Cefepime, not Piperacillin/Tazobactam use, for empirical treatment of bloodstream infections caused by Enterobacter spp.: Results from a population pharmacokinetic/pharmacodynamic analysis.

OBJECTIVE: There is a paucity of published data to evaluate the efficacy and safety of imipenem, cefepime and piperacillin/tazobactam dosing regimens against bloodstream infections caused by Klebsiella aerogenes (BSIs-Kae) and Enterobacter cloacae complex (BSIs-Ecc) in patients with various degrees of renal function. METHODS: Pathogens were isolated from China's blood bacterial resistant investigation network. The dosing regimens of imipenem, cefepime and piperacillin were simulated with intermittent infusion and extended infusion. Monte Carlo simulation was performed to calculate the probability of target attainment and a cumulative fraction of response (CFR) against BSIs-Kae/Ecc. RESULTS: In total, 203 BSIs-Kae, and 785 BSIs-Ecc were isolated from the surveillance network. Imipenem showed the highest in vitro activity against BSIs-Kae/Ecc, followed by cefepime (85%) and piperacillin/tazobactam (70-80%). The MIC90 values of imipenem, cefepime and piperacillin/tazobactam aginst BSIs-Kae and BSIs-Ecc were 1/1 mg/L, 16/16 mg/L, and 64/128 mg/L, respectively. The simulation results showed imipenem achieved the highest CFRs in patients with normal or decreased renal function, with values of 91-99%, followed by FEP (88-96%), without risk of excessive dosing. However, the intermittent and extended dosing regimens of piperacillin/tazobactam were unlikely to provide adequate exposure for empirical management of BSIs-Kae/Ecc (CFRs, 50-80%), regardless of renal function. Besides, the traditional intermittent piperacillin/tazobactam dosing regimens were highly likely to contribute to suboptimal therapeutic exposure when MIC was close to clinical breakpoints. CONCLUSIONS: Cefepime, not piperacillin/tazobactam, can be a reasonable carbapenem-sparing option in empirically treating BSIs-Kae/Ecc.

In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

Clinical and Bacterial Characteristics of Klebsiella pneumoniae Affecting 30-Day Mortality in Patients With Bloodstream Infection.

Background: There is a paucity of studies using clinical characteristics and whole-genome sequencing together to fully identify the risk factors of patients with Klebsiella pneumoniae (KP) bloodstream infection (BSI). Methods: We retrospectively analyzed the clinical and microbiological characteristics of patients with KP BSI. Isolates were processed using Illumina NGS, and relevant bioinformatics analysis was conducted (multi-locus sequence typing, serotype, phylogenetic reconstruction, detection of antibiotic resistance, and virulence genes). A logistic regression model was used to evaluate the risk factors of hosts and causative KP isolates associated with 30-day mortality in patients infected with KP BSI. Results: Of the 79 eligible patients, the 30-day mortality rate of patients with KP BSI was 30.4%. Multivariate analysis showed that host-associated factors (increased APACHE II score and septic shock) were strongly associated with increased 30-day mortality. For the pathogenic factors, carriage of iutA (OR, 1.46; 95% CI, 1.11-1.81, p = 0.002) or Kvar_1549 (OR, 1.31; 95% CI, 1.02-1.69, p = 0.043) was an independent risk factor, especially when accompanied by a multidrug-resistant phenotype. In addition, ST11-K64 hypervirulent carbapenem-resistant KP co-harbored acquired blaKPC-2 together with iutA (76.5%, 13/17) and Kvar_1549 (100%, 17/17) genes. Comparative genomic analysis showed that they were clustered together based on a phylogenetic tree, and more virulence genes were observed in the group of ST11-K64 strains compared with ST11-non-K64. The patients infected with ST11-K64 strains were associated with relatively high mortality (47.2%, 7/17). Conclusion: The carriage of iutA and Kvar_1549 was seen to be an independent mortality risk factor in patients with KP BSI. The identification of hypervirulent and carbapenem-resistant KP strains associated with high mortality should prompt surveillance.

Acquisition of the mcr-1 Gene Lowers the Target Mutation to Impede the Evolution of a High-Level Colistin-Resistant Mutant in Escherichia coli.

OBJECTIVE: The spread of the plasmid-mediated colistin resistance gene mcr-1 poses a significant public health threat. Little information is available on the development of high-level colistin-resistant mutants (HLCRMs) in MCR-1-producing Escherichia coli (MCRPEC). The present study was designed to evaluate the impact of chromosomal modifications in pmrAB, phoPQ, and mgrB combined with mcr-1 on colistin resistance in E. coli. METHODS: Five MCRPEC and three non-MCRPEC (E. coli ATCC25922 and two plasmid-curing) strains were used. The HLCRMs were selected through multi-stepwise colistin exposure. Moreover, two E. coli C600-pMCRs were constructed and used for selection of HLCRMs. Further analysis included mutation rates and DNA sequencing. Transcripts of pmrABC, phoP, mgrB, and mcr-1 were quantified by real-time quantitative PCR. RESULTS: All tested HLCRMs were successfully isolated from their parental strains. Non-MCRPEC strains had higher minimum inhibitory concentrations (MICs) and mutation rates than MCRPEC strains. Nineteen amino acid substitutions were identified: seven in PmrA, six in PmrB, one in PhoP, three in PhoQ, and two in MgrB. Most were detected in non-MCRPEC strains. Sorting Intolerant From Tolerant predicted that four substitutions, PmrA Gly15Arg, Gly53Arg, PmrB Pro94Gln, and PhoP Asp86Gly, affected protein function. Two HLCRM isolates did not show amino acid substitutions in contrast to their parental MCRPEC isolates. No further mutations were detected in the second- and third-step mutants. Further transcriptional analysis showed that the up-regulation of pmrCAB expression was greater in the mutant of E. coli C600 than in E. coli C600-pMCR. CONCLUSION: Acquisition of the mcr-1 gene had a negative impact on the development of HLCRMs in E. coli, but was associated with low-level colistin resistance. Thus, colistin-based combination regimens may be effective against infections with MCR-1-producing isolates.

Socioeconomic burden of bloodstream infections caused by carbapenem-resistant and carbapenem-susceptible Pseudomonas aeruginosa in China.

OBJECTIVES: Drug resistance in Pseudomonas aeruginosa (PAE) is a serious health threat. Additionally, it is important to understand the associated socioeconomic burden. METHODS: Clinical information and hospital cost data for patients with PAE bloodstream infections (BSIs) in a tertiary teaching hospital (2011-2016) were collected retrospectively to estimate the direct economic burden. Socioeconomic loss incurred by patients was calculated using the human capital approach combined with estimating disability-adjusted life years (DALYs). Differences in socioeconomic burden between BSIs caused by carbapenem-resistant (CR) and carbapenem-susceptible (CS) PAE were compared. RESULTS: This study included data for 220 patients, of which were 29.5% (65/220) CR-PAE BSIs. The median direct economic burden of patients following CR-PAE BSI was significantly higher than following CS-PAE BSI ($5005.94 vs. $1462.86; P < 0.001). The median DALY loss was significantly higher in the CR-PAE group compared with CS-PAE group (0.024 vs. 0.008; P = 0.001). The median indirect socioeconomic loss of patients in the CR-PAE group tended to be significantly higher than in the CS-PAE group ($64.06 vs. $29.71; P = 0.011). The annual economic burden of CR-PAE is higher (up to >1.5 times) than the Chinese annual per capita GDP. CONCLUSION: The economic burden of PAE BSIs is significant, irrespective of carbapenem resistance. The direct economic burden of CR-PAE BSI was at least three-fold that of CS-PAE BSI. The DALY loss caused by CR-PAE BSI is three-fold that caused by CS-PAE BSI. The indirect socioeconomic loss caused by CR-PAE BSI is more than twice that of CS-PAE BSI.

Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation.

BACKGROUND: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. RESULTS: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%). CONCLUSIONS: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Epidemiology and risk factors of infective endocarditis in a tertiary hospital in China from 2007 to 2016.

BACKGROUND: To explore the trends in epidemiology and the risk factors related to the prognosis of infective endocarditis in a tertiary hospital over the past ten years. METHODS: A retrospective cohort study was performed. A total of 407 consecutive patients who were admitted with infective endocarditis were included. The clinical characteristics and the risk factors related to the prognosis of infective endocarditis during this period were analyzed. RESULTS: A total of 407 patients with infective endocarditis were included, the average age was 48 ± 16 years old with an increasing trend and in-hospital mortality rate was 10.6% and one-year mortality rate was 11.3%. Among patients with underlying heart disease, congenital heart disease was the most common (25.8%), followed by rheumatic heart disease (17.0%) which showed a decreased trend during this period (P < 0.001). There were 222(54.5%) patients with positive blood cultures results and Streptococci (24.6%) was the main pathogens with an increasing trend. There were 403 patients (99%) with surgical indications, but only 235 patients (57.7%) received surgical treatment. Hemodialysis (P = 0.041, OR = 4.697, 95% CI 1.068-20.665), pulmonary hypertension (P = 0.001, OR = 5.308, 95% CI 2.034-13.852), Pitt score ≥ 4 (P < 0.001, OR = 28.594, 95% CI 5.561-148.173) and vegetation length>30 mm (P = 0.011, OR = 13.754, 95% CI 1.832-103.250) were independent risk factors for in-hospital mortality. CONCLUSIONS: There were no significant changes in the overall incidence of infective endocarditis, but the clinical features of infective endocarditis had slightly changed during the past ten years. Streptococci infective endocarditis was still the predominant. Patients with hemodialysis, pulmonary hypertension, Pitt score ≥ 4 and vegetation length>30 mm had an worse in-hospital outcome.

The clinical features and prognosis of infective endocarditis in the elderly from 2007 to 2016 in a tertiary hospital in China.

BACKGROUND: Infective endocarditis (IE) especially in the elderly is a serious disease, with a worse prognosis. METHODS: A retrospective cohort study was conducted. A total of 405 patients with definite IE were divided into three groups: 205 patients under 50 years old, 141 patients between 50 and 64 years old and 59 patients over 65 years old. RESULTS: For older patients, clinical symptoms such as fever, anemia, and heart murmur were as common as the younger patients. IE in old patients had more frequent nosocomial origin (P = 0.007) and tended to be more frequent with bad oral hygiene (p = 0.008). The most frequent isolated pathogens in the old groups was streptococci and coagulase-negative staphylococci. The old patients had a lower operation rate (40.7% vs 58.9% vs 62.4%, P = 0.012) and higher in-hospital mortality (20.3% vs 10.6% vs 8.8%, P = 0.044) compared with the younger patients. Surgical treatment was a significant predictor of one-year mortality even after adjusting for the confounders (HR = 2.45, 95% CI 1.027-10.598, P = 0.009). The one-year survival rate was higher for older patients with surgical intervention than those without (95.8% vs 68.6%, P = 0.007). CONCLUSIONS: Older patients with IE presented with more comorbidities, bad oral hygiene, more nosocomial origin and a more severe prognosis than younger patients. Streptococci was the most frequent micro-organisms in this group. Surgery were underused in old patients and those with surgical treatment had better prognosis.

Simulating moxalactam dosage for extended-spectrum ß-lactamase-producing Enterobacteriaceae using blood antimicrobial surveillance network data.

Objectives: Monte Carlo simulation (MCS) was used to evaluate optimal dosage for cefepime (FEP), moxalactam (MOX), and cefperazone/sulbactam (CFZ/SBT) against extended-spectrum ß-lactamase (ESBL) producers isolated from the Blood Bacterial Resistant Investigation Collaborative System. Methods: Minimum inhibitory concentration (MIC) was tested by agar dilution, and ESBL producers were identified by modified Clinical and Laboratory Standards Institute tests. Pharmacokinetic parameters were derived from data on healthy individuals, and probability of target attainment (PTA) and cumulative fraction of response (CFR) %fT >MIC values were estimated by MCS. Results: A total of 2032 Escherichia coli (875 ESBL-producing) and Klebsiella pneumoniae (157 ESBL-producing) strains, and 371 other Enterobacteriaceae strains, were isolated from patients with bloodstream infections (BSIs). MIC90 values for FEP, MOX, and CFZ/SBT against ESBL-producing E. coli and K. pneumoniae were 64/64 mg/L, 2/32 mg/L, and 64/128 mg/L, respectively. Conventional MOX and CFZ/SBT doses failed to reach 90% PTA against isolates with MICs ≥8 mg/L and ≥4 mg/L, respectively. Against ESBL producers, neither FEP nor CFZ/SBT achieved ≥90% CFR, while CFRs for MOX (1 g iv q6h, 2 g iv q12h, and 2 g iv q8h) exceeded 90% against ESBL-producing E. coli. Simulated CFRs for FEP and MOX were similar (>90%) against non-ESBL-producing Enterobacteriaceae, and higher than CFRs for CFZ/SBT. Conclusion: ESBL producers from BSIs were highly susceptible to MOX, and PTA values were generally higher for MOX than FEP or CFZ/SBT for conventional dosing regimens. This large MCS analysis shows that MOX but not FEP or CFZ/SBT can be used empirically to treat BSIs caused by ESBL-producing E. coli strains.

A retrospective analysis of Pseudomonas aeruginosa bloodstream infections: prevalence, risk factors, and outcome in carbapenem-susceptible and -non-susceptible infections.

Background: Pseudomonas aeruginosa (PA) is a leading cause of nosocomial infections, and carbapenem non-susceptible strains are a major threat to patient safety. Methods: A single center, retrospective comparative analysis of carbapenem-non-susceptible PA (CnSPA) and carbapenem-susceptible PA (CSPA) bloodstream infections (BSIs) was conducted between January 1, 2007, and December 31, 2016. Prevalence and risk factors associated with CnSPA BSIs were examined. Results: The study enrolled 340 patients with PA BSIs; 30.0% (N = 101) of patients had CnSPA. High APACHE II scores (≥15), central venous catheterization, and delayed application of appropriate definitive therapy were independently associated with higher risk of mortality in PA BSIs. Multivariate analysis revealed that respiratory disease and exposure to carbapenems within the previous 90 days to onset of BSI were independent risk factors for acquisition of CnSPA BSIs. Overall all-cause 30-day mortality associated with PA BSIs was 26.8% (91/340). In addition, mortality was higher in patients with CnSPA than in those with CSPA (37.6% vs. 22.2%, respectively; P = 0.003). Corticosteroid therapy and delayed receipt of effective definitive therapy were independent risk factors for death from CnSPA BSIs. Conclusion: Increased incidence of CnSPA BSIs was observed during the study period, with higher mortality seen in patients with these infections. Respiratory disease and exposure to carbapenems were independent risk factors for development of CnSPA BSIs. Appropriate definitive therapy reduced mortality rates. BLBLIs were as effective as carbapenems as a treatment for PA BSIs.

A retrospective analysis of risk factors and outcomes in patients with extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infections.

OBJECTIVE: Risk factors and outcomes associated with extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) bloodstream infections (BSI) are not yet fully understood. METHODS: This was a retrospective analysis of patients with E. coli BSI treated over a 4-year period. The characteristics of bacteremia caused by ESBL-producing versus non-ESBL-producing E. coli were compared. Factors influencing mortality were also assessed. RESULTS: Of 554 eligible patients, 58.9% developed ESBL-producing E. coli. Multivariate analysis showed that urinary tract infections, stomach tube catheterization, and prior cephalosporin exposure were independent risk factors for the emergence of ESBL-producing E. coli BSI. No significant differences in 30-day mortality were seen in patients with BSI caused by ESBL-producing or non-ESBL-producing E. coli (11.1% vs. 9.2%; P=0. 642). Factors independently associated with a higher risk of mortality were previous carbapenem exposure, high APACHE II score, and respiratory tract origin. CONCLUSIONS: This study showed that prior UTIs and previous cephalosporin exposure represent significant risk factors for the development of ESBL-producing E. coli BSI. Previous carbapenem exposure, high APACHE II score, and a respiratory tract origin were seen to be independent mortality risk factors in patients with E. coli BSI.

In vitro antibacterial effect of fosfomycin combination therapy against colistin-resistant Klebsiella pneumoniae.

OBJECTIVES: Colistin is still a "last-resort" antibiotic used to manage human infections due to multidrug-resistant (MDR) Klebsiella pneumoniae. However, colistin-resistant K. pneumoniae (CR-Kp) isolates emerged a decade ago and had a worldwide distribution. The purpose of this study was to evaluate the genetic data of CR-Kp and identify the antibacterial activity of fosfomycin (FM) alone and in combination with amikacin (AMK) or colistin (COL) against CR-Kp in vitro. METHODS: Three clinical CR-Kp isolates from three patients were collected. Whole-genome sequencing and bioinformatics analysis were performed. The Pharmacokinetics Auto Simulation System 400, by simulating human pharmacokinetics in vitro, was employed to simulate FM, AMK, and COL alone and in combination. Different pharmacodynamic parameters were calculated for determining the antimicrobial effect. RESULTS: Whole-genome sequencing revealed that none of the three isolates contain mcr gene and that no insertion was found in pmrAB, phoPQ, or mgrB genes. We found the antibacterial activity of AMK alone was more efficient than FM or COL against CR-Kp. The area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was higher than 170 LogCFU/mL·h-1. In addition, the area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with COL (75,000 IU/kg every12 hours) was higher than that of monotherapies (>100 LogCFU/mL·h-1 vs <80 LogCFU/mL·h-1). CONCLUSION: FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was effective at maximizing bacterial killing against CR-Kp.