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)

Bacterial keratitis in a tertiary hospital in São Paulo: a 21-year review of the epidemiological, laboratory, and clinical data.

Infectious keratitis is a sight-threatening condition that is usually an ocular emergency. The visual outcome depends on prompt and accurate clinical management as well as geographic and epidemiological awareness. We conducted a retrospective observational study to define the epidemiological and laboratory profile, as well as the clinical course of bacterial keratitis in a tertiary hospital in São Paulo over 21 years. Information about age, sex, predisposing factors, topical and surgical treatment, visual acuity, ulcers' classification, bacterioscopy, culture, and antibiotic sensitivity tests were collected. This study included 160 patients. The mean age was 65.1 ± 18.4 years and risk factors were identified in 83.1 % of the patients. Empirical topical fortified cephalosporin with an aminoglycoside or fourth-generation fluoroquinolone was curative for 66.2 % of the cases. The mean treatment duration was 22.5 ± 9 days. The mean variation of visual acuity was -0.25 logMAR, p < 0.001. Culture revealed 64 % of Gram-positive bacteria. All Gram-positive bacteria were sensitive to cephalothin, vancomycin, and quinolones. All Gram-negative bacteria were sensitive to gentamicin, tobramycin, amikacin, and ciprofloxacin. These findings reinforce the importance of prompt empirical treatment of severe corneal ulcers with a fortified cephalosporin and aminoglycoside or a fourth-generation fluoroquinolone as there are equally effective. Collected data was insufficient to evaluate resistance of ocular infections over time in this population.

[In vitro Activity of Rifabutin and Clofazimine to Macrolide-Resistant Mycobacterium abscessus Complex Clinical Isolates]. / Rifabutin ve Klofaziminin Makrolidlere Dirençli Mycobacterium abscessus Kompleks Klinik Izolatlarina In vitro Etkinligi.

Mycobacterium abscessus complex (MABSC) is one of the most resistant bacteria against antimicrobial agents. The number of agents that can be used by oral route, such as macrolides, is limited in antimicrobial therapy. In recent years, rifabutin and clofazimine have gained importance as they can be administered by oral route and have shown synergistic effects with macrolides and aminoglycosides. The aim of this study was to determine the in vitro activity of rifabutin and clofazimine against clinical isolates of MABSC resistant to macrolides. A total of 48 MABSC isolates obtained from respiratory tract and other clinical samples in the Tuberculosis Laboratories of the Faculty of Medicine of Manisa Celal Bayar and Ege Universities were included in the study. Subspecies differentiation and aminoglycoside and macrolide resistance of the isolates were determined by GenoType NTM-DR test. Rifabutin and clofazimine susceptibilities were determined by standard broth microdilution method. Of the MABSC isolates 42 were identified as M.abscessus subsp. abscessus, three as M.abscessus subsp. bolletii and three as M.abscessus subsp. massiliense. None of the isolates exhibited rrs and rrl mutations indicating acquired macrolide resistance and aminoglycoside resistance. However, the erm(41) T28 genotype which is associated with inducible macrolide resistance was detected in 41 (85%) of the strains. All M.abscessus subsp. massiliense isolates were found to be genotypically susceptible to macrolides. The minimum inhibitory concentration (MIC) range values for rifabutin were 0.0625 to 32 µg/mL, while for clofazimine, the range was 0.0625 to 1 µg/mL. Rifabutin MIC values were significantly higher (mean 5.98 µg/mL vs 0.5 µg/mL, p= 0.026) in the isolates with macrolide resistance. There was no correlation between macrolide resistance and clofazimine MIC values (mean 0.25 µg/mL vs. 0.214 µg/mL, p= 0.758). The MIC50 and MIC90 values for rifabutin were 1 and 8 µg/mL, respectively, while for clofazimine they were 0.25 and 0.5 µg/mL. Macrolide resistance was found to be higher in isolates with rifabutin MIC values above the MIC50 value (p= 0.045). In conclusion, the determination of higher rifabutin MIC values in isolates resistant to macrolides suggested that susceptibility testing should be performed before adding rifabutin to the treatment regimen. The low MIC values of clofazimine in all strains indicated that it may be used as a first choice in the combination therapy. However, further studies using a larger number of clinical isolates and applying genotypic and phenotypic susceptibility tests are needed to determine threshold MIC values to assist clinicians in making treatment decisions.

Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies.

BACKGROUND: Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures. METHODS: A systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023. RESULTS: 26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low. CONCLUSION: Animal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.

Self-application of aminoglycoside-based creams to treat cutaneous leishmaniasis in travelers.

BACKGROUND: In endemic foci, the use of an aquaphilic cream containing paromomycin with/without gentamicin to treat cutaneous leishmaniasis (CL) is safe, painless and cures 78-82% of patients with New and Old World CL. Self-application in travelers requires evaluation. METHODS: Travelers with 1-10 lesions of confirmed CL were prospectively treated with the paromomycin-gentamicin formulation (WR279396, 2012-2017, Group 1) and carefully follow up, or treated with a locally produced paromomycin-only cream (2018-2022, Group 2). The cream was applied once under supervision, then self-applied daily for 20-30 days. A cured lesion was defined as 100% re-epithelialization at day 42 without relapse at three months. RESULTS: Medical features were similar in Group 1 (17 patients), and Group 2 (23 patients). Patients were infected with either Leishmania major, L. infantum, L. killicki, L. guyanensis, L. braziliensis, or L. naiffi. Intention-to-treat and per-protocol cure rates were 82% (95% confidence interval (CI) [64.23;100.00]) and 87% (95% CI [71,29;100.00]) in Group 1, and 69% (95% CI [50.76; 88.37]) and 76% (95% CI [57.97; 94.41]) in Group 2. In the pooled Group 1&2, 75% (95% CI [61.58;88.42]) (30/40) and 81% (95% CI [68,46;93.6]) (30/37) of patients were cured in intention-to-treat and per-protocol, respectively. There were no significant differences observed in the success rates between Old World and New World CL (83.3% vs. 60%, p = 0.14). Prospective observations in Group 1 showed that adverse events were mainly pruritus (24%) and pain (18%) on lesions (all mild or moderate). No mucosal involvement was observed in either group. DISCUSSION: In this representative population of travelers who acquired CL either in the Old or New World, the 81% per-protocol cure rate of a self-applied aminoglycoside cream was similar to that observed in clinical trials.

CpxA/R-Controlled Nitroreductase Expression as Target for Combinatorial Therapy against Uropathogens by Promoting Reactive Oxygen Species Generation.

The antibiotic resistances emerged in uropathogens lead to accumulative treatment failure and recurrent episodes of urinary tract infection (UTI), necessitating more innovative therapeutics to curb UTI before systematic infection. In the current study, the combination of amikacin and nitrofurantoin is found to synergistically eradicate Gram-negative uropathogens in vitro and in vivo. The mechanistic analysis demonstrates that the amikacin, as an aminoglycoside, induced bacterial envelope stress by introducing mistranslated proteins, thereby constitutively activating the cpxA/R two-component system (Cpx signaling). The activation of Cpx signaling stimulates the expression of bacterial major nitroreductases (nfsA/nfsB) through soxS/marA regulons. As a result, the CpxA/R-dependent nitroreductases overexpression generates considerable quantity of lethal reactive intermediates via nitroreduction and promotes the prodrug activation of nitrofurantoin. As such, these actions together disrupt the bacterial cellular redox balance with excessively-produced reactive oxygen species (ROS) as "Domino effect", accelerating the clearance of uropathogens. Although aminoglycosides are used as proof-of-principle to elucidate the mechanism, the synergy between nitrofurantoin is generally applicable to other Cpx stimuli. To summarize, this study highlights the potential of aminoglycoside-nitrofurantoin combination to replenish the arsenal against recurrent Gram-negative uropathogens and shed light on the Cpx signaling-controlled nitroreductase as a potential target to manipulate the antibiotic susceptibility.

Characterization of aminoglycoside resistance genes in multidrug-resistant Klebsiella pneumoniae collected from tertiary hospitals during the COVID-19 pandemic.

Since the peak of the coronavirus disease 2019 (COVID-19) pandemic, concerns around multidrug-resistant (MDR) bacterial pathogens have increased. This study aimed to characterize aminoglycoside resistance genes in MDR Klebsiella pneumoniae (K. pneumoniae) collected during the COVID-19 pandemic. A total of 220 clinical isolates of gram-negative bacteria were collected from tertiary hospitals in Makkah, Saudi Arabia, between April 2020 and January 2021. The prevalence of K. pneumoniae was 40.5%; of the 89 K. pneumoniae isolates, MDR patterns were found among 51 (57.3%) strains. The MDR isolates showed elevated resistance rates to aminoglycoside agents, including amikacin (100%), gentamicin (98%), and tobramycin (98%). PCR assays detected one or more aminoglycoside genes in 42 (82.3%) MDR K. pneumoniae strains. The rmtD gene was the most predominant gene (66.7%; 34/51), followed by aac(6')-Ib and aph(3')-Ia (45.1%; 23/51). The aac(3)-II gene was the least frequent gene (7.8%; 4/51) produced by our isolates. The rmtC gene was not detected in the studied isolates. Our findings indicated a high risk of MDR bacterial infections through the COVID-19 outbreak. Therefore, there is a need for continuous implementation of effective infection prevention control (IPC) measures to monitor the occurrence of MDR pathogens and the emergence of MDR bacterial infections through the COVID-19 outbreak.

Addition of aminoglycosides reduces recurrence of infections with multidrug-resistant Gram-negative bacilli in patients with sepsis and septic shock.

OBJECTIVES: Aminoglycosides and ß-lactams have been recommended for treatment of sepsis/septic shock despite a lack of mortality benefit. Previous studies have examined resistance emergence for the same bacterial isolate using old dosing regimens and during a narrow follow-up window. We hypothesised that combination regimens employing aminoglycosides will decrease the cumulative incidence of infections due to multidrug-resistant (MDR) Gram-negative bacilli (GNB) compared with ß-lactams alone. METHODS: All adult patients admitted to Barnes Jewish Hospital between 2010 and 2017 with a diagnosis of sepsis/septic shock were included in this retrospective cohort study. Patients were divided into two treatment groups, with and without aminoglycosides. Patient demographics, severity of presentation, administered antibiotics, follow-up cultures with susceptibility results for a period of 4-60 days, and mortality were extracted. After propensity score matching, a Fine-Gray subdistribution proportional hazards model summarised the estimated incidence of subsequent infections with MDR-GNB in the presence of all-cause death as a competing risk. RESULTS: A total of 10 212 septic patients were included, with 1996 (19.5%) treated with at least two antimicrobials including one aminoglycoside. After propensity score matching, the cumulative incidence of MDR-GNB infections between 4-60 days was lower in the combination group (incidence at 60 days 0.073, 95% CI 0.062-0.085) versus patients not receiving aminoglycosides (0.116, 95% CI 0.102-0.130). Patients aged ≤65 years and with haematological malignancies had a larger treatment effect in subgroup analyses. CONCLUSION: Addition of aminoglycosides to ß-lactams may protect against subsequent infections due to MDR-GNB in patients with sepsis/septic shock.