An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus an aminoglycoside + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial-an update to the published protocol.

This article reports an update to the protocol of the IMASOY trial, which was prospectively registered on clinicaltrials.gov (NCT04110340) in October 2019.

Therapeutic targeting of TP53 nonsense mutations in cancer.

Mutations in the TP53 tumor suppressor gene occur with high prevalence in a wide range of human tumors. A significant fraction of these mutations (around 10%) are nonsense mutations, creating a premature termination codon (PTC) that leads to the expression of truncated inactive p53 protein. Induction of translational readthrough across a PTC in nonsense mutant TP53 allows the production of full-length protein and potentially restoration of normal p53 function. Aminoglycoside antibiotics and a number of novel compounds have been shown to induce full-length p53 in tumor cells carrying various TP53 nonsense mutations. Full-length p53 protein generated by translational readthrough retains the capacity to transactivate p53 target genes and trigger tumor cell death. These findings raise hopes for efficient therapy of TP53 nonsense mutant tumors in the future.

Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study.

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models.

BACKGROUND: The aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed. METHODS: The resistance gene annotations of 40 888 blood-culture isolates were analysed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for a total of nine Escherichia coli and Klebsiella pneumoniae isolates. RESULTS: Genotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10-9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia. CONCLUSION: Encouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI.

Prospective evaluation of single-dose aminoglycosides for treatment of complicated cystitis in the emergency department.

BACKGROUND: Antimicrobial resistance among Enterobacterales continues to be a growing problem, particularly in those with urinary infections. Previous studies have demonstrated safety and efficacy with the use of single-dose aminoglycosides in uncomplicated cystitis. However, data in complicated infections are limited. Single-dose aminoglycosides may provide a convenient alternative for those with or at risk for resistant pathogens causing complicated urinary infections, especially when oral options are unavailable due to resistance, allergy, intolerance, or interactions with other medications. This study evaluated the safety and effectiveness of single-dose aminoglycosides in treatment of complicated cystitis in the emergency department (ED). METHODS: This was a multicenter, prospective study performed between July 2022 and March 2023 of patients who met criteria for complicated cystitis and were otherwise stable for discharge at an academic ED. Primary outcomes were clinical or microbiologic failure within 14 days of treatment. Safety was assessed by review of adverse events. Descriptive statistics were used. RESULTS: Thirteen patients were included. Complicating factors were male sex (n = 4), kidney stone (n = 2), urinary catheter (n = 6), recent urologic procedure (n = 1), urinary hardware (n = 1), antibiotic allergy precluding use of alternate oral options (n = 4), immunocompromised status (n = 2), and <1-year history of multidrug-resistant organisms on urine culture (n = 8). Eleven patients (85%) had positive urine cultures in the preceding 12 months with no oral antimicrobial option. Eight patients (62%) received amikacin (median dose 15 mg/kg), four patients (31%) received gentamicin (median dose 5 mg/kg), and one patient (8%) received tobramycin (5 mg/kg) for treatment. Ten patients (77%) reported resolved urinary symptoms after treatment and 11 patients (85%) reported no new urinary symptoms since discharge. No patient required hospital admission for treatment failure, and no adverse events were noted. CONCLUSIONS: Single-dose aminoglycosides appear to be a reasonably effective and safe treatment for complicated cystitis, which avoided hospital admission in this cohort.

A comparison of aminoglycoside antibiotic serum concentrations collected by peripheral veins and peripherally inserted central catheters in adults with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) are frequently hospitalized for treatment of pulmonary exacerbation. The Cystic Fibrosis Foundation Pulmonary Guidelines support the use of intravenous aminoglycosides with therapeutic drug monitoring for the treatment of pulmonary exacerbation due to Pseudomonas aeruginosa. Serum intravenous tobramycin concentrations are commonly collected by peripheral venipuncture (PV). Discomfort associated with collection of samples by PV prompts collection via PICC, but the accuracy of intravenous tobramycin serum levels collected by PICC has not been documented in adult PwCF. The primary study objective was to evaluate the difference between intravenous tobramycin serum levels collected by PV and PICC in adult PwCF. METHODS: The authors conducted a prospective case-control study of adult PwCF admitted to University of Utah Health for a pulmonary exacerbation receiving tobramycin by a single lumen PICC. The authors compared tobramycin peak and random serum levels collected by PV and PICC using a detailed flush and waste protocol. RESULTS: The authors analyzed a total of 19 patients with peripheral and PICC samples. The mean tobramycin peak collected by PV (27.2 mcg/mL) was similar to the mean peak collected by PICC (26.9 mcg/mL) (paired samples Wilcoxon signed-rank test, p = .94). The correlation coefficient was 0.88 (95% CI = 0.85-0.91, p < .001). CONCLUSION: Tobramycin serum samples collected by PICC appear to be similar in value to PV collections. Collecting aminoglycoside levels by PICC rather than PV may reduce patient discomfort and improve quality of life. Additional multicenter studies are needed to confirm these results.

Addition of single dose gemtuzumab ozogamicin to intensive induction chemotherapy in core-binding factor acute myeloid leukemia.

In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). Given the heterogeneous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We conducted a single-center retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with or without a single dose of GO 3 mg/m2, during induction only. We included 87 patients (GO=32, control=55). The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p<0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups. There were no significant differences between the two groups in terms of toxicity. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9).In multivariable analysis, age and MRD positive status were risk factors for inferior outcomes. We find that survival of patients with CBF-AML is favorable in the real-world setting. The addition of single-dose GO, during induction, did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.

Stop codon readthrough as a treatment option for epidermolysis bullosa-Where we are and where we are going.

In the context of rare genetic diseases caused by nonsense mutations, the concept of induced stop codon readthrough (SCR) represents an attractive avenue in the ongoing search for improved treatment options. Epidermolysis bullosa (EB)-exemplary for this group of diseases-describes a diverse group of rare, blistering genodermatoses. Characterized by extreme skin fragility upon minor mechanical trauma, the most severe forms often result from nonsense mutations that lead to premature translation termination and loss of function of essential proteins at the dermo-epidermal junction. Since no curative interventions are currently available, medical care is mainly limited to alleviating symptoms and preventing complications. Complementary to attempts of gene, cell and protein therapy in EB, SCR represents a promising medical alternative. While gentamicin has already been examined in several clinical trials involving EB, other potent SCR inducers, such as ataluren, may also show promise in treating the hitherto non-curative disease. In addition to the extensively studied aminoglycosides and their derivatives, several other substance classes-non-aminoglycoside antibiotics and non-aminoglycoside compounds-are currently under investigation. The extensive data gathered in numerous in vitro experiments and the perspectives they reveal in the clinical setting will be discussed in this review.

Gentamicin should remain part of the empirical sepsis regimen for adults. / Gentamicin bør fortsatt inngå i empirisk sepsisregime hos voksne.

In the Norwegian guidelines, the combination of a narrow-spectrum beta-lactam antibiotic and aminoglycoside should remain the first choice for empirical antibiotic therapy for the majority of severe infections.

Systematic Review: Clinical Features, Antimicrobial Treatment, and Outcomes of Human Tularemia, 1993-2023.

BACKGROUND: Francisella tularensis, the causative agent of tularemia, is endemic throughout the Northern Hemisphere and requires as few as 10 organisms to cause disease, making this potential bioterrorism agent one of the most infectious bacterial pathogens known. Aminoglycosides, tetracyclines, and, more recently, fluoroquinolones are used for treatment of tularemia; however, data on the relative effectiveness of these and other antimicrobial classes are limited. METHODS: Nine databases, including Medline, Global Health, and Embase, were systematically searched for articles containing terms related to tularemia. Articles with case-level data on tularemia diagnosis, antimicrobial treatment, and patient outcome were included. Patient demographics, clinical findings, antimicrobial administration, and outcome (eg, intubation, fatality) were abstracted using a standardized form. RESULTS: Of the 8878 publications identified and screened, 410 articles describing 870 cases from 1993 to 2023 met inclusion criteria. Cases were reported from 35 countries; more than half were from the United States, Turkey, or Spain. The most common clinical forms were ulceroglandular, oropharyngeal, glandular, and pneumonic disease. Among patients treated with aminoglycosides (n = 452 [52%]), fluoroquinolones (n = 339 [39%]), or tetracyclines (n = 419 [48%]), the fatality rate was 0.7%, 0.9%, and 1.2%, respectively. Patients with pneumonic disease who received ciprofloxacin had no fatalities and the lowest rates of thoracentesis/pleural effusion drainage and intubation compared to those who received aminoglycosides and tetracyclines. CONCLUSIONS: Aminoglycosides, fluoroquinolones, and tetracyclines are effective antimicrobials for treatment of tularemia, regardless of clinical manifestation. For pneumonic disease specifically, ciprofloxacin may have slight advantages compared to other antimicrobials.

Tularemia Clinical Manifestations, Antimicrobial Treatment, and Outcomes: An Analysis of US Surveillance Data, 2006-2021.

BACKGROUND: Tularemia, a potentially fatal zoonosis caused by Francisella tularensis, has been reported from nearly all US states. Information on relative effectiveness of various antimicrobials for treatment of tularemia is limited, particularly for newer classes such as fluoroquinolones. METHODS: Data on clinical manifestations, antimicrobial treatment, and illness outcome of patients with tularemia are provided voluntarily through case report forms to the US Centers for Disease Control and Prevention by state and local health departments. We summarized available demographic and clinical information submitted during 2006-2021 and evaluated survival according to antimicrobial treatment. We grouped administered antimicrobials into those considered effective for treatment of tularemia (aminoglycosides, fluoroquinolones, and tetracyclines) and those with limited efficacy. Logistic regression models with a bias-reduced estimation method were used to evaluate associations between antimicrobial treatment and survival. RESULTS: Case report forms were available for 1163 US patients with tularemia. Francisella tularensis was cultured from a clinical specimen (eg, blood, pleural fluid) in approximately half of patients (592; 50.9%). Nearly three-quarters (853; 73.3%) of patients were treated with a high-efficacy antimicrobial. A total of 27 patients (2.3%) died. After controlling for positive culture as a proxy for illness severity, use of aminoglycosides, fluoroquinolones, and tetracyclines was independently associated with increased odds of survival. CONCLUSIONS: Most US patients with tularemia received high-efficacy antimicrobials; their use was associated with improved odds of survival regardless of antimicrobial class. Our findings provide supportive evidence that fluoroquinolones are an effective option for treatment of tularemia.

Neuroinvasive Francisella tularensis Infection: Report of 2 Cases and Review of the Literature.

BACKGROUND: Neuroinvasive infection with Francisella tularensis, the causative agent of tularemia, is rare. Establishing clinical suspicion is challenging if risk factors or clinical features classically associated with tularemia are absent. Tularemia is treatable with antibiotics; however, there are limited data to inform management of potentially fatal neuroinvasive infection. METHODS: We collected epidemiologic and clinical data on 2 recent US cases of neuroinvasive F. tularensis infection, and performed a literature review of cases of neuroinvasive F. tularensis infection published after 1950. RESULTS: One patient presented with focal neurologic deficits and brain lesions; broad-range molecular testing on resected brain tissue detected F. tularensis. The other patient presented with meningeal signs; tularemia was suspected based on animal exposure, and F. tularensis grew in cerebrospinal fluid (CSF) culture. Both patients received combination antibiotic therapy and recovered from infection. Among 16 published cases, tularemia was clinically suspected in 4 cases. CSF often displayed lymphocytic pleocytosis. Among cases with available data, CSF culture was positive in 13 of 16 cases, and F. tularensis antibodies were detected in 11 of 11 cases. Treatment typically included an aminoglycoside combined with either a tetracycline or a fluoroquinolone. Outcomes were generally favorable. CONCLUSIONS: Clinicians should consider neuroinvasive F. tularensis infection in patients with meningitis and signs suggestive of tularemia or compatible exposures, lymphocyte-predominant CSF, unrevealing standard microbiologic workup, or lack of response to empiric bacterial meningitis treatment. Molecular testing, culture, and serologic testing can reveal the diagnosis. Favorable outcomes can be achieved with directed antibiotic treatment.

Prognosis of prosthetic valve infective endocarditis due to Streptococcus spp., a retrospective multi-site study to assess the impact of antibiotic treatment duration.

PURPOSE: The duration of antibiotic treatment for prosthetic valve endocarditis caused by Streptococcus spp. is largely based on clinical observations and expert opinion rather than empirical studies. Here we assess the impact of a shorter antibiotic duration. OBJECTIVES: To assess the impact of antibiotic treatment duration for streptococcal prosthetic valve endocarditis on 12-month mortality as well as subsequent morbidity resulting in additional cardiac surgical interventions, and rates of relapse and reinfection. METHODS: This retrospective multisite (N= 3) study examines two decades of data on patients with streptococcal prosthetic valve endocarditis receiving either 4 or 6 weeks of antibiotics. Overall mortality, relapse, and reinfection rates were also assessed for the entire available follow-up period. RESULTS: The sample includes 121 patients (median age 72 years, IQR [53; 81]). The majority (74%, 89/121) received a ß-lactam antibiotic combined with aminoglycoside in 74% (89/121, median bi-therapy 5 days [1; 14]). Twenty-eight patients underwent surgery guided by ESC-guidelines (23%). The 12-month mortality rate was not significantly affected by antibiotic duration (4/40, 10% in the 4-week group vs 3/81, 3.7% in the 6-week group, p=0.34) or aminoglycoside usage (p=0.1). Similarly, there were no significant differences between the 2 treatment groups for secondary surgical procedures (7/40 vs 21/81, p=0.42), relapse or reinfection (1/40 vs 2/81 and 2/40 vs 5/81 respectively). CONCLUSIONS: Our study found no increased adverse outcomes associated with a 4-week antibiotic duration compared to the recommended 6-week regimen. Further randomized trials are needed to ascertain the optimal duration of treatment for streptococcal endocarditis.

An Open-Label, Randomized Trial Comparing Fidaxomicin With Oral Vancomycin for the Treatment of Clostridioides difficile Infection in Hospitalized Patients Receiving Concomitant Antibiotics for Concurrent Infections.

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode. METHODS: We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile, and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin. RESULTS: Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P = .195) and rCDI (3.3% vs 4.0%; P > .99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI. CONCLUSIONS: In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov (NCT02692651).

Aminoglycoside uptake, stress, and potentiation in Gram-negative bacteria: new therapies with old molecules.

SUMMARYAminoglycosides (AGs) are long-known molecules successfully used against Gram-negative pathogens. While their use declined with the discovery of new antibiotics, they are now classified as critically important molecules because of their effectiveness against multidrug-resistant bacteria. While they can efficiently cross the Gram-negative envelope, the mechanism of AG entry is still incompletely understood, although this comprehension is essential for the development of new therapies in the face of the alarming increase in antibiotic resistance. Increasing antibiotic uptake in bacteria is one strategy to enhance effective treatments. This review aims, first, to consolidate old and recent knowledge about AG uptake; second, to explore the connection between AG-dependent bacterial stress and drug uptake; and finally, to present new strategies of potentiation of AG uptake for more efficient antibiotic therapies. In particular, we emphasize on the connection between sugar transport and AG potentiation.

Impact of the national shortage of polymyxin B in critically ill patients during the COVID-19 pandemic / Impacto da escassez nacional de polimixina B em pacientes gravemente enfermos durante a pandemia de COVID-19 / Impacto del desabasto nacional de polimixina B en pacientes críticos durante la pandemia de COVID-19

Background and Objectives: during the COVID-19 pandemic, the number of critical patients requiring intensive care increased considerably, resulting in an increase in infections due to multi-resistant microorganisms. In Brazil, in 2021, due to the high demand for polymyxin B use, there was a national shortage of the medication. One strategy used to overcome this situation was aminoglycoside use. The work aimed to analyze the impact of replacing polymyxin B with amikacin and gentamicin in the final stage of patients. Method: an analytical study with an observational, cross-sectional design, with a quantitative approach, through a retrospective analysis through the analysis of medical records, with the primary stages being discharges or deaths. Results: mortality was similar between the group treated with aminoglycoside and the group treated with polymyxin B. Within the aminoglycoside group, mortality was higher in the group that had bacteria resistant to the drug than in the group that had infection with an organism sensitive to this drug. Mortality was not affected by comorbidities, age, or number of hospital infections. The main factor that led to the need for dialysis was the combination of two nephrotoxic medications. Conclusion: two hypotheses emerged: the first would be that replacing polymyxin B with aminoglycosides did not impact mortality; the other would be that, regardless of the antibiotic group used, patients had a high risk of death. Despite sample limitations, the study corroborates the adoption of strategies for the rational use of antimicrobials.(AU)

Justificativa e Objetivos: durante a pandemia de COVID-19, o número de pacientes críticos que necessitaram de cuidados intensivos aumentou consideravelmente, resultando em aumento de infecções por microrganismos multirresistentes. No Brasil, em 2021, devido à grande demanda pelo uso da polimixina B, houve escassez nacional do medicamento. Uma estratégia utilizada para superar essa situação foi o uso de aminoglicosídeos. O trabalho teve como objetivo analisar o impacto da substituição da polimixina B por amicacina e gentamicina na fase final dos pacientes. Método: estudo analítico com desenho observacional, transversal, com abordagem quantitativa, por meio de análise retrospectiva por meio de análise de prontuários, sendo as etapas primárias as altas ou óbitos. Resultados: a mortalidade foi semelhante entre o grupo tratado com aminoglicosídeo e o grupo tratado com polimixina B. Dentro do grupo aminoglicosídeo, a mortalidade foi maior no grupo que apresentava bactérias resistentes ao medicamento do que no grupo que apresentava infecção por organismo sensível a este medicamento. medicamento. A mortalidade não foi afetada por comorbidades, idade ou número de infecções hospitalares. O principal fator que levou à necessidade de diálise foi a combinação de dois medicamentos nefrotóxicos. Conclusão: surgiram duas hipóteses: a primeira seria que a substituição da polimixina B por aminoglicosídeos não impactou a mortalidade; a outra seria que, independentemente do grupo de antibióticos utilizado, os pacientes apresentavam alto risco de morte. Apesar das limitações amostrais, o estudo corrobora a adoção de estratégias para o uso racional de antimicrobianos.(AU)

Antecedentes y Objetivos: durante la pandemia de COVID-19, el número de pacientes críticos que requirieron cuidados intensivos aumentó considerablemente, resultando en un aumento de infecciones por microorganismos multirresistentes. En Brasil, en 2021, debido a la alta demanda del uso de polimixina B, hubo escasez nacional del medicamento. Una estrategia utilizada para superar esta situación fue el uso de aminoglucósidos. El trabajo tuvo como objetivo analizar el impacto de la sustitución de la polimixina B por amikacina y gentamicina en la etapa final de los pacientes. Método: estudio analítico con diseño observacional, transversal, con enfoque cuantitativo, mediante un análisis retrospectivo mediante el análisis de historias clínicas, siendo las etapas primarias las altas o defunciones. Resultados: la mortalidad fue similar entre el grupo tratado con aminoglucósido y el grupo tratado con polimixina B. Dentro del grupo de aminoglucósido, la mortalidad fue mayor en el grupo que tenía bacterias resistentes al fármaco que en el grupo que tenía infección con un organismo sensible a este. droga. La mortalidad no se vio afectada por las comorbilidades, la edad o el número de infecciones hospitalarias. El principal factor que llevó a la necesidad de diálisis fue la combinación de dos medicamentos nefrotóxicos. Conclusión: surgieron dos hipótesis: la primera sería que la sustitución de polimixina B por aminoglucósidos no impactó la mortalidad; la otra sería que, independientemente del grupo de antibióticos utilizado, los pacientes tenían un alto riesgo de muerte. A pesar de las limitaciones de la muestra, el estudio corrobora la adopción de estrategias para el uso racional de antimicrobianos.(AU)