg of EV71 antigen with 150 μg of adjuvant (Group A05) or 10 μg of EV71 antigen with 300 μg of adjuvant (Group B10). Serologic analysis was performed at baseline, day 21, and day 42. RESULTS There were no serious adverse events. Mild injection site pain and myalgia were the most common adverse events with either vaccine formulation. The immunogenicity data showed that 90% of vaccine recipients have a 4-fold or greater increase in neutralization antibody titers (NT) after the first dose, without a further increase in NT after the second dose. The seroconversion rates on day 21 and day 42 were 86.7% and 93.1% respectively, in Group A05, and 92.9% and 96.3%, respectively, in Group B10. Thus, 5 μg and 10 μg of the EV71 vaccine can induce a remarkable immune response in healthy adults after only the first vaccination. CONCLUSION The 5 μg and 10 μg adjuvanted EV71 vaccines are generally safe and immunogenic in healthy adults. (ClinicalTrials.gov number, NCT01268787).

Invasive fungal sinusitis in patients with hematological malignancy: 15 years experience in a single university hospital in Taiwan

BackgroundRisk factors and outcomes in hematological patients who acquire invasive fungal sinusitis (IFS) are infrequently reported in the modern medical era.MethodA retrospective study of hospitalized patients with hematological disease was conducted at National Taiwan University Hospital between January 1995 and December 2009.ResultsClinical characteristics and outcomes with their associated radiographic and microbiological findings were analyzed. Forty-six patients with IFS and 64 patients with chronic non-invasive sinusitis were enrolled as comparsion. IFS developed more commonly in patients with acute myeloid leukemia (AML) and with prolonged neutropenia (absolute neutrophil count less than 500/mm3 for more than 10 days) (p < 0.001). Aspergillus flavus was the most common pathogen isolated (44%). Serum Aspergillus galactomannan antigen was elevated in seven of eleven patients (64%) with IFS caused by aspergillosis but negative for all three patients with mucormycosis. Bony erosion and extra-sinus infiltration was found in 15 of 46 (33%) patients on imaging. Overall, 19 of 46 patients (41.3%) died within 6 weeks. Patients with disease subtype of AML (p = 0.044; Odds Ratio [OR], 5.84; 95% confidence interval [95% CI], 1.02-30.56) and refractory leukemia status (p = 0.05; OR, 4.27; 95% CI, 1.003-18.15) had worse prognosis. Multivariate analysis identified surgical debridement as an independent good prognostic factor (p = 0.047) in patients with IFS.ConclusionsPatients of AML with prolonged neutropenia (> 10 days) had significantly higher risk of IFS. Early introduction of anti-fungal agent and aggressive surgical debridement potentially decrease morbidity and mortality in high risk patients with IFS.

Excess Mortality Associated With Colistin-Tigecycline Compared With Colistin-Carbapenem Combination Therapy for Extensively Drug-Resistant Acinetobacter baumannii Bacteremia: A Multicenter Prospective Observational Study.

Objectives:Since few therapeutic options exist for extensively drug resistant Acinetobacter baumannii, an emerging threat in ICUs worldwide, and comparative prospective studies of colistin-based combination therapies are lacking, our objective was to compare the outcomes of patients with extensively drug-resistant A. baumannii bacteremia, treated with colistin-carbapenem and colistin-tigecycline combinations. Design:Prospective, observational, multicenter study. Setting, Patients, and Interventions:Adults with extensively drug-resistant A. baumannii bacteremia were prospectively followed from 2010 to 2013 at three hospitals in Taiwan. Extensively drug-resistant A. baumannii was defined as A. baumannii (genospecies 2) nonsusceptible to all drug classes except for colistin and tigecycline, and standard combination therapy as use of parenteral colistin-carbapenem or colistin-tigecycline for at least 48 hours after onset of bacteremia. Measurements and Main Results:Primary outcome measure was 14-day mortality. Of the 176 episodes of extensively drug-resistant A. baumannii bacteremia evaluated, 55 patients with a median (interquartile range) age of 62 years (44–79 yr) and Sequential Organ Failure Assessment score of 9 (5–13) points received standard combination therapy: colistin-tigecycline in 29 patients and colistin-carbapenem in 26. Crude 14-day and in-hospital mortality rates for patients receiving colistin-tigecycline versus patients receiving colistin-carbapenem were 35% versus 15% (p = 0.105) and 69% versus 50% (p = 0.152), respectively. Breakthrough extensively drug-resistant A. baumannii bacteremia under steady state concentrations of combination therapy for colistin-tigecycline group was 18% and for colistin-carbapenem group was 0% (p = 0.059). Eleven patients (20.0%) developed nephrotoxicity. After adjusting for age, sex, comorbidity, initial disease severity, loading colistin dose, polymicrobial infection, and primary infection site, excess 14-day mortality was associated with the use of colistin-tigecycline in the subgroup with tigecycline minimum inhibitory concentration greater than 2 mg/L compared with the use of colistin-carbapenem (hazard ratio, 6.93; 95% CI, 1.61–29.78; p = 0.009). Conclusions:Increased 14-day mortality was associated with colistin-tigecycline therapy given tigecycline minimum inhibitory concentration greater than 2 mg/L compared with colistin-carbapenem therapy for extensively drug-resistant A. baumannii bacteremia.

CNS infections caused by Mycobacterium abscessus complex: clinical features and antimicrobial susceptibilities of isolates

OBJECTIVES CNS infections caused by non-tuberculous mycobacteria (NTM) are rare and only three cases of CNS infections due to Mycobacterium abscessus complex have been reported. METHODS We searched the Mycobacteriology Database of the National Taiwan University Hospital and identified patients with CNS infections due to NTM. RESULTS A total of 15 patients, namely 4 HIV-seropositive patients and 11 HIV-seronegative patients, with CNS infections caused by NTM were identified during 2000-10. All of the HIV-seropositive patients had disseminated Mycobacterium avium complex infections. Among the 11 HIV-seronegative patients, NTM CNS infections were due to M. abscessus complex in 8 patients, M. avium complex in 2 patients and Mycobacterium kansasii in 1 patient. All the six preserved M. abscessus complex isolates were confirmed to be Mycobacterium massiliense by erm(41) PCR and 23S rRNA gene sequence analysis. Among the eight patients with infections due to M. abscessus complex, three had otolaryngological diseases, four had received neurosurgery and one had disseminated disease. Five patients received surgical debridement or intracranial device removal and three patients died of M. abscessus complex CNS infection. Among the five patients who survived, all received clarithromycin-based combination therapy with a median duration of 12 months and four received surgical intervention. All six isolates available for drug susceptibility testing showed uniform susceptibility to clarithromycin and five were susceptible to amikacin. CONCLUSIONS Our study revealed that M. abscessus complex isolates, particularly M. massiliense, should be considered potential pathogens causing CNS infections. Long-duration clarithromycin-based combination therapy plus surgical intervention may provide the best chance of cure.

Safety and efficacy of high-dose daptomycin as salvage therapy for severe gram-positive bacterial sepsis in hospitalized adult patients

BackgroundIncreasing the dosage of daptomycin may be advantageous in severe infection by enhancing bactericidal activity and pharmacodynamics. However, clinical data on using daptomycin at doses above 6 mg/kg in Asian population are limited.MethodsA retrospective observational cohort study of all hospitalized adult patients treated with daptomycin (> 6 mg/kg) for at least 72 hours was performed in Taiwan.ResultsA total of 67 patients (40 males) with a median age of 57 years received a median dose of 7.61 mg/kg (range, 6.03-11.53 mg/kg) of daptomycin for a median duration of 14 days (range, 3–53 days). Forty-one patients (61.2%) were in intensive care units (ICU). Sites of infections included complicated skin and soft tissue infections (n = 16), catheter-related bacteremia (n = 16), endocarditis (n = 11), primary bacteremia (n = 10), osteomyelitis and septic arthritis (n = 9), and miscellaneous (n = 5). The median Pitt bacteremia score among the 54 (80.6%) patients with bacteremia was 4. The most common pathogen was methicillin-resistant Staphylococcus aureus (n = 38). Fifty-nine patients (88.1%) were treated with daptomycin after glycopepetide use. Overall, 52 (77.6%) patients achieved clinical success. The all-cause mortality rate at 28 day was 35.8%. In multivariate analysis, the significant predictors of in-hospital mortality in 54 bacteremic patients were malignancies (P = 0.01) and ICU stay (P = 0.02). Adverse effects of daptomycin were generally well-tolerated, leading to discontinuation in 3 patients. Daptomycin-related creatine phosphokinase (CPK) elevations were observed in 4 patients, and all received doses > 8 mg/kg.ConclusionsTreatment with high dose daptomycin as salvage therapy was generally effective and safe in Taiwan. CPK level elevations were more frequent in patients with dose > 8 mg/kg.

Intracranial hemorrhage in adult patients with hematological malignancies.

BackgroundClinical characteristics and outcomes of intracranial hemorrhage (ICH) among adult patients with various hematological malignancies are limited.MethodsA total of 2,574 adult patients diagnosed with hematological malignancies admitted to a single university hospital were enrolled into this study between 2001 and 2010. The clinical characteristics, image reports and outcomes were retrospectively analyzed.ResultsA total of 72 patients (48 men and 24 women) with a median age of 56 (range 18 to 86) had an ICH. The overall ICH incidence was 2.8% among adult patients with hematological malignancies. The incidence of ICH was higher in acute myeloid leukemia (AML) patients than in patients with other hematological malignancies (6.3% vs 1.1%, P = 0.001). ICH was more common among patients with central nervous system (CNS) involvement of lymphoma than among patients with CNS involved acute leukemia (P <0.001). Sites of ICH occurrence included the cerebral cortex (60 patients, 83%), basal ganglia (13 patients, 18%), cerebellum (10 patients, 14%), and brainstem (5 patients, 7%). A total of 33 patients (46%) had multifocal hemorrhages. In all, 56 patients (77%) had intraparenchymal hemorrhage, 22 patients (31%) had subdural hemorrhage, 15 patients (21%) had subarachnoid hemorrhage (SAH), and 3 patients (4%) had epidural hemorrhage. A total of 22 patients had 2 or more types of ICH. In all, 46 (64%) patients died of ICH within 30 days of diagnosis, irrespective of the type of hematological malignancy. Multivariate analysis revealed three independent prognostic factors: prolonged prothrombin time (P = 0.008), SAH (P = 0.021), and multifocal cerebral hemorrhage (P = 0.026).ConclusionsThe incidence of ICH in patients with AML is higher than patients with other hematological malignancies. But in those with intracranial malignant disease, patients with CNS involved lymphoma were more prone to ICH than patients with CNS involved acute leukemia. Mortality was similar regardless of the type of hematological malignancy. Neuroimaging studies of the location and type of ICH could assist with prognosis prediction for patients with hematological malignancies.

Infections caused by unusual Methylobacterium species

ABSTRACT We describe six patients with hospital-acquired bacteremia caused by Methylobacterium species, including M. radiotolerans (n = 2), M. thiocyanatum (n = 2), M. aminovorans (n = 1), and M. lusitanum (n = 1), which were confirmed to species level by 16S rRNA gene sequence analysis. Among these patients, five had catheter-related bacteremia and all had favorable outcomes.

Bacteremia caused by Pantoea agglomerans at a medical center in Taiwan, 2000–2010

BACKGROUND/PURPOSE There are only three case reports of adult patients with spontaneous Pantoea agglomerans bacteremia in the English literature. The aim of this study was to investigate clinical and microbiologic characteristics patients of P agglomerans bacteremia. METHODS We studied all adult patients with P agglomerans bacteremia at a medical center from 2000 to 2010. The isolates were identified using two commercial identification systems. RESULTS Of the 18 patients identified, 72% (n = 13) had active gastroesophageal disease treated with antacids. Two-thirds of patients had indwelling central lines and advanced cancers. None of the removed catheter tips yielded P agglomerans and line persistence was not associated with adverse outcomes. Initial disease severity was low, hypotension was uncommon and no patient died of bacteremia. Recurrence of bacteremia occurred in one patient with deep-seated infection. 16srRNA gene sequencing identified only half of the isolates as P agglomerans. The remaining nine isolates were Enterobacter species for six, Pantoea ananatis for two, and Exiguobacterium profundum for one. There were no significant differences between the characteristics of the subgroup molecularly identified as P agglomernas and the overall group characteristics. Eleven (61%) of the 18 isolates were susceptible to cefazolin, six (33%) susceptible to fosfomycin (MIC ≤ 64 mg/ml). Two isolates had colistin MICs ≥ 4 mg/ml. CONCLUSION Bacteremia caused by P agglomerans is associated with gastroesophageal reflux disease and receipt of antacids. 16srRNA gene sequencing should not be used as the sole basis for its identification and we have highlighted the need for another molecular-based technique to conclusively characterize P agglomerans.

Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: a propensity-matched analysis.

PURPOSE Limited data on the outcomes of adults with active sepsis undergoing extracorporeal membrane oxygenation (ECMO) exist. MATERIALS AND METHODS We analyzed our prospective database for adults undergoing their first ECMO from 2001 to 2009. Patients with preexisting sepsis had newly emerging or uncontrolled infections precipitating refractory respiratory and/or circulatory failure within 7 days preceding ECMO. Propensity score matching was performed to equalize potential prognostic factors between patients with and patients without sepsis. RESULTS Of the 514 adults receiving their first ECMO, 108 with preexisting sepsis were matched with 108 without sepsis by propensity score. Overall survival to discharge did not differ between those with (28.7%) and those without sepsis (37.0%; P = .192). When venovenous ECMO and venoarterial ECMO were considered separately, survival tended to be worse for septic patients on venoarterial ECMO (24.4%) compared with nonseptic adults on venoarterial ECMO (34.9%; P = .147). After adjustments for age, stroke, acute myocarditis, inter-extracorporeal cardiopulmonary resuscitation, and post-ECMO renal and neurologic deficits by multivariate analysis, the increased risk of mortality persisted for septic adults receiving venoarterial ECMO (hazard ratio, 2.54; 95% confidence intervals, 1.75-3.70; P < .01). Patients on venovenous ECMO had similar outcomes regardless of preexisting sepsis. CONCLUSIONS Preexisting sepsis is not a contraindication for ECMO. However, venoarterial ECMO should be used with caution, given active sepsis.