Evaluation of the synergistic effect of eravacycline and tigecycline against carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a substantial healthcare challenge. This study assessed the in vitro efficacy of selected antibiotic combinations against CRKP infections. METHODS: Our research involved the evaluation of 40 clinical isolates of CRKP, with half expressing Klebsiella pneumoniae carbapenemase (KPC) and half producing Metallo-ß-lactamase (MBL), two key enzymes contributing to carbapenem resistance. We determined the minimum inhibitory concentrations (MICs) of four antibiotics: eravacycline, tigecycline, polymyxin-B, and ceftazidime/avibactam. Synergistic interactions between these antibiotic combinations were examined using checkerboard and time-kill analyses. RESULTS: We noted significant differences in the MICs of ceftazidime/avibactam between KPC and MBL isolates. Checkerboard analysis revealed appreciable synergy between combinations of tigecycline (35%) or eravacycline (40%) with polymyxin-B. The synergy rates for the combination of tigecycline or eravacycline with polymyxin-B were similar among the KPC and MBL isolates. These combinations maintained a synergy rate of 70.6% even against polymyxin-B resistant isolates. In contrast, combinations of tigecycline (5%) or eravacycline (10%) with ceftazidime/avibactam showed significantly lower synergy than combinations with polymyxin-B (P < 0.001 and P = 0.002, respectively). Among the MBL CRKP isolates, only one exhibited synergy with eravacycline or tigecycline and ceftazidime/avibactam combinations, and no synergistic activity was identified in the time-kill analysis for these combinations. The combination of eravacycline and polymyxin-B demonstrated the most promising synergy in the time-kill analysis. CONCLUSION: This study provides substantial evidence of a significant synergy when combining tigecycline or eravacycline with polymyxin-B against CRKP strains, including those producing MBL. These results highlight potential therapeutic strategies against CRKP infections.

Effectiveness and evolution of anti-SARS-CoV-2 spike protein titers after three doses of COVID-19 vaccination in people with HIV.

BACKGROUND: Real-world vaccine effectiveness following the third dose of vaccination against SARS-CoV-2 remains less investigated among people with HIV (PWH). METHODS: PWH receiving the third dose of BNT162b2 and mRNA-1273 (either 50- or 100-µg) were enrolled. Participants were followed for 180 days until the fourth dose of COVID-19 vaccination, SARS-CoV-2 infection, seroconversion of anti-nucleocapsid IgG, death, or loss to follow-up. Anti-spike IgG was determined every 1-3 months. RESULTS: Of 1427 participants undergoing the third-dose COVID-19 vaccination, 632 (44.3%) received 100-µg mRNA-1273, 467 (32.8%) 50-µg mRNA-1273, and 328 (23.0%) BNT162b2 vaccine and the respective rate of SARS-CoV-2 infection or seroconversion of anti-nucleocapsid IgG was 246.1, 280.8 and 245.2 per 1000 person-months of follow-up (log-rank test, p = 0.28). Factors associated with achieving anti-S IgG titers >1047 BAU/mL included CD4 count <200 cells/mm3 (adjusted odds ratio [aOR], 0.11; 95% CI, 0.04-0.31), plasma HIV RNA >200 copies/mL (aOR, 0.27; 95% CI, 0.09-0.80), having achieved anti-spike IgG >141 BAU/mL within 3 months after primary vaccination (aOR, 3.69; 95% CI, 2.68-5.07), receiving BNT162b2 vaccine as the third dose (aOR, 0.20; 95% CI, 0.10-0.41; reference, 100-µg mRNA-1273), and having previously received two doses of mRNA vaccine in primary vaccination (aOR, 2.46; 95% CI, 1,75-3.45; reference, no exposure to mRNA vaccine). CONCLUSIONS: PWH receiving different types of the third dose of COVID-19 vaccine showed similar vaccine effectiveness against SARS-CoV-2 infection. An additional dose with 100-µg mRNA-1273 could generate a higher antibody response than with 50-µg mRNA-1273 and BNT162b2 vaccine.

In vitro activity of cefiderocol and comparator antibiotics against multidrug-resistant non-fermenting Gram-negative bacilli.

Background: This study evaluated the in vitro activity of cefiderocol, ceftazidime/avibactam, and aztreonam/avibactam against clinically important multidrug-resistant non-fermenting Gram-negative bacilli. Methods: Bacteraemic isolates of 126 multidrug-resistant Acinetobacter baumannii (MDRAB), 110 imipenem-resistant Pseudamoas aeruginosa [including 14 difficult-to-treat resistant P. aeruginosa (DTRPA)], 45 beta-lactam-non-susceptible Burkholderia cepacia complex (BCC), 47 levofloxacin or trimethoprim/sulfamethoxazole-non-susceptible Stenotrophomonas maltophilia and 22 ciprofloxacin-non-susceptible Elizabethkingia spp. collected between 2019 and 2021 were subjected to MIC determination for cefiderocol, ceftazidime/avibactam and aztreonam/avibactam. Results: The MIC50/90s of cefiderocol for drug-resistant A. baumannii, P. aeruginosa, BCC, S. maltophilia and Elizabethkingia spp. were 0.25/2, 0.25/1, ≤0.06/≤0.06, ≤0.06/0.25 and >32/>32 mg/L, respectively. Cefiderocol inhibited 94.4% (119/126) of MDRAB, 100% of imipenem-resistant P. aeruginosa, 100% of DTRPA and 100% of BCC at an MIC ≤4 mg/L, and 97.9% (46/47) of S. maltophilia at ≤1 mg/L. Ceftazidime/avibactam inhibited 76.4% (84/110) of imipenem-resistant P. aeruginosa, 21.4% (3/14) of DTRPA and 68.9% (31/45) of BCC at an MIC ≤8 mg/L. Aztreonam/avibactam had MIC50/90s of 16/>32, 8/16 and 4/8 mg/L for imipenem-resistant P. aeruginosa, BCC and S. maltophilia, respectively. At ≤8 mg/L, aztreonam/avibactam inhibited 7.1% (1/14) of DTRPA and 93.6% (44/47) of S. maltophilia isolates. Elizabethkingia spp. demonstrated high MICs for cefiderocol, ceftazidime/avibactam and aztreonam/avibactam, with all MIC50s and MIC90s > 32 mg/L. Conclusion: Cefiderocol may serve as an alternative treatment for multidrug-resistant A. baumannii, P. aeruginosa, BCC and S. maltophilia when other antibiotics have been ineffective or intolerable. The role of ceftazidime/avibactam and aztreonam/avibactam in the management of BCC or S. maltophilia infections warrants further investigation.

Weight and metabolic changes among virally-suppressed people living with HIV who switched to co-formulated bictegravir/emtricitabine/tenofovir alafenamide.

OBJECTIVE: We aimed to investigate the evolution of weight, lipid profiles, and glucose homeostasis among virally-suppressed people living with HIV (PLWH) who switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). METHODS: PLWH with viral suppression who switched to BIC/FTC/TAF between October 2019 and May 2021 were followed for 96 weeks to examine the change of weight, lipid profiles (total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)), and glycated hemoglobin (HbA1c) levels. RESULTS: 889 PLWH with an average weight of 72.1 kg at baseline were included. At week 96, over 95% of PLWH consistently maintained plasma HIV RNA load <50 copies/mL at each 24-week interval of follow-up while the weight change was small (+0.7 kg, p<0.0001), though statistically significant. Baseline levels of TC, LDL-C, HDL-C, TG, and HbA1c were 191.8 mg/dL, 114.2 mg/dL, 48.9 mg/dL, 174.3 mg/dL, and 5.31%, respectively. After 96 weeks, changes were observed in TC (-11.6 mg/dL, p<0.0001), LDL-C (-3.4 mg/dL, p=0.0084), HDL-C (+0.6 mg/dL, p=0.1089), TG (-30.2, p<0.0001), and HbA1c (+0.12%, p<0.0001). A 5% or more weight gain was associated with age of 30-40 years, normal weight at baseline, and prior use of non-integrase inhibitors or tenofovir disoproxil fumarate. Obesity was associated with development of both dyslipidemia and diabetes mellitus after switch. CONCLUSIONS: Stable switch to BIC/FTC/TAF maintained high rates of viral suppression and had a small impact on weight and metabolic changes in virally suppressed PLWH. Follow-up of the weight and metabolic changes is warranted in PLWH on long-term antiretroviral therapy.

Effectiveness of second-generation integrase strand-transfer inhibitor-based regimens for antiretroviral-experienced people with HIV who had viral rebound.

BACKGROUND: Antiretroviral regimens containing a second-generation integrase strand-transfer inhibitor (INSTI) plus 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) are the recommended therapy for people with HIV (PWH) who are antiretroviral-naïve or on stable antiretroviral therapy (ART) with viral suppression. Real-world data on the virologic effectiveness of co-formulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) among PWH with virologic failure while receiving other ART remain sparse. METHODS: We retrospectively reviewed the medical records of PWH who had viral rebound with plasma HIV RNA >1000 copies/mL and were switched to either dolutegravir combined with 2 NRTIs or BIC/FTC/TAF. The primary end point was re-achieving viral suppression within the first 48 weeks of switch. The association between NRTI-related resistance-associated mutations (RAMs) and virologic effectiveness was examined. RESULTS: Seventy-nine PWH with viral rebound while receiving other antiretroviral regimens were included. Within the first 48 weeks of switch, the overall probability of re-achieving viral suppression was 79.7% (82.5% [33/40] and 76.9% [30/39] for BIC/FTC/TAF and dolutegravir-based regimens, respectively, p = 0.78). PWH with a higher CD4 lymphocyte count (adjusted odds ratio, per 100-cell/mm3 increase, 1.41; 95% confidence interval, 1.02-1.95) were more likely to re-achieve viral suppression. Among PWH switching to BIC/FTC/TAF who had pre-existing RAMs to NRTIs before switch, 14 of 15 (93.3%) successfully achieved viral suppression. CONCLUSIONS: Switching to BIC/FTC/TAF and dolutegravir-based regimens could re-achieve viral suppression in four-fifth of the PWH who experienced viral rebound during treatment with other antiretroviral regimens. Pre-existing NRTI-related RAMs did not have adverse impact on the effectiveness of dolutegravir combined with 2 NRTIs or BIC/FTC/TAF.

Higher serologic responses of early syphilis to single-dose benzathine penicillin G plus doxycycline versus single-dose benzathine penicillin G alone among people with HIV.

BACKGROUND: Single-dose benzathine penicillin G (BPG) is the preferred therapy for early syphilis, but poorer serologic responses have been observed among people with HIV (PWH). No enhanced regimen has previously been shown to improve serologic outcomes of early syphilis. METHODS: We conducted a retrospective study to compare the treatment responses to single-dose BPG combined with 7-day doxycycline versus BPG alone in PWH who presented with early syphilis. Rapid plasma reagin (RPR) titers were determined every 3-6 months for all included PWH. Serologic response was defined as at least a fourfold decline in RPR titers at month 12. RESULTS: During January 2018 to March 2022, 223 PWH with 307 episodes of early syphilis received single-dose BPG plus doxycycline and 347 PWH with 391 episodes received BPG alone. The median age was 36 years and baseline CD4 count was 600 cells/mm3. In the intention-to-treat with last-observation-carried-forward analysis, PWH receiving BPG plus doxycycline had a significantly higher serologic response rate at 12 months of treatment than those receiving BPG alone (79.5% vs 70.3%, respectively; P= .006). The factors associated with 12-month serologic response were RPR titer (per 1-log2 increase, adjusted odds ratio [AOR], 1.25; 95% CI, 1.15-1.35) and receipt of BPG plus doxycycline (AOR, 1.71; 95% CI, 1.20-2.46). In the subgroup analyses, BPG plus doxycycline was consistently associated with a better serologic response than BPG alone at month 12. CONCLUSIONS: Among PWH with early syphilis, single-dose BPG plus doxycycline achieved higher serologic responses than BPG alone during a 12-month follow-up period.

Optimal Frequency of Hepatitis C Virus (HCV) RNA Testing for Detection of Acute HCV Infection Among At-risk People With Human Immunodeficiency Virus: A Multicenter Study.

Using 3-stage pooled-plasma hepatitis C virus (HCV) RNA testing performed quarterly among at-risk people with human immunodeficiency virus (PWH), we found that if testing had been performed every 6 or 12 months, 58.6%-91.7% of PWH who recently acquired HCV would be delayed for diagnosis and might contribute to onward HCV transmission with longer durations.

A Randomized Clinical Trial of 1-Dose vs Accelerated 2-Dose Schedule for Hepatitis A Virus (HAV) Revaccination Among People With Human Immunodeficiency Virus Who Were Nonresponders or Had Seroreversion After Primary HAV Vaccination.

BACKGROUND: For people with human immunodeficiency virus (PWH) who have no serological responses to their primary hepatitis A virus (HAV) vaccination or have seroreversion after successful primary vaccination, the optimal revaccination strategy remains unclear. METHODS: In this open-label, randomized clinical trial, PWH who tested negative for anti-HAV antibodies after receiving a standard 2-dose series of primary HAV vaccination were enrolled and assigned in a 1:1 ratio to receive either 1 dose (the 1-dose group) or 2 doses of HAV vaccine administered 4 weeks apart (the 2-dose group). Serological response rates and anti-HAV antibody titers were compared at weeks 24 and 48. RESULTS: Of the 153 participants (77 in the 1-dose group and 76 in the 2-dose group), the overall serological response rates at week 48 after revaccination were similar between the 2 groups (2- vs 1-dose, 80.2% vs 71.4%, P = .20). However, anti-HAV antibody titers were consistently higher in the 2-dose group than in the 1-dose group. In subgroup analysis, PWH who were nonresponders to primary HAV vaccination were significantly more likely to mount a serological response after 2-dose HAV revaccination (68.4% vs 44.1%, P = .038). No severe adverse events were reported throughout the study. CONCLUSIONS: Two-dose HAV revaccination administered 4 weeks apart yielded similar serological responses as 1-dose revaccination among PWH who were nonresponders or had seroreversion after primary HAV vaccination. The 2-dose revaccination schedule generated significantly higher anti-HAV antibody titers and was more likely to elicit serological responses at week 48 among PWH who were nonresponders to primary HAV vaccination. Clinical Trials Registration. NCT03855176.

Immune Reconstitution Inflammatory Syndrome in People Living with HIV Who Presented with Interstitial Pneumonitis: an Emerging Challenge in the Era of Rapid Initiation of Antiretroviral Therapy.

Studies on immune reconstitution inflammatory syndrome (IRIS) in people living with HIV (PLWH) and presenting with interstitial pneumonitis (IP) are limited in the era of rapid antiretroviral therapy (ART) initiation, particularly with integrase strand-transfer inhibitor (INSTI)-containing regimens. Adult PLWH presenting with IP in whom ART was initiated within 30 days of IP diagnosis between 2015 and 2021 were retrospectively identified. The primary outcome was the occurrence of IRIS within 30 days after admission. Of 88 eligible PLWH with IP (median age, 36 years; CD4 count, 39 cells/mm3), Pneumocystis jirovecii and cytomegalovirus (CMV) DNA were detected via polymerase-chain-reaction assay in 69.3% and 91.7% of respiratory specimens, respectively. 22 PLWH (25.0%) had manifestations that met French's IRIS criteria for paradoxical IRIS. There were no statistically significant differences in terms of the all-cause mortality (0.0% versus 6.1%, P = 0.24), the occurrence of respiratory failure (22.7% versus 19.7%, P = 0.76), and pneumothorax (9.1% versus 7.6%, P = 0.82) between PLWH with and those without paradoxical IRIS. In a multivariable analysis, the factors associated with IRIS were the decline of the 1 month plasma HIV RNA load (PVL) with ART (adjusted hazard ratio [aHR] per 1 log decrease, 3.45; 95% CI, 1.52 to 7.81), a baseline CD4-to-CD8 ratio of <0.1 (aHR, 3.47; 95% CI, 1.16 to 10.44), and the rapid initiation of ART (aHR, 7.95; 95% CI, 1.04 to 60.90). In conclusion, we found a high rate of paradoxical IRIS among PLWH with IP in the era of rapid ART initiation with INSTI-containing ART and this was associated with immune depletion at baseline, a rapid decline of PVL, and an interval of <7 days between the diagnosis of IP and the initiation of ART. IMPORTANCE Our study of PLWH who presented with IP mainly due to Pneumocystis jirovecii demonstrates that a high rate of paradoxical IRIS and a rapid decline of PVL with the initiation of ART, a CD4-to-CD8 ratio of <0.1 at baseline, and a short interval (<7 days) between the diagnosis of IP and the initiation of ART were associated with paradoxical IP-IRIS in PLWH. Paradoxical IP-IRIS was not associated with mortality or respiratory failure with heightened awareness among the HIV-treating physicians, rigorous investigations to exclude the possibilities of concomitant infections, or the malignancies and adverse effects of medications, including the cautious use of corticosteroids.

Risk factors for mortality after linezolid treatment of vancomycin-resistant Enterococcus bloodstream infection.

OBJECTIVES: We analyzed the risk factors affecting linezolid treatment outcome in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI). METHODS: We conducted a multicenter observational study of patients who received linezolid 600 mg every 12 hours for VRE BSI. The primary outcome was 28-day mortality. The estimated area under the concentration-time curve and trough concentration were calculated. Multivariable logistic regression was used for the outcome analysis. RESULTS: A total of 170 patients were included: 114 (67.1%) survived and 56 (32.9%) did not. A total of 26 (18.2%) isolates showed a linezolid minimum inhibitory concentration (MIC) of ≤1 mg/l, 113 (79.0%) of 2 mg/l, and 4 (2.8%) of 4 mg/l. The univariable analysis showed that the linezolid MIC and concentration-time curve/MIC were not associated with mortality (P = 0.95 and P = 0.42, respectively). After adjusting for underlying comorbidity and disease severity, the linezolid dose per body weight (LDBW), body height, and interaction between them were independent risks for mortality. Marginal analysis showed that increasing the LDBW was protective in patients with a body height <160 cm. A trough concentration of >12.2 mg/l was a risk factor for thrombocytopenia. CONCLUSION: The LDBW and body height were interactively associated with clinical outcomes of linezolid treatment for VRE BSI.

Patient-reported outcomes among virally suppressed people living with HIV after switching to Co-formulated bictegravir, emtricitabine and tenofovir alafenamide.

BACKGROUND: While some evidence has suggested the benefits of co-formulated bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) in improving the quality of life of people living with HIV (PLWH), patient-reported outcome studies that focus on Asian population remain scarce. We aimed to determine the changes in HIV-related symptom burden in virally-suppressed PLWH switching to B/F/TAF in a real-world setting. METHODS: PLWH on stable antiretroviral therapy (ART) for ≥6 months with plasma HIV RNA <200 copies/mL who decided to switch to B/F/TAF were eligible for the study. Participants' experience with 20 symptoms were assessed using HIV Symptom Index at baseline and weeks 24 and 48. Responses were dichotomized in two ways: 1) present vs. not present; and 2) bothersome vs. not bothersome, and compared across time points. RESULTS: Six hundred and thirty participants (prior regimen, 94.4% integrase inhibitor-based) who completed week 48 visit were included in the analysis. Forty-eight weeks after switching to B/F/TAF, six symptoms were significantly less prevalent, and seven symptoms were significantly less bothersome. Improvement was more pronounced in participants whose prior regimen was elvitegravir-based versus dolutegravir-based. Logistic regression results showed that prior dolutegravir-based ART and pre-existing diabetes independently predicted improvement in diarrhea/loose bowels and muscle aches/joint pain, respectively. Despite the overall improvement, some symptoms persisted in a substantial proportion of participants. CONCLUSIONS: Virally-suppressed PLWH might benefit from a regimen switch to B/F/TAF to reduce the prevalence and level of bother of HIV-related symptoms. Nevertheless, additional multidisciplinary interventions are warranted to further alleviate the symptom burden of PLWH.

The Combination of Daptomycin with Fosfomycin is More Effective than Daptomycin Alone in Reducing Mortality of Vancomycin-Resistant Enterococcal Bloodstream Infections: A Retrospective, Comparative Cohort Study.

INTRODUCTION: High-dose daptomycin-based combinations are recommended for vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI). Preclinical data have shown a synergistic effect of daptomycin/fosfomycin combinations against VRE. However, clinical studies comparing daptomycin monotherapy with daptomycin/fosfomycin combinations are unavailable. METHODS: An observational study of VRE-BSI was performed between 2010-2021 on patients receiving daptomycin monotherapy (≥ 8 mg/kg) or daptomycin combined with intravenous fosfomycin. Patients treated with concomitant ß-lactam combinations were excluded. The primary outcome was in-hospital mortality. Outcomes were analyzed using multivariable logistic regression and augmented inverse probability weighting (AIPW) analyses. RESULTS: Among 224 patients, 176 received daptomycin monotherapy, and 48 received fosfomycin combinations. The median daptomycin and fosfomycin doses were 9.8 mg/kg and 12 g/day, respectively. In-hospital mortality was 77.3% and 47.9% in the daptomycin monotherapy and fosfomycin combination groups (P < 0.001), respectively. Multivariable logistic regression analysis predicted lower mortality with fosfomycin combination treatment (adjusted odds ratio, 0.35; 95% confidence interval (CI), 0.17-0.73; P = 0.005). AIPW demonstrated a 17.8% reduced mortality with fosfomycin combinations (95% CI, - 30.6- - 4.9%; P = 0.007). The survival benefit was significant, especially among patients with a lower Pitt bacteremia score or fosfomycin minimum inhibitory concentration (MIC) ≤ 64 mg/l. Fosfomycin combination resulted in higher hypernatremia (10.4% vs. 2.8%, P = 0.04) and hypokalemia (33.3% vs. 15.3%, P = 0.009) compared to daptomycin monotherapy. CONCLUSION: The combination of high-dose daptomycin with fosfomycin improved the survival rate of patients with VRE-BSI compared to daptomycin alone. The benefit of the combination was most pronounced for VRE with fosfomycin MIC ≤ 64 mg/l and for patients with a low Pitt bacteremia score.

In vitro susceptibility of common Enterobacterales to eravacycline in Taiwan.

BACKGROUND: New tetracycline derivatives exhibit broad-spectrum antimicrobial activities. This study aimed to assess the in vitro activity of eravacycline against common Enterobacterales. METHODS: Clinical Enterobacterales isolates were collected between 2017 and 2021. The minimum inhibitory concentration (MIC) was determined using a broth microdilution test. RESULTS: We identified Klebsiella pneumoniae (n = 300), Escherichia coli (n = 300), Klebsiella oxytoca (n = 100), Enterobacter cloacae complex (n = 100), Citrobacter freundii (n = 100), and Proteus mirabilis (n = 100). All P. mirabilis strains were resistant to eravacycline. Excluding P. mirabilis, the susceptibility rates to eravacycline, omadacycline, and tigecycline were 75.2%, 66.9%, and 73%, respectively. The MIC50 and MIC90 (mg/L) of eravacycline were 0.5 and 4 for K. pneumoniae, 0.5 and 1 for E. coli, 0.5 and 1 for K. oxytoca, 0.5 and 2 for E. cloacae complex, and 0.25 and 1 for C. freundii. In cefotaxime non-susceptible and meropenem susceptible Enterobacterales, excluding P. mirabilis, the susceptibility rates of eravacycline, omadacycline, and tigecycline were 69.7%, 57.1%, and 66.2%. We found decreased susceptibility rates of three new tetracycline derivatives against meropenem non-susceptible Enterobacterales (eravacycline: 47.1%, omadacycline: 39.4%, and tigecycline: 39.4%). Eravacycline showed a high susceptibility rate against cefotaxime non-susceptible and meropenem susceptible K. oxytoca (100%), C. freundii (93.2%), E. coli (85.9%), and meropenem non-susceptible E. coli (100%). CONCLUSION: This study provides the MIC and susceptibility rate of eravacycline for common Enterobacterales. Eravacycline could be a therapeutic choice for cefotaxime non-susceptible or meropenem non-susceptible Enterobacterales, especially K. oxytoca, C. freundii, and E. coli.

The combination of daptomycin with ß-lactam antibiotics is more effective than daptomycin alone for vancomycin-resistant Enterococcus faecium bloodstream infection.

BACKGROUND: The treatment options for vancomycin-resistant Enterococcus (VRE) are limited. A combination of daptomycin (DAP) and ß-lactam (BL) has been suggested; however clinical studies supporting this are lacking. METHODS: Patients with VR E. faecium bacteremia who received ≥ 8 mg/kg daptomycin for ≥ 72 h and initiated ≤ 5 days of culture collection between 2010 and 2021 were included. DAP+BL was defined as receiving BL for ≥ 24 h and within 24 h of DAP initiation. The primary endpoint was a composite clinical success (neither 14-day mortality, microbiological failure, nor change in the anti-VRE regimen). Outcomes were analyzed using multivariable logistic regression and augmented inverse probability weighting (AIPW). RESULTS: A total of 430 patients were enrolled (DAP, n = 45; DAP+BL, n = 385). Clinical success was achieved in 19 (42.2%) patients in the DAP group and 244 (63.4%) in the DAP+BL group [adjusted odds ratio, 3.19; 95% confidence interval (CI) 1.61-6.33; P = 0.001]. Marginal analysis showed that the efficacy of DAP+BL was particularly significant with DAP dose ≥ 9 mg/kg and DAP minimum inhibitory concentration (MIC) ≥ 2 mg/L. With the balance of AIPW, standardized mean clinical success rates for DAP and DAP+BL 37.3% and 63.5%, respectively. The difference between DAP+BL and DAP was of 26.2% in favor of DAP+BL (95% CI, 10.0-42.3%; P = 0.001). CONCLUSIONS: DAP+BL was associated with a significantly higher rate of compositive clinical success than DAP for treatment of VR E. faecium bacteremia. The study suggested BL in combination with high-dose DAP for VR E. faecium bacteremia treatment, especially when VRE showed a high DAP MIC.

Virological responses to tenofovir-alafenamide-containing antiretroviral therapy in people living with HIV co-infected with lamivudine-resistant or lamivudine-susceptible hepatitis B virus.

BACKGROUND: Data on the effectiveness of tenofovir alafenamide (TAF) against lamivudine-resistant (LAM-R) hepatitis B virus (HBV) among patients co-infected with human immunodeficiency virus (HIV) and HBV are limited. METHODS: Between April and December 2018, HIV-positive patients co-infected with LAM-R or lamivudine-susceptible (LAM-S) HBV who switched from tenofovir-disoproxil-fumarate-containing antiretroviral therapy (ART) to TAF-containing ART were followed for 96 weeks. Plasma HBV and HIV loads, HBV serological markers, and liver function before and after the switch were analysed. RESULTS: In total, 182 patients co-infected with HIV and HBV were included in this study: 45 with LAM-R HBV and 137 with LAM-S HBV. At baseline, 28.9% and 7.4% of patients in the LAM-R and LAM-S groups, respectively, tested positive for hepatitis B virus envelope antigen (HBeAg) (P<0.001), and the respective percentages of patients who had achieved plasma HBV DNA <20 IU/mL were 95.5% and 97.1%. At weeks 48 and 96, 100% and 94.9% of patients in the LAM-R group, respectively, and 97.1% and 95.6% of patients in the LAM-S group, respectively, maintained plasma HBV DNA <20 IU/mL. Lamivudine resistance of HBV and baseline hepatitis B virus surface antigen (HBsAg) level were associated with HBsAg decrement at week 96 at a degree of 0.25 log10 IU/mL [95% confidence interval (CI) 0.059-0.246] and 0.22 log10 IU/mL (per 1-log10IU/mL increase, 95% CI 0.018-0.101), respectively. At week 96, 2.2% (4/182) of patients had HBsAg loss; no patients in the LAM-R group and 25.0% (2/8) of patients in the LAM-S group had HBeAg seroconversion. CONCLUSIONS: Switching to TAF-containing regimens maintained high rates of HBV viral suppression in patients co-infected with either LAM-R or LAM-S HBV. The decrease in HBsAg was minimal, and HBsAg seroconversion occurred infrequently.

A High Daptomycin Dose Is Associated with Better Bacterial Clearance in Infections Caused by Vancomycin-Resistant Enterococcus faecium Regardless of Daptomycin Minimum Inhibitory Concentration in a Rat Infective Endocarditis Model.

A high daptomycin dose has been suggested for treating vancomycin-resistant Enterococcus faecium (VREf) infections. However, even a 12 mg/kg daptomycin dose might be insufficient for treating VREf with high daptomycin minimum inhibitory concentrations (MICs). Additionally, animal pharmacodynamic and infection models to confirm the efficacy of 12 mg/kg daptomycin are lacking. Male Wistar rats were used for pharmacokinetic profiling and for the development of an infective endocarditis (IE) model. Daptomycin-susceptible dose-dependent VREf (DSE) (MIC of 0.5 mg/L) and daptomycin nonsusceptible VREf (DNSE) (MIC of 8 mg/L) were used for the IE models. The bacterial load of vegetation was the primary outcome and was evaluated after 3 days of daptomycin treatment. Daptomycin administered subcutaneously (s.c.) at 45 and 90 mg/kg, which corresponded to maximum serum concentrations (Cmax) of 122.6 mg/L and 178.5 mg/L, respectively, was equivalent to doses of 8 mg/kg and 12 mg/kg, respectively, in humans. The Cmax/MIC value was correlated with the bacterial load of vegetation after treatment (r = -0.88, P < 0.001). The 90 mg/kg s.c. group showed a significantly lower bacterial load of vegetation (log10 CFU/g) than the 45 mg/kg s.c. group against DSE (0 versus 4.75, P < 0.001) and DNSE (5.12 versus 6.98, P = 0.002). The 90 mg/kg s.c. group did not sterilize the vegetation against DNSE. Although the human equivalent dose of 12 mg/kg daptomycin was more effective than the smaller dose in reducing the bacterial load in DSE and DNSE IE, the dose could not sterilize the vegetation during a DNSE treatment. Further treatment strategies by which to manage severe VREf infections, especially at high daptomycin MICs, are urgently needed. IMPORTANCE Using a rat IE model with pharmacokinetic analysis, the treatment response of VREf IE was found to be daptomycin dose-dependent, presented as Cmax/MIC or as the 24 h area under the concentration-time curve (AUC0-24)/MIC. Daptomycin 90 mg/kg s.c. significantly reduced the bacterial load against DSE and DNSE. It also showed significant activity against DSE and DNSE, compared to 45 mg/kg s.c. Although daptomycin 90 mg/kg can eradicate the bacterial load after 3 days of treatment against DSE, eradication cannot be achieved with 90 mg/kg daptomycin against DNSE.

Daptomycin area under the curve to minimum inhibitory concentration ratio by broth microdilution for predicting the outcome of vancomycin-resistant Enterococcus bloodstream infection.

OBJECTIVES: Different methods are used to determine the minimum inhibitory concentration (MIC) for daptomycin. The threshold is unknown for the free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) of daptomycin using broth microdilution (BMD) to predict outcome of vancomycin-resistant enterococcus (VRE) bacteremia. The MIC testing method which is best for predicting the outcome remains unclear. METHODS: This is a retrospective cohort study. The inclusion criterion was VRE bacteremia treated with ≥ 8 mg/kg of daptomycin. As we aimed to compare different daptomycin MIC testing methods for predicting the clinical outcome of VRE bacteremia, the inclusion criteria included the availability of MIC values for BMD, Etest, and automated antimicrobial susceptibility testing (AST). The primary end point was 28-day mortality. The fAUC/MIC was dichotomized using classification and regression tree analysis for predicting survival. RESULTS: A total of 393 patients were included; 215 survived and 178 died. In the multivariable logistic model for predicting mortality, the dichotomized fAUC/MICs for Etest and AST were 0.508 and 0.065 times as probable, respectively, as that for BMD to minimize information loss. An fAUC/MIC > 75.07 for BMD significantly predicted lower mortality (adjusted odds ratio, 0.53, 95% confidence interval, 0.30-0.95; P = 0.03) after adjusting for underlying disease and bacteremia severity. Using Monte Carlo simulation, none of the doses had a probability of target attainment of ≥ 50% with an MIC of ≥ 2 mg/L. CONCLUSION: The dichotomized threshold for fAUC/MIC for BMD was the best predictor of mortality. An fAUC/MIC > 75.07 for BMD independently predicted better survival.

Low-level viraemia and virologic failure among people living with HIV who received maintenance therapy with co-formulated bictegravir, emtricitabine and tenofovir alafenamide versus dolutegravir-based regimens.

Real-world experience with low-level viraemia (LLV) and its impact remain less reported among people living with HIV (PLWH) who receive antiretroviral therapy (ART) containing second-generation integrase strand transferase inhibitors, including dolutegravir and bictegravir. This retrospective cohort study included virally suppressed PLWH who achieved plasma HIV-RNA viral load (PVL) <50 copies/mL for ≥6 months and were switched to either dolutegravir- or bictegravir-based ART. Incidence rates of developing LLV events (PVL, 50-200 copies/mL) and virologic failure (VF) (PVL ≥1000 copies/mL) were compared between the dolutegravir and bictegravir cohorts. A total of 623 and 862 PLWH switched to dolutegravir-based and bictegravir-based ART, respectively, were included. The incidence rate of developing LLV was 6.2 per 100 person-years of follow-up (PYFU) in the bictegravir cohort and 3.8 per 100 PYFU in the dolutegravir cohort [incidence rate ratio (IRR) = 1.63, 95% confidence interval (CI), 0.90-2.95; P = 0.08], while rates of VF were 0.69 per 100 PYFU and 0.95 per 100 PYFU, respectively, in the bictegravir and dolutegravir cohorts (IRR = 0.72, 95% CI 0.12-3.39; P = 0.34). Presence of LLV events was not associated with subsequent VF in multivariate analysis. Secondary analysis also demonstrated that resistance-associated mutations (RAMs) to nucleoside reverse transcriptase inhibitors (NRTIs) before switch were not associated with adverse virologic outcomes in either cohort. In conclusion, among virally suppressed PLWH, the incidences of developing LLV or VF were similar after switch to dolutegravir- or bictegravir-based ART. Pre-existing RAMs to NRTIs or LLV events were not associated with subsequent VF.

Evaluation of the synergistic effect of ceftaroline against methicillin-resistant Staphylococcus aureus.

OBJECTIVES: We aimed to determine the synergistic effects of ceftaroline (CPT) in combination with daptomycin (DAP), vancomycin (VAN), or linezolid (LNZ) against various methicillin-resistant Staphylococcus aureus (MRSA) strains. METHODS: MRSA strains randomly selected from 2014 to 2018 were studied. Checkerboard titration and in vitro time-kill analyses were used to determine the synergistic activities of the antibiotic combinations. RESULTS: A total of 10 genetically distinct MRSA strains were included in this study. The checkerboard titration analysis revealed that the CPT-DAP, CPT-VAN, and CPT-LNZ combinations had a synergistic effect against 30%, 10%, and 10% of the selected MRSA strains, respectively. Using time-kill analysis, we showed that CPT-DAP exhibited a significant synergistic and sustained bactericidal effect against both DAP-susceptible (Δ colony-forming units/ml, -5.79; P = 0.0495) and DAP-resistant (Δ colony-forming units/ml, -6.40; P = 0.0463) MRSA strains at a concentration of 0.5 × the minimum inhibitory concentration of CPT plus 0.5 × the minimum inhibitory concentration of DAP. No synergistic bactericidal effects were observed for the CPT-VAN and CPT-LNZ combinations against the selected strains. CONCLUSION: The CPT-DAP combination showed better synergistic activity than the CPT-VAN and CPT-LNZ combinations against the enrolled MRSA strains. DAP, rather than VAN or LNZ, might be a better choice for CPT combination in the treatment of MRSA infections.

Three-Stage Pooled Plasma Hepatitis C Virus RNA Testing for the Identification of Acute HCV Infections in At-Risk Populations.

Timely diagnosis and treatment of hepatitis C virus (HCV) infection may prevent its transmission. We evaluated the performance and cost reductions of the pooled plasma HCV RNA testing strategy to identify acute HCV infections among people living with HIV (PLWH). PLWH with sexually transmitted infections, elevated aminotransferases within the past 6 months or past HCV infections (high-risk) and those without (low-risk) were enrolled prospectively. Participants underwent three-stage pooled plasma HCV RNA testing every 12 to 24 weeks until detection of HCV RNA or completion of a 48-week follow-up. The three-stage strategy combined 20 individual specimens into a stage 1 pool, 5 individual specimens from the stage 1 pool that tested positive for HCV RNA in the stage 2 mini-pool, followed by testing of individual specimens of the stage 2 mini-pool tested positive for HCV RNA. A simulation was constructed to investigate the cost reductions and pooled sensitivity and specificity under different combinations of HCV prevalence and pool/mini-pool sizes. Between June 25, 2019 and March 31, 2021, 32 cases of incident HCV viremia were identified in 760 high-risk PLWH that were enrolled 834 times, giving an incidence rate of 56.6 per 1000 person-years of follow-up (PYFU). No cases of HCV viremia were identified in 557 low-risk PLWH during a total of 269.2 PYFU. Simulation analysis suggested that this strategy could reduce HCV RNA testing cost by 50% to 86% with HCV viremia prevalence of 1% to 5% and various pooled sizes despite compromised pooled sensitivity. This pooled plasma HCV RNA testing strategy is cost-saving to identify acute HCV infections in high-risk populations with HCV viremia prevalence of 1% to 5%. IMPORTANCE Our three-stage pooled plasma HCV RNA testing successfully identified HCV viremia in high-risk PLWH with a testing cost reduction of 84.5%. Simulation analysis offered detailed information regarding the selection of pool and mini-pool sizes in settings of different HCV epidemiology and the performance of HCV RNA testing to optimize the cost reduction.