Background and purpose Carbapenem-resistant Klebsiella pneumoniae is an emerging problem worldwide. The object of this study was to investigate the risk factors, characteristics and outcomes of ...ertapenem-nonsusceptible K pneumoniae (ENSKp) bacteremia. Methods We conducted a 1:2 ratio matched case-control study. The controls were randomly selected among patients with ertapenem-susceptible K pneumoniae (ESKp) bacteremia and were matched with ENSKp cases for bacteremia. Results Seventy-five patients were included in this study (25 cases and 50 controls). Bivariate analysis showed that prior exposure to either β-Lactam/β-Lactam-lactamase inhibitors ( p = 0.008) or 4th generation cephalosporins ( p < 0.001), chronic obstructive pulmonary disease (COPD) ( p = 0.001), acute renal failure ( p = 0.021), chronic kidney disease without dialysis ( p = 0.021), recent hospital stay ( p = 0.016), intensive care unit stay ( p = 0.002), mechanical ventilation ( p = 0.003), central venous catheter placement ( p = 0.016), Foley indwelling ( p = 0.022), polymicrobial bacteremia ( p = 0.003) and higher Pittsburgh bacteremia score ( p < 0.001) were associated with ENSKp bacteremia. The multivariate analysis showed that prior exposure to 4th generation cephalosporins (odds ratio OR, 28.05; 95% confidence interval CI, 2.92–269.85; p = 0.004), COPD (OR, 21.38; 95% CI, 2.95–154.92; p = 0.002) and higher Pittsburgh bacteremia score (OR, 1.35; 95% CI, 1.10–1.66; p = 0.004) were independent factors for ENSKp bacteremia. ENSKp bacteremia had a higher 14-day mortality rate than ESKp bacteremia (44.0% vs. 22.0%; p = 0.049). The overall in-hospital mortality rates for these two groups were 60.0% and 40.0% respectively ( p = 0.102). Conclusion ENSKp bacteremia had a poor outcome and the risk factors were prior exposure of 4th generation cephalosporins, COPD and higher Pittsburgh bacteremia score. Antibiotic stewardship may be the solution for the preventive strategy.
Abstract Between 2003 and 2009, the prevalence of extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) increased significantly in northern Taiwan from 1.0% to 2.1%. Molecular methods were used ...to investigate the genetic relatedness and carbapenem resistance mechanisms of a collection of 203 non-repetitive XDR-PA isolates available for study. Using pulsed-field gel electrophoresis (PFGE), 52 genotypes were observed; one predominant genotype (pulsotype 1) was found in 57.6% of the isolates. Polymerase chain reaction (PCR), sequencing and quantitative reverse-transcriptase PCR analyses demonstrated that one horizontally acquired mechanism metallo-β-lactamase (MBL) genes and two mutational mechanisms (efflux and porins) accounted for the carbapenem resistance. The most predominant horizontally acquired mechanism was carriage of blaVIM-3 , which was found in 61.1% of isolates. Decreased expression of oprD was the most prevalent mutational mechanism and was found in 70.0% of the XDR-PA isolates, whereas overexpression of mexA was found in 27.6% of the isolates. The highlight of this study was the discovery of statistically significant relationships between certain horizontally acquired and mutational resistance mechanisms and their contribution to carbapenem susceptibility. MBL-producers expressed significantly lower MexAB and higher OprD than non-MBL-producers. Amongst isolates without an acquired β-lactamase gene, oprD expression was significantly reduced, whilst expression of efflux pumps was increased. Reduced OprD expression alone or the production of VIM-type MBLs showed similar contributions to a low to intermediate MIC50 (minimum inhibitory concentration for 50% of the organisms) for carbapenems. Isolates with reduced OprD expression that simultaneously harboured blaVIM exhibited high levels of resistance to carbapenems, which implied that these two mechanisms had a synergistic effect on the MICs.
Incidence of Salmonella enterica serovar Enteritidis infection seems to be on the rise in Taiwan, and therefore, the characteristics of the isolate, including genotypes, were epidemiologically ...investigated. Of the 71 clinical strains isolated in 1997–1999, 61 (86%) remained susceptible to the eight antibiotics tested, while the remaining ten, eight of which were isolated in 1999, were resistant to one to three of the agents including three multiply resistant strains. The majority, 69 or 97% of the isolates, harbored a 60‐kb spvC gene‐carrying virulence plasmid and 12 of them harbored one or two additional various‐sized plasmids. Strains with more than one plasmid were isolated mostly in 1999. Pulse‐field gel electrophoresis (PFGE) revealed three major genotypes (Types A, B and C), in which Type A was the predominant type. Of the 68 Type A, which contained 8 subtypes, 59 (83%) belonged to only two subtypes. Similar results were obtained with a PCR‐based typing method, the infrequent‐restriction‐site (IRS) PCR. All four methods detected types that were rarely seen before and most of these were of recent isolates, indicating that these unusual types were new or strains of foreign origin. Though all four methods discriminated types well, PFGE and IRS‐PCR showed higher sensitivity for classification. Between the two, the latter, though less discriminatory than PFGE, seems the method of choice, since it is simpler, less time‐consuming and above all easy to perform.
Abstract The rapid identification of mycobacteria from smear-positive sputum samples is very important. To identify the Mycobacterium tuberculosis complex (MTBC) and frequently isolated ...nontuberculous mycobacteria strains directly from smear-positive sputum samples, an improved multiplex polymerase chain reaction (PCR) assay was developed. Nine pairs of primers targeting the 16S–23S rDNA internal transcribed spacer-1, hsp 65, and the early secretory antigen (ESAT-6) gene sequences were developed, and their efficacy was evaluated in comparison to traditional culturing and 16S rRNA gene sequencing methods. A total of 200 smear- and culture-positive sputum specimens collected between November 2005 and May 2006 were used for the analysis. The results of the assay showed an accurate identification rate for acid-fast bacilli (AFB) 3+, AFB 2+, and AFB rare/1+ samples of 98%, 95%, and 53%, respectively. The improved multiplex PCR method saves time and has advantages for identifying mycobacteria from AFB 2+ and 3+ sputum samples. The method is suitable for use in countries with a high MTBC prevalence rate.
An increasing incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections has been reported worldwide. The aim of this study was to investigate the mechanism underlying carbapenem ...resistance and its relationship to antibiotic exposure. Sixteen isolates with various carbapenem susceptibilities recovered from five patients between 2003 and 2006 were subjected to molecular study. The medical records of the patients were also reviewed. All of the patients were admitted for complicated respiratory illness, had a prolonged hospital stay, and were exposed to antibiotics. Carbapenems were prescribed before the emergence of the CRKP. Various combinations of extended-spectrum cephalosporinase genes belonging to the SHV, CTX-M, and AmpC groups were found among the isolates. Other carbapenem resistance-associated genes, such as bla(IMP), bla(VIM), bla(OXA), and bla(KPC), were not found. OmpK35 was not expressed in any of the isolates, and additional loss of OmpK36 was observed in all CRKP isolates. Two insertion elements, ISPa13 or IS5, were found inserted into OmpK36 in the isolates derived from three patients. These IS elements were also identified in their parental carbapenem-susceptible isolates, suggesting that an internal transposition into OmpK36 resulted in resistance. OmpK36 loss represents the major mechanism for the development of CRKP in extended-spectrum cephalosporinase-producing isolates. A prolonged hospital stay and recent carbapenem exposure may predispose patients to CRKP, impacting the clinical outcome.
Background/Purpose The objective of this study was to determine the predictive value of teicoplanin minimal inhibitory concentrations (MICs) for treatment failure among patients with ...methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Methods In this study, all patients with ≥1 tracheal aspirates or sputum cultures positive for MRSA admitted to the hospital between April 2011 and September 2011 were reviewed. We enrolled patients who are ≥18 years of age, with a diagnosis of pneumonia, and with a receipt of teicoplanin therapy throughout the course. The relationship between teicoplanin Etest MICs and treatment outcomes of MRSA pneumonia was analyzed to identify the breakpoint of teicoplanin MICs influencing treatment outcomes. Results Of the 80 patients enrolled, 31 had a lower teicoplanin MIC level (<2.0 mg/L) and 49 had a higher MIC level (≥2.0 mg/L) for MRSA. The lower MIC group had a higher clinical resolution rate in 14 days 24 (77.4%) vs. 23 (46.9%), p = 0.007 and a lower treatment failure rate at the end of teicoplanin treatment 4 (12.9%) vs. 18 (36.7%), p = 0.020. A comparison between the treatment success and failure groups showed that the former had a longer duration of teicoplanin use (18.76 ± 10.34vs.12.41 ± 5.65 days; p = 0.014). Results of a multivariate analysis showed that teicoplanin MICs ≥ 2.0 mg/Land shorter duration of teicoplanin therapy were independent risk factors for treatment failure. Conclusion A higher teicoplanin MIC value (≥2.0 mg/L) may predict the treatment failure among patients with teicoplanin-treated MRSA pneumonia.
ABSTRACTWe report a rare case of Mycoplasma hominis septic arthritis occurring simultaneously with acute gout. A Taiwanese native aboriginal presented with right ankle swelling, erythema, local ...tenderness, and limitation of range of motion after a vertebroplasty. He had a history of gout without regular follow-up. Under the polarized light microscopy examination, his synovial fluid revealed neutrophilic leukocytosis and monosodium urate crystals. Subsequently, 2 consecutive anaerobic synovial fluid cultures yielded a cell wall–free microorganism, which was identified as M. hominis based on polymerase chain reaction of its 16S rDNA. He did not defervesce under colchicine and indomethacin treatment until we prescribed a doxycycline and moxifloxacin regimen. He responded well to 6-week doxycycline and moxifloxacin treatment without bone destruction and loss of joint function.
Since 1996, Vibrio parahaemolyticus serotype O3:K6 and closely related strains have been associated with an increased incidence of V. parahaemolyticus gastroenteritis worldwide, suggesting the ...emergence of strains with enhanced abilities to cause disease. One hypothesis for the recent emergence of V. parahaemolyticus O3:K6 and related strains is an enhanced capacity for environmental survival relative to other strains, which might result in increased human exposure to these organisms. Therefore, the objective of this study was to test the hypothesis that survival or growth characteristics of clinical V. parahaemolyticus isolates differ from those of nonclinical isolates under different environmental conditions. Twenty-six V. parahaemolyticus isolates selected to represent either clinical or food sources were monitored for either survival following exposure to high magnesium (300 mM) or growth under iron-limited conditions. Isolates in each category (clinical or food) differed widely in survival capabilities following 24 h of exposure to 300 mM Mg(2+). Although 4 of 15 clinical isolates grew better at approximately 0.96 micromolar Fe(2+) (iron-limited conditions) than at 50 micromolar Fe(2+) (iron-rich conditions), as an entire group clinical isolates in this study were not more effective at growing under iron-limited conditions than were strains not associated with disease. Within the diverse collection of strains examined in these experiments, neither growth characteristics in low-iron environments nor survival capabilities following exposure to high magnesium concentrations were uniformly different between clinical and nonclinical V. parahaemolyticus isolates. Therefore, neither phenotypic characteristic can be used to reliably differentiate potentially pathogenic V. parahaemolyticus strains.
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Background: Delta-like ligand 3 (DLL3), a ligand of the Notch-family, is a potential therapeutic target in small cell lung cancer (SCLC). High expression levels of DLL3 are observed in SCLC, ...however different methods and thresholds are used. A systematic literature review (SLR) was conducted to estimate the prevalence of DLL3 expression in SCLC. Methods: A comprehensive literature search was conducted in the PubMed, EMBASE, Web of Science, and Cochrane Library databases, as well as on clinicaltrials.gov, using a pre-specified search strategy. This SLR was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42022351119). Prevalence of DLL3 expression was evaluated overall and by method of DLL3 assessment and positivity threshold. Results: Of the 30 studies that met our study inclusion criteria, 22 (73.3%) were observational and 8 (26.7%) were clinical trials. Most studies (N = 21, 70%) evaluated less than 100 patient specimens (range: 20 to 1,362 patient specimens). Twelve studies (40%) were conducted in Asia, six (20%) in Europe, five (17%) in North America, five (17%) were multi-country, one in Brazil, and geographical location was not reported in one study. DLL3 testing methods varied across studies, with immunohistochemistry (IHC) being used in 26 (86.7%) studies. Two studies used real-time polymerase chain reaction, one used quantitative mass spectrometry, and one study did not report the testing method. Thirteen of the studies (13/26, 50%) that evaluated DLL3 expression by IHC used the Ventana SP347 assay. DLL3 expression was evaluated at various thresholds of tumor cell staining and showed a wide range of expression, across studies (Table). Conclusions: The SLR findings indicate that most studies assessing DLL3 in SCLC have relied on IHC methodology. Despite the range of thresholds used for evaluating positivity, DLL3 is notably expressed in SCLC. The frequency and impact of aberrant DLL3 localization was not addressed in these studies and minimal data on comparison of IHC with other methodologies exists. Results of this SLR also highlight the need to define a standardized method and threshold of evaluating DLL3 expression. Table: see text
5012 Background: NEPC is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. NEPC can be characterized by late, treatment-emergent transformation from ...adenocarcinoma to high-grade neuroendocrine carcinoma (NEC), in 10–15% of mCRPC patients (pts). DLL3 is overexpressed in high-grade NECs, including NEPC, and minimally expressed on normal tissue. Tarlatamab, a bispecific T-cell engager immunotherapy with clinical activity in small cell lung cancer (SCLC), binds DLL3 and CD3 resulting in T-cell mediated tumor lysis. Here, we report primary analysis data of tarlatamab in NEPC (NCT04702737). Methods: This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years y) pts with metastatic de novo or treatment-emergent NEPC by histologic, genomic, or immunohistochemistry (IHC) criteria. The starting dose was the highest safe and tolerable dose in the phase 1 SCLC trial (NCT03319940). Safety was the primary objective; anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by IHC using the Ventana SP347 assay. Results: As of 28 March 2023, 40 pts received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). Median (range) age was 64.5 (43–83) y, prior lines of therapy was 3 (1–9), prostate specific antigen at baseline was 0.2 (0.0–5000.0) μg/L. Treatment-related adverse events (TRAE) occurred in all patients, with no fatal TRAE. Most common TRAEs were cytokine-release syndrome (CRS; 65.0%), pyrexia (52.5%) and dysgeusia (42.5%). CRS occurred primarily in treatment cycle 1; events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to TRAE was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab SCLC studies. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was 10.5% (95% CI, 2.9, 24.8); median progression free survival (mPFS) was 1.9 months (m) (95% CI, 1.7, 3.5). Retrospective DLL3 IHC analysis showed that 18 of 32 (56.3%) biopsy evaluable pts had ≥1% DLL3 tumor positivity (DLL3+). As of 24 January 2024, ORR in DLL3+ pts was 22.2% (95% CI, 6.4, 47.6); durations of response in the 4 pts with response were 25.8 m, 9.2 m, 5.5 m, 3.7 m; mPFS in DLL3+ pts was 3.75 m (95% CI, 1.87, 11.01). Efficacy is shown in Table. Conclusions: Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing. Clinical trial information: NCT04702737 . Table: see text
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