Journal of Antimicrobial Chemotherapy最新文献

Background: Data from surveillance on antibiotic resistance have shown an increasing prevalence of non-enzymatic resistance (β-lactamase-negative ampicillin-resistant) to β-lactam antibiotics among H. influenzae strains in the Czech Republic. Aminopenicillins are recommended agents for non-invasive Haemophilus influenzae infections. The phenomenon of non-enzymatic resistance to β-lactams is complicated by the fact that the phenotypic detection of PBP3 with specific amino acid substitutions (rPBP3) is challenging, since rPBP3 isolates have repeatedly been demonstrated to be split by the epidemiological cut-off values (ECOFF) for aminopenicillins defined by EUCAST.

Objectives: We sought to determine whether the penicillin disc has sufficient detection ability to predict the non-enzymatic mechanism; whether other antibiotics can be used for detection; and what is the agreement between the broth microdilution and disc diffusion methods.

Methods: We undertook susceptibility testing of selected antibiotics according to EUCAST of 153 rPBP3 strains, and sequencing of the ftsI gene to determination amino acid substitutions.

Results: For a selected set of rPBP strains: (i) the detection capability for penicillin, ampicillin, cefuroxime and amoxicillin/clavulanate was found to be 91.5%, 94.4%, 89.5% and 70.6%, respectively; (ii) the categorical agreement between the disc diffusion method and the MIC for ampicillin and cefuroxime was 71.1% and 83.8%, respectively.

Conclusions: We observed better recognition of rPBP3 strains by the ampicillin disc than by the penicillin disc. There is frequently a discrepancy in the interpretation of susceptibility results between the methods used.

Objective: To compare the rate of clinical cure and adverse effects in patients receiving definitive treatment with trimethoprim-sulfamethoxazole versus minocycline monotherapy for Stenotrophomonas maltophilia pneumonia.

Methods: A single-centre, retrospective cohort study of patients with S. maltophilia pneumonia admitted 1 March 2018-30 September 2023 was conducted comparing treatment with trimethoprim-sulfamethoxazole versus minocycline monotherapy. The primary outcome was the rate of clinical cure, defined as meeting two of the three prespecified criteria for a period of 48 hours while on definitive therapy: normalization of white blood cell count, absence of fever and hypothermia and decreased oxygen support. Secondary outcomes evaluated included time to clinical cure, infection-related and in-hospital mortality, pneumonia recurrence and incidence of adverse effects, which was a composite of acute kidney injury (AKI), hyperkalaemia and thrombocytopenia.

Results: Of 93 patients included, 48 received trimethoprim-sulfamethoxazole and 45 received minocycline. There was no difference in the primary outcome of clinical cure between the trimethoprim-sulfamethoxazole and minocycline groups (72.9% versus 66.7%, P = 0.51). S. maltophilia pneumonia recurrence was more common in the minocycline group compared to the trimethoprim-sulfamethoxazole group (35.6% versus 10.4%, P = 0.006). In-hospital mortality was higher in the trimethoprim-sulfamethoxazole group although there was no difference in infection-related in-hospital mortality (6.3% versus 2.3%, P = 0.62). The incidence of AKI, hyperkalaemia and thrombocytopenia did not differ between groups.

Conclusion: There was no difference in clinical cure rate for S. maltophilia pneumonia treatment between trimethoprim-sulfamethoxazole and minocycline monotherapy although higher rates of recurrent pneumonia were observed in patients treated with minocycline. Rates of adverse effects were similar between groups.

Background: Variations in neonatal aciclovir prescribing for suspected herpes simplex virus (HSV) disease are well-known, but there are limited data describing aciclovir prescribing in older children.

Methods: Medical records of neonates (≤28 days) and children (29 days to 18 years) prescribed intravenous aciclovir for suspected HSV disease (1 January 2019-12 December 2019) in eight Australian and New Zealand hospitals were reviewed. Prescribing indication, HSV testing, aciclovir prescription details, adverse events and discharge diagnosis were recorded.

Results: 1426 received empirical aciclovir. For neonates (n = 425), the median duration was 1 day (IQR 1-3), 411/425 underwent HSV investigations and 13/425 had HSV disease (two with disseminated encephalitis, four with encephalitis and seven with skin, eye, mouth disease). Of the 1001 children, 906 were immunocompetent. 136/906 suspected of mucocutaneous disease received aciclovir for a median of 2 days (1-2), 121/136 underwent HSV testing, and 69/136 had proven disease. 770/906 received aciclovir for suspected disseminated disease or encephalitis for a median of 1 day (1-2), 556/770 underwent HSV testing, and 5/770 had disseminated disease or encephalitis. Among 95 immunocompromised children, 53/58 with suspected mucocutaneous disease had HSV testing and this was confirmed in 22. Disseminated disease or encephalitis was suspected in 37/95, HSV testing conducted in 23/37 and detected in one. The median aciclovir duration was 3 (2-7) days for immunocompromised children. Nephrotoxicity occurred in 7/1426 and 24/1426 had an extravasation injury.

Conclusion: Frequent and often unnecessary intravenous aciclovir prescribing for suspected HSV encephalitis or disseminated disease occurred in children, as evidenced by incomplete HSV investigations and only 5/770 older children having the diagnosis confirmed.

Background: Virological failures of first-line second-generation (SG) INSTI-based regimens are rare, usually characterized by low viremia and absence of drug resistance mutations.

Objectives: To explore the efficacy of rescue regimens introduced after virological failure (VF) to a first-line SG-INSTI therapy.

Patients and methods: This was a retrospective study on people living with HIV (PWH) failing a first-line SG-INSTI regimen [DTG/3TC, BIC/FTC/TAF, DTG-based three-drug regimen (DTG-3DR)] between 24 March 2016 and 31 December 2021. Follow-up accrued from the second viral load (VL) ≥ 50 copies/mL under SG-INSTI regimen (baseline) until virological success (VS, achievement of at least one VL < 50 copies/mL after baseline) or last visit. Cumulative probabilities of VS were estimated by Kaplan-Meier curves and compared using a log-rank test.

Results: Overall, of 521 naïve PWH who started a first-line SG-INSTI regimen, 45 (8.6%) had VF after a median of 14.9 (IQR = 6.9-25.9) months: 33/395 (8.4%) individuals failed a DTG-3DR, 11/102 (10.8%) a BIC/FTC/TAF and 1/24 (4.2%) failed a DTG/3TC.At baseline, 12/45 (27%) PWH changed antiretroviral therapy [median baseline VL 134 (IQR = 81-233) copies/mL], while 33 (73%) maintained their failing regimen [median baseline VL 75 (IQR = 60-145) copies/mL].During a median follow-up of 5.13 (IQR = 3.8-7.1) months, 34 (75.6%) PWH achieved VS: 25/33 (75.8%) maintaining their failing regimen, 9/12 (75%) switched regimen; the estimated 6- and 12-months probabilities of VS were 59% and 84%, respectively.There was no difference in VS curves between PWH who maintained their failing regimen and those who switched therapy.

Conclusions: Most individuals remained on their failing regimen, achieving spontaneous virological suppression in most cases. These data help to understand a real-life VF scenario in the context of the current SG-INSTI era.

Objectives: This study aimed to assess the frequency of co-resistance to antibiotics recommended in acute pyelonephritis among Escherichia coli clinical strains isolated from urinary tract infections (UTIs) acquired in community or nursing homes (NHs), and to identify situations without alternatives to fluoroquinolones (FQs).

Methods: All antimicrobial susceptibility test (AST) results of E. coli culture-positive urine samples from females living in the community or in NHs, collected through a large network of clinical laboratories in 2020 in France, were included. The percentages of strains resistant to amoxicillin alone or combined with a resistance to one to four alternatives among amoxicillin/clavulanic acid, trimethoprim/sulfamethoxazole, cefixime and FQs were calculated and compared between age categories and settings.

Results: Among 291 367 E. coli strains from community-acquired UTIs, 60.3% were susceptible to amoxicillin (<65-year-olds: 61.8% versus ≥65-year-olds: 58.8%; P < 0.001), and 99.1% to oral alternatives to FQs. Co-resistance to amoxicillin and trimethoprim/sulfamethoxazole was higher among females ≥65 years old versus <65 years old (7.1% versus 6.1%; P < 0.01), as well as co-resistance to amoxicillin, amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole (8.6% versus 10%; P < 0.001). Among 11 340 strains from NH UTIs, 51.2% were susceptible to amoxicillin, and 98% to oral alternatives to FQs. Co-resistance to amoxicillin, amoxicillin/clavulanic acid and/or cefixime was higher in isolates from females ≥65 years old living in NHs versus in the community (respectively 11.9% versus 15.3%, P < 0.001; 0.8% versus 2.8%, P < 0.01; 1.7% versus 4.4%, P < 0.01).

Conclusions: Based on AST results, prescribing oral alternatives to FQs for females may be possible in ≥99% of E. coli acute pyelonephritis cases in the community, and ≥98% in NHs.

Background: Empiric antibiotics active against Pseudomonas aeruginosa are recommended by professional societies for certain infections and are commonly prescribed for hospitalized patients. The effect of this practice on mortality is uncertain.

Methods: A systematic literature search was conducted using Embase, Medline, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from earliest entry through 9 October 2023. We included studies of patients hospitalized with P. aeruginosa infections that compared mortality rates depending on whether patients received active empiric antibiotics.

Results: We found 27 studies of 12 522 patients that reported adjusted OR of active empiric antibiotics on mortality. The pooled adjusted OR was 0.40 (95% CI, 0.32-0.50), favouring active empiric antibiotics. In practice, the mortality effect of empiric antibiotics against P. aeruginosa depends on the prevalence of P. aeruginosa and baseline mortality. The estimated absolute mortality benefit was 0.02% (95% CI, 0.02-0.02) for soft tissue infections, 0.12% (95% CI, 0.10-0.13) for urinary tract infections and community-acquired pneumonia, 0.3% (0.25-0.34) for sepsis without shock, 1.1% (95% CI, 0.9-1.4) for septic shock and 2.4% (95% CI, 1.9-2.8) for nosocomial pneumonia.

Conclusions: The mortality effect for empiric antibiotics against P. aeruginosa depends crucially on the prevalence of P. aeruginosa and baseline mortality by type of infection. For soft tissue infections, urinary tract infections and community-acquired pneumonia, the mortality benefit is low. Meaningful benefit of empiric antibiotics against P. aeruginosa is limited to patients with approximately 30% mortality and 5% prevalence of P. aeruginosa, which is largely limited to patients in intensive care settings.

Background: Itraconazole is the treatment of choice for many fungal infections, including histoplasmosis. While the tolerability of itraconazole has been described in short-term trial settings, there are few studies on side effects during long-term therapy. Fluconazole, which is usually thought to be less toxic, is associated with 52% toxicity in long-term treatment.

Objectives: To determine the frequency, types, and timing of side effects from itraconazole therapy, the resulting changes to treatment plans, and associations between patient characteristics and itraconazole serum levels with side effect status.

Methods: We conducted a single-centre, retrospective study of adult patients with histoplasmosis receiving itraconazole therapy for at least 28 days from 2002 to 2021. Reported side effects were characterized, and propensity score matching was used to compare itraconazole serum levels between patients with and without side effects.

Results: Sixty-three out of 227 (27.8%) patients experienced at least one side effect, the most common of which were hepatotoxicity (7.0%), nausea/vomiting (6.6%), and diarrhoea (6.2%). 12 (19.0%) patients with side effects underwent an itraconazole dose reduction and 29 (46.0%) had itraconazole discontinued. The median time to side effect was 45 days. Median itraconazole serum levels were significantly higher among patients with side effects than in a propensity score-matched population without side effects (2.9 versus 1.8 mcg/mL, P = 0.009).

Conclusions: Side effects were experienced by approximately one-quarter of patients with histoplasmosis receiving long-term itraconazole therapy. About two-thirds of these patients had a therapeutic intervention. Itraconazole resulted in a lower frequency of side effects than fluconazole, as measured in other studies.

Objective: To determine the epidemiological cut-off (ECOFF) values of etimicin against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii and Staphylococcus aureus.

Methods: We selected 1500 isolates from five hospitals throughout five cities in China spanning from January 2018 to December 2021 in the study. Minimal inhibit concentrations (MICs) of etimicin were determined using the broth microdilution method. ECOFFs of etimicin against six species were calculated using ECOFFinder software and visual estimation following EUCAST principles.

Results: MICs of etimicin were distributed from 0.064 to >128 mg/L for S. aureus, from 0.125 to >128 mg/L for P. aeruginosa, from 0.25 to >128 mg/L for K. pneumoniae, P. mirabilis and A. baumannii, and from 0.5 to >128 mg/L for E. coli. The MIC ECOFF of etimicin was 2 mg/L for K. pneumoniae, 8 mg/L for E. coli and P. mirabilis, 16 mg/L for P. aeruginosa and A. baumannii, and the tentative ECOFF (TECOFF) of etimicin was 2 mg/L for S. aureus.

Conclusions: (T)ECOFFs of etimicin against E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, A. baumannii and S. aureus were determined, which will be helpful to differentiate wild-type strains.

Background: Bovine mastitis is the costliest disease in the dairy sector and the main cause of antibiotic use in dairy cattle, potentially contributing to the antimicrobial resistance crisis. Antimicrobial peptides (AMPs) offer promise as antibiotic alternatives for controlling mastitis pathogens.

Methods: The efficacy of five AMPs (Lynronne-1 [Lyn-1], Lynronne-2 [Lyn-2], Bovicin HC5, AMP 660, and AMP 1043) and two bioactive compounds (disodium ethylenediaminetetraacetic acid [EDTA] and glycerol monolaurate) was assessed against a range of 35 mastitis-causing pathogens. The fractional inhibitory concentrations index (FICI) was calculated to determine the interaction effect and values ≤0.5 were indicative of synergism. Time-dependent killing assays were performed to assess bactericidal efficacy of the combination. Cytotoxicity was evaluated using the MTT assay and haemolytic activity was assessed against fresh bovine erythrocytes.

Results: Lyn-1 and EDTA exhibited the highest broad spectrum antimicrobial activity and reduced bacterial growth (OD600 nm) by 95.1% and 86.9%, respectively. FICI values ranged from 0.1 to 0.5, indicating synergism. The combination of lyn-1 (0.03 mg/mL) and EDTA (1.02 mg/mL) exhibited higher antimicrobial activity against all bacterial strains, at significantly lower concentrations than each compound individually. Lyn-1-EDTA combination reduced viable population by >10 000-fold within 12 h. The combination was non-haemolytic in concentrations up to 8-fold the established MIC values (P > 0.05), although cytotoxic effects were observed at concentrations above MIC (P < 0.01).

Conclusions: These findings highlight the therapeutic potential of Lyn-1 and Lyn-1-EDTA for developing antibiotic-free formulations to combat contagious and environmental mastitis pathogens and treat udder infections.

Background: The lengthy duration and high frequency of drug resistance associated with currently used antimycobacterial drug treatments have intensified the need for alternative therapies against Mycobacterium tuberculosis, the causative agent of TB.

Methods: MICs and intracellular macrophage cfu counts were tested to evaluate the antibacterial activity of nintedanib and pirfenidone against drug-susceptible and -resistant M. tuberculosis. A chronic murine model of pulmonary infection was used to assay the therapeutic efficacy of nintedanib. Macrophage transcriptome deep sequencing, a confocal assay, siRNA knockdown, Western blotting, quantitative RT-PCR and a cfu assay were used to investigate the antibacterial mechanism of nintedanib.

Results: The MIC90 of nintedanib against M. tuberculosis standard strain H37Rv was 23.56-40.51 mg/L. TB murine model studies showed that nintedanib, coadministered with isoniazid, rifampicin and pyrazinamide, shortened treatment duration, and ameliorated pulmonary inflammation and fibrosis. In mechanism studies, transcriptome sequencing analysis revealed that nintedanib may eliminate M. tuberculosis through up-regulating macrophage autophagy. Furthermore, inhibition of autophagy by using siRNA targeting ATG5 or the autophagy inhibitor 3-methyladenine almost completely abolished nintedanib-mediated suppression of M. tuberculosis. Nintedanib induced autophagy by the JAK2/STAT3/Beclin1 pathway. When JAK2 or Beclin1 were knocked down through siRNA, nintedanib no longer inhibited M. tuberculosis. JAK2 activator coumermycin A1 and STAT3 agonist colivelin also reversed this phenotype.

Conclusions: In vitro activity of nintedanib against drug-susceptible and -resistant M. tuberculosis and efficacy in murine infections warrant the continued clinical evaluation of nintedanib as a new adjuvant therapy for standard treatment of TB.