Comparative Bactericidal Activity Of Representative ß-Lactams Against Enterobacterales, Acinetobacter Baumannii and Pseudomonas Aeruginosa

[Posted 25/May/2022]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: ß-Lactam sub-classes (penicillins, cephalosporins, monobactams and carbapenems) have different antibacterial effects against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Extrapolation of in vitro pharmacodynamic findings from one species to another or one sub-class of ß-lactam to another is not justified.

BACKGROUND: There is surprisingly little comparative published data on the bactericidal action of different sub-classes of ß-lactams against aerobic Gram-negative rods, and the assumption is that all behave in the same way. Purpose of this study is to describe a systematic investigation of a representative penicillin, cephalosporin, monobactam and carbapenem against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.

DETAILS: Concentration-time-kill curves (TKC) were determined for three strains each of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. All strains were susceptible to the agents used. The antibiotics were piperacillin/tazobactam, ceftazidime, aztreonam and meropenem. The initial inoculum was 106 cfu/mL and TKC were determined over 48 h. The area-under-the-bacterial-kill curve to 24 h (AUBKC 24 log cfu.h/mL) and 48 h (AUBKC 48) were used to measure antibacterial effect (ABE). Population profiles before and after antibiotic exposure were recorded. Against E. coli and K. pneumoniae meropenem had a maximal ABE at >=MIC x 1 concentrations while piperacillin/tazobactam and ceftazidime had maximal effect at >=MIC x 4 and aztreonam at >=MIC x 8 concentrations. Ceftazidime, aztreonam and meropenem had less ABE against K. pneumoniae than E. coli. Against P. aeruginosa, meropenem was most bactericidal, with a maximum ABE at 8x/16 x MIC. Other ß-lactams had notably less ABE. In contrast, against A. baumannii, ceftazidime and meropenem had the greatest ABE, with a maximal effect at >=MIC x 4, concentration changes in population profiles were least apparent with E. coli.

Copyright © Oxford University Press. All rights reserved.

Source: Noel, A. R., Attwood, M., Bowker, K. E., et al. (2022). Comparative Bactericidal Activity Of Representative ß-Lactams Against Enterobacterales, Acinetobacter Baumannii and Pseudomonas Aeruginosa. Journal of Antimicrobial Chemotherapy. 2022; 77(5): 1306-1312. Published: May, 2022. DOI: 10.1093/jac/dkac026.

A Prospective, Open-Label, Non-Inferiority, Randomised Controlled Trial

[Posted 8/Apr/2024]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis.

BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG).

DETAILS: Authors did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. Authors recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2.4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49.8 to 86.2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87.7 to 100.0) in the BPG group (treatment difference -29.6, 95% CI -50.5 to -8.8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5.8 to 35.8 in the linezolid group vs five [17%] of 30, 5.6 to 34.7, in the BPG group). No serious adverse events were reported during follow-up.

Copyright © Elsevier Ltd. All rights reserved.

Source: Ubals, M., Nadal-Baron, P., Arando, M., et al. (2024). Oral Linezolid Compared With Benzathine Penicillin G for Treatment of Early Syphilis in Adults (Trep-AB Study) in Spain: A Prospective, Open-Label, Non-Inferiority, Randomised Controlled Trial. The Lancet. 2024; 24(4): 404-416. Published: April, 2024. DOI: 10.1016/S1473-3099(23)00683-7.

[Posted 12/Mar/2024]

AUDIENCE: Nursing

KEY FINDINGS: Making Time for Exercise Self-efficacy was more significant than Resisting Relapse for both physical function and functional exercise capacity. Interventions to promote achievement of physical activity need to use multiple measurement strategies.

BACKGROUND: Objective of this study is to determine if there were differences between the subjective and objective assessments of physical activity while controlling for sociodemographic, anthropometric, and clinical characteristics. A total of 810 participants across eight sites located in three countries. Both univariate and multivariant analyses were used.

DETAILS: Subjective instruments were the two subscales of Self-efficacy for Exercise Behaviors Scale: Making Time for Exercise and Resisting Relapse and Patient-Reported Outcomes Measurement Information System, which measured physical function. The objective measure of functional exercise capacity was the 6-minute Walk. Physical function was significantly associated with Making Time for Exercise (β = 1.76, p = .039) but not with Resisting Relapse (β = 1.16, p = .168). Age (β = -1.88, p = .001), being employed (β = 16.19, p < .001) and race (βs = 13.84–31.98, p < .001), hip–waist ratio (β = -2.18, p < .001), and comorbidities (β = 7.31, p < .001) were significant predictors of physical functioning. The model predicting physical function accounted for a large amount of variance (adjusted R2 = .938). The patterns of results predicting functional exercise capacity were similar. Making Time for Exercise self-efficacy scores significantly predicted functional exercise capacity (β = 0.14, p = .029), and Resisting Relapse scores again did not (β = -0.10, p = .120). Among the covariates, age (β = -0.16, p < .001), gender (β = -0.43, p < .001), education (β = 0.08, p = .026), and hip–waist ratio (β = 0.09, p = .034) were significant. This model did not account for much of the overall variance in the data (adjusted R2 = .081). We found a modest significant relationship between physical function and functional exercise capacity (r = 0.27).

Copyright © SAGE Publications. All rights reserved.

Source: Nokes, K. M., Sokhela, D. G., Orton, P, M., et al. (2024). Exploring the Interrelationships Between Physical Function, Functional Exercise Capacity, and Exercise Self-Efficacy in Persons Living with HIV. XXXXXXXX. 2024; 33(2-3): 165-175. Published: March, 2024. DOI: 10.1177/10547738241231626.

A Phase 3, Randomised, Controlled, Non-Inferiority Study in the Dominican Republic

[Posted 4/Mar/2024]

AUDIENCE: Infectious Disease, Pediatric

KEY FINDINGS: Two nOPV2 doses administered 1 week or 2 weeks apart from age 6 weeks to 8 weeks were safe and immunogenic. Immune responses after a 2-week interval were non-inferior to those after the standard 4-week interval, but marked responses after a 1-week interval suggest that schedules with an over 1-week interval can be used to provide flexibility to campaigns to improve coverage and hasten protection during circulating vaccine-derived poliovirus type 2 outbreaks.

BACKGROUND: The novel oral poliovirus vaccine type 2 (nOPV2) is now authorised by a WHO emergency use listing and widely distributed to interrupt outbreaks of circulating vaccine-derived poliovirus type 2. As protection of vulnerable populations, particularly young infants, could be facilitated by shorter intervals between the two recommended doses, we aimed to assess safety and non-inferiority of immunogenicity of nOPV2 in 1-week, 2-week, and 4-week schedules.

DETAILS: In this phase 3, open-label, randomised trial, healthy, full-term, infants aged 6-8 weeks from a hospital or a clinic in the Dominican Republic were randomly allocated (1:1:1 ratio) using a pre-prepared, computer-generated randomisation schedule to three groups to receive two doses of nOPV2 immunisations with a 1-week interval (group A), 2-week interval (group B), or 4-week interval (group C). The nOPV2 vaccine was given at a 0.1 mL dose and contained at least 105 50% cell culture infective dose. Neutralising antibodies against poliovirus types 1, 2, and 3 were measured before each immunisation and 4 weeks after the second dose. The primary outcome was the type 2 seroconversion rate 28 days after the second dose, and the non-inferiority margin was defined as a lower bound 95% CI of greater than -10%. Safety and reactogenicity were assessed through diary cards completed by the parent or guardian. Authors enrolled 905 infants between Dec 16, 2021, and March 28, 2022. 872 infants were included in the per-protocol analyses: 289 in group A, 293 in group B, and 290 in group C. Type 2 seroconversion rates were 87.5% (95% CI 83.2 to 91.1) in group A (253 of 289 participants), 91.8% (88.1 to 94.7) in group B (269 of 293 participants), and 95.5% (92.5 to 97.6) in group C (277 of 290 participants). Non-inferiority was shown for group B compared with group C (difference in rates -3.7; 95% CI -7.9 to 0.3), but not for group A compared with group C (-8.0; -12.7 to -3.6). 4 weeks after the second nOPV2 dose, type 2 neutralising antibodies increased in all three groups such that over 95% of each group was seroprotected against polio type 2, although final geometric mean titres tended to be highest with longer intervals between doses. Immunisation with nOPV2 was well tolerated with no causal association to vaccination of any severe or serious adverse event; one death from septic shock during the study was unrelated to the vaccine.

Copyright © Elsevier Ltd. All rights reserved.

Source: Mejia, L. R., Mendez, L. P., Bandyopadhyay, A. S., et al. (2024). Safety and Immunogenicity of Shorter Interval Schedules of the Novel Oral Poliovirus Vaccine Type 2 in Infants: A Phase 3, Randomised, Controlled, Non-Inferiority Study in the Dominican Republic. The Lancet. 2024; 24(3): 275-284. Published: March, 2024. DOI: 10.1016/S1473-3099(23)00519-4.

[Posted 6/Feb/2024]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: The study demonstrated that prior infection with HSV partly protects against HZ.

BACKGROUND: The incidence of herpes zoster (HZ) has increased in the United States concurrent with decrease in herpes simplex virus (HSV) prevalence. Authors hypothesized that lack of HSV-elicited cross-reactive immunity to varicella-zoster virus (VZV) results in an increased risk of HZ. Using specimens from the placebo arm of the Shingles Prevention Study, authors investigated whether persons who develop HZ are less likely to have prior HSV infection than persons who do not develop HZ, and whether HZ is less severe in persons with HSV than in HSV seronegative persons.

DETAILS: Authors conducted a nested case-control (1:2) study comparing the seroprevalence of HSV-1 and HSV-2 in cases (persons with polymerase chain reaction-confirmed HZ) to age-, sex-, and health-matched controls (persons without HZ). Sera from 639 study participants (213 cases and 426 controls) yielded definitive HSV antibody results and were analyzed. Overall, HSV seropositivity rate was 75%. HSV seronegativity was significantly higher in HZ cases than controls (30.5% vs 22.3%; P = .024), with a 55% higher risk of HZ in HSV seronegative than HSV seropositive participants. HSV seropositivity was associated with more severe HZ (P = .021).

Copyright © Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Harbecke, R., Oxman, M. N., Selke, S., et al. (2024). Prior Herpes Simplex Virus Infection and the Risk of Herpes Zoster. The Journal of Infectious Diseases. 2024; 229(1): 64-72. Published: January 15, 2024. DOI: 10.1093/infdis/jiad259.

A Randomized, Controlled Phase 1 Study

[Posted 22/Jan/2024]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: This first-in-human candidate HPS vaccine trial demonstrated that an ANDV DNA vaccine was safe and induced a robust, durable immune response.

BACKGROUND: Andes virus (ANDV), a rodent-borne hantavirus, causes hantavirus pulmonary syndrome (HPS). The safety and immunogenicity of a novel ANDV DNA vaccine was evaluated.

DETAILS: Phase 1, double-blind, dose-escalation trial randomly assigned 48 healthy adults to placebo or ANDV DNA vaccine delivered via needle-free jet injection. Cohorts 1 and 2 received 2 mg of DNA or placebo in a 3-dose (days 1, 29, 169) or 4-dose (days 1, 29, 57, 169) schedule, respectively. Cohorts 3 and 4 received 4 mg of DNA or placebo in the 3-dose and 4-dose schedule, respectively. Subjects were monitored for safety and neutralizing antibodies by pseudovirion neutralization assay (PsVNA₅₀) and plaque reduction neutralization test (PRNT₅₀). While 98% and 65% of subjects had at least 1 local or systemic solicited adverse event (AE), respectively, most AEs were mild or moderate; no related serious AEs were detected. Cohorts 2, 3, and 4 had higher seroconversion rates than cohort 1 and seropositivity of at least 80% by day 197, sustained through day 337. PsVNA50 geometric mean titers were highest for cohort 4 on and after day 197.

Copyright © Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Paulsen, G. C., Frenck, R., Tomashek, K. M., et al. (2024). Safety and Immunogenicity of an Andes Virus DNA Vaccine by Needle-Free Injection: A Randomized, Controlled Phase 1 Study . Journal of Infectious Diseases. 2024; 229(1): 30-38. Published: January 15, 2024. DOI: 10.1093/infdis/jiad235.