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.

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.

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)

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.

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.

Collateral sensitivity between tetracyclines and aminoglycosides constrains resistance evolution in carbapenem-resistant Klebsiella pneumoniae.

AIMS: The acquisition of resistance to one antibiotic may confer an increased sensitivity to another antibiotic in bacteria, which is an evolutionary trade-off between different resistance mechanisms, defined as collateral sensitivity (CS). Exploiting the role of CS in treatment design could be an effective method to suppress or even reverse resistance evolution. METHODS: Using experimental evolution, we systematically studied the CS between aminoglycosides and tetracyclines in carbapenem-resistant Klebsiella pneumoniae (CRKP) and explored the underlying mechanisms through genomic and transcriptome analyses. The application of CS-based therapies for resistance suppression, including combination therapy and alternating antibiotic therapy, was further evaluated in vitro and in vivo. RESULTS: Reciprocal CS existed between tetracyclines and aminoglycosides in CRKP. The increased sensitivity of aminoglycoside-resistant strains to tetracyclines was associated with the alteration of bacterial membrane potential, whereas the unbalanced oxidation-reduction process of tetracycline-resistant strains may lead to an increased bacterial sensitivity to aminoglycosides. CS-based combination therapy could efficiently constrain the evolution of CRKP resistance in vitro and in vivo. In addition, alternating antibiotic therapy can re-sensitize CRKP to previously resistant drugs, thereby maintaining the trade-off. CONCLUSIONS: These results provide new insights into constraining the evolution of CRKP resistance through CS-based therapies.

Outcome and safety of colistin usage in pediatric cancer patients with carbapenem-resistant enterobacteriaceae bacteremia at children cancer hospital Egypt.

Background: Carbapenem resistant Enterobacteriacae (CRE) bloodstream infection (BSI) causes complicated infections, especially in immunocompromised patients. This study aimed to assess the renal toxicity and the efficacy of therapy with colistin in a cohort of pediatric cancer patients with BSIs due to CRE and sensitivity to colistin. Patients and Methods: This was an observational, prospective cohort study from May 2017 to October 2017 in Children's Cancer Hospital Egypt 57,357. All patients who had blood stream infections due to CRE receiving intravenous colistin were prospectively enrolled. We used a standardized case form to record patient characteristics, including age, sex, weight, underlying comorbidities, type of infection, causative organism, and antibiotic susceptibility testing. Daily doses, duration of colistin therapy, and co-administered antibiotics (aminoglycosides, vancomycin) were collected. Furthermore, clinical and microbiological responses to treatment were reported. The dosing schedule was based on a loading dose of 5 MU and a 5-MU twice-daily divided maintenance dose, titrated on renal function. Clinical cure, bacteriological clearance, and daily serum creatinine were recorded. Results: One hundred and forty-one Blood Stream infectious episodes mainly due to Klebsiella Species (pneumoniae and Oxytoca) (27%) and Escherichia coli (68%) were analyzed. All strains were susceptible to colistin with Minimum inhibitory concentration (MICs) of 0.19-1.5 mg/L. Patients were predominantly females (69%), with a mean age of 7 years. It was used as a combination therapy with carbapenems (69.2%) or aminoglycosides (80%). The median duration of treatment was 9 days (Range 1-50 days). Clinical and microbiological cure was observed in 110 cases (80%). Acute kidney injury developed during five treatment courses (4%) in which colistin was used in combination with amikacin. No renal replacement therapy was required and subsided within 7 days from colistin discontinuation. Conclusions: Our study showed that colistin had a high efficacy without significant renal toxicity in severe infections due to CRE Gram-negative bacteria.

Résumé Carbapenem-resistant Gram-negative (CRE) bloodstream infection (BSI) causes complicated infections, especially in immunocompromised patients .This study aimed to assess the renal toxicity and the efficacy of therapy with colistin in a cohort of pediatric cancer patients with BSIs due to CRE and sensitivity to colistin. colistin proved to be effective and safe in managing CRE in children with cancer Mots-clés: Colistin, cancer, children, and Carbapenem-Resistant Enterobacteriaceae.

Aminoglycosides' dosage in hematological malignancies and febrile neutropenia: extended interval or conventional dosage?

A patient with acute myeloid leukemia presented various episodes of febrile neutropenia, for which there was no positive response to antibiotic treatments. Following an episode of bacteremia by extensively drug-resistant Klebsiella pneumoniae, amikacin was prescribed, pharmacokinetic analyses of its plasma concentrations were performed and the dosage interval was narrowed to 12 and 8 h in order to counteract the reduced postantibiotic effect due to the patient being immunocompromised. The patient responded positively, with procalcitonin decreasing and body temperature normalizing. Recovery was finally achieved, without renal or auditory damage. This case proposes tightening dosage intervals for aminoglycosides as an effective strategy in immunocompromised patients. Aminoglycosides are given over extended intervals (24 h), considering concentration-dependent effectiveness, nephrotoxicity and postantibiotic effect. Leukocytes appear to play a determining role in the postantibiotic effect, with no proposed dosing strategy for strongly immunocompromised patients.

Aminoglycoside Pharmacokinetics in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

BACKGROUND: There are few studies describing aminoglycoside pharmacokinetics during continuous renal replacement therapy (CRRT). OBJECTIVE: To characterize the effect of CRRT on aminoglycoside clearance and volume of distribution (Vd). METHODS: Retrospective observational pharmacokinetic study of adult critically ill oncologic patients who received a first dose of amikacin or tobramycin during CRRT between February 2012 and May 2017. Study outcomes included aminoglycoside clearance, Vd, and attainment of the target peak: MIC (minimum inhibitory concentration) ratio as a surrogate for dosing appropriateness. RESULTS: In total, 80 patients were included, sustained low-efficiency dialysis (SLED), n = 49; continuous venovenous hemodialysis (CVVHD), n = 19; continuous venovenous hemofiltration (CVVH), n = 12. Fifty-one patients received amikacin at a median dose of 14.5 mg/kg per actual body weight and achieved a median peak level of 26.7 mg/L. Twenty-nine patients received tobramycin at a median dose of 6.5 mg/kg actual body weight and achieved a median peak level of 10.3 mg/L. The median aminoglycoside clearance was 63.1 mL/min and was similar between CRRT modality groups (P = 0.97). The median Vd was 0.47 L/kg and was different between the SLED and CVVH groups (P = 0.007). Attainment of target peak: MIC occurred in 29% in the total study population and 44% in the subgroup of 23 patients with isolates tested for aminoglycoside susceptibility. CONCLUSION AND RELEVANCE: Critically ill oncology patients undergoing CRRT exhibited reduced clearance and expanded Vd that was not significantly different between CRRT modalities. Current dosing regimens led to low peak concentrations and poor attainment of pharmacokinetic targets.

Noncanonical Mismatch Repair Protein NucS Modulates the Emergence of Antibiotic Resistance in Mycobacterium abscessus.

NucS/EndoMS-dependent noncanonical mismatch repair (MMR) ensures the stability of genomic DNA in mycobacteria and acts as a guardian of the genome by preventing the accumulation of point mutations. In order to address whether the inactivation of noncanonical MMR could increase the acquisition of drug resistance by mutation, a ΔnucS strain was constructed and explored in the emerging pathogen Mycobacterium abscessus. Deletion of nucS resulted in a mutator phenotype with increased acquisition of resistance to macrolides and aminoglycosides, the two main groups of antimycobacterial agents for M. abscessus treatment, and also to second-line drugs such as fluoroquinolones. Inactivation of the noncanonical MMR in M. abscessus led to increases of 10- to 22-fold in the appearance of spontaneous mutants resistant to the macrolide clarithromycin and the aminoglycosides amikacin, gentamicin, and apramycin, compared with the wild-type strain. Furthermore, emergence of fluoroquinolone (ciprofloxacin) resistance was detected in a nucS-deficient strain but not in a wild-type M. abscessus strain. Acquired drug resistance to macrolides and aminoglycosides was analyzed through sequencing of the 23S rRNA gene rrl and the 16S rRNA gene rrs from independent drug-resistant colonies of both strains. When the acquisition of clarithromycin resistance was examined, a different mutational profile was detected in the M. abscessus ΔnucS strain compared with the wild-type one. To summarize, M. abscessus requires the NucS-dependent noncanonical MMR pathway to prevent the emergence of drug-resistant isolates by mutation. To our knowledge, this is the first report that reveals the role of NucS in a human pathogen, and these findings have potential implications for the treatment of M. abscessus infections. IMPORTANCE Chronic infections caused by M. abscessus are an emerging challenge in public health, posing a substantial health and economic burden, especially in patients with cystic fibrosis. Treatment of M. abscessus infections with antibiotics is particularly challenging, as its complex drug resistance mechanisms, including constitutive resistance through DNA mutation, lead to high rates of treatment failure. To decipher the evolution of antibiotic resistance in M. abscessus, we studied NucS-dependent noncanonical MMR, a unique DNA repair pathway involved in genomic maintenance. Inactivation of NucS is linked to the increase of DNA mutations (hypermutation), which can confer drug resistance. Our analysis detected increased acquisition of mutations conferring resistance to first-line and second-line antibiotics. We believe that this study will improve the knowledge of how this pathogen could evolve into an untreatable infectious agent, and it uncovers a role for hypermutators in chronic infectious diseases under antibiotic pressure.

Systematic review on efficacy of preventive measures for surgical site infection by multiple-drug resistant gram-negative bacilli.

BACKGROUND: There are no specific recommendations for prevention of surgical site infection (SSI) caused by multidrug resistant Gram-negative bacilli (MDR-GNB). Our objective was to systematically review the literature evaluating the efficacy and safety of measures specifically designed to prevent MDR-GNB SSI. METHODS: We searched MEDLINE, EMBASE, CINAHL and LILACS databases up to February 18, 2020. Randomized trials and observational cohort studies evaluating the efficacy of preventive measures against MDR-GNB SSI in adult surgical patients were eligible. We evaluated methodological quality of studies and general quality of evidence using Newcastle-Ottawa scale, Cochrane ROBINS-I and GRADE method. Random-effects meta-analyses were performed using Review Manager V.5.3 software. RESULTS: A total of 10,663 titles by searching databases were identified. Two retrospective observational studies, comparing surgical antibiotic prophylaxis (SAP) with or without aminoglycoside in renal transplantation recipients, and one non-randomized prospective study, evaluating ertapenem vs. cephalosporin plus metronidazole for SAP in extended spectrum beta-lactamase producing Enterobacteriales carriers undergoing colon surgery, were included. Risk of bias was high in all studies. Meta-analysis was performed for the renal transplantation studies, with 854 patients included. Combined relative risk (RR) for MDR GNB SSI was 0.57 (95%CI: 0.25-1.34), favoring SAP with aminoglycoside (GRADE: moderate). CONCLUSIONS: There are no sufficient data supporting specific measures against MDR-GNB SSI. Prospective, randomized studies are necessary to assess the efficacy and safety of SAP with aminoglycoside for MDR-GNB SSI prevention among renal transplantation recipients and other populations. PROSPERO 2018 CRD42018100845.

No Evidence that CD33 rs12459419 Polymorphism Predicts Gemtuzumab Ozogamicin Response in Consolidation Treatment of Acute Myeloid Leukemia Patients: Experience of the PETHEMA Group.

Gemtuzumab ozogamicin (GO) is a conjugate of a monoclonal antibody and calicheamicin, which has been reapproved for the treatment of acute myeloid leukemia (AML). AML patients with the CD33 rs12459419 CC genotype might benefit from the addition of GO to intensive treatment in contrast to patients with CT/TT genotypes. Nevertheless, contradictory results have been reported. We sought to shed light on the prediction of GO response in AML patients with rs12459419 polymorphism who were treated with GO in the consolidation (n = 70) or reinduction (n = 20) phase. The frequency distribution of the rs12459419 polymorphism in the complete cohort of patients was 44.4% (n = 40), 50% (n = 45), and 5.6% (n = 5) for CC, CT, and TT genotypes, respectively. Regarding the patients treated with GO for consolidation, we performed a Kaplan-Meier analysis of overall survival and relapse-free survival according to the rs12459419 polymorphism (CC vs. CT/TT patients) and genetic risk using the European Leukemia Net (ELN) 2010 risk score. We also carried out a Cox regression analysis for the prediction of overall survival, with age and ELN 2010 as covariates. We found no statistical significance in the univariate or multivariate analysis. Additionally, we performed a global Kaplan-Meier analysis for the patients treated with GO for reinduction and did not find significant differences; however, our cohort was too small to draw any conclusion from this analysis. The use of GO in consolidation treatment is included in the approval of the compound; however, evidence regarding its efficacy in this setting is lacking. Rs12459419 polymorphism could help in the selection of patients who might benefit from GO. Regrettably, in our cohort, the rs12459419 polymorphism does not seem to be an adequate tool for the selection of patients who might benefit from the addition of GO in consolidation cycles.

Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.

BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. METHODS: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. CONCLUSIONS: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

[Chemotherapy-induced febrile neutropenia in a Tunisian Department of Pediatric Oncology]. / Neutropénie fébrile chimio-induite dans une unité d'oncologie pédiatrique tunisienne.

Chemotherapy-induced neutropenia (FN) is the most common infectious complication in pediatric oncology. To our knowledge, no pediatric research has been published in Tunisia. The purpose of our study was to describe the features of FN among Tunisian children and to investigate factors correlated with FN. We conducted a prospective study of children with chemotherapy-induced FN at the Department of Pediatric Medicine A of the Tunis Children´s Hospital from July 2019 to December 2019. We recorded 50 episodes of FN in 32 patients whose mean age was 5.3 years (3 months-16 years). We included 26 patients with solid tumors (81%) and six patients with hemopathies (18.7%). The mean time between last treatment and fever onset was 10.67 days. Bacteriological investigation was contributory in 18% of cases and mainly showed gram positive cocci. Therapeutic protocol including 1st line empirical antibiotic therapy (3rd generation cephalosporin with aminoglycoside) was effective in 62% of cases. Mortality rate of patients with FN was 2%. The statistical study did not reveal any factor of correlation with late-onset neutropenia. In conclusion, our results are consistent with literature data on bacteriological documentation and mortality. Our 1st line treatment option based on 3rd generation cephalosporin associated with aminoglycoside was effective in 2/3 of the cases. In the future, oral antibiotics may be considered in patients at low risk for infection.

Treatment Outcomes of Cavitary Nodular Bronchiectatic-Type Mycobacterium avium Complex Pulmonary Disease.

We investigated the treatment outcomes of patients with cavitary nodular bronchiectatic (C-NB)-type Mycobacterium avium complex (MAC) pulmonary disease (PD) via outcome comparisons between the fibrocavitary (FC) and C-NB types treated with guideline-based therapy (GBT) composed of daily three-drug oral antibiotics and injectable aminoglycoside. Additionally, we analyzed whether treatment with oral antibiotics alone would result in acceptable outcomes for the C-NB type. From 2002 to 2019, patients with cavitary MAC-PD who received three-drug oral antibiotics with or without an injectable aminoglycoside for ≥1 year were retrospectively enrolled at a tertiary referral center in South Korea. We compared the rates of culture conversion at 12 months according to the radiological type and treatment regimen. The overall culture conversion rate at 12 months of 154 patients with cavitary MAC-PD who received GBT was 75.3%. Among them, the culture conversion rates of 114 patients with the C-NB type were higher than that of 40 patients with the FC-type (80.7% versus 60.0%, respectively; P = 0.009). Of 166 patients with the C-NB-type treated with oral medications with or without an injectable drug, 83.7% achieved culture conversion at 12 months. The conversion rates of those who received oral medications alone and those treated with oral medications and an injectable aminoglycoside were similar (90.4% versus 80.7%, respectively; P = 0.117). In conclusion, the culture conversion rates of the patients with C-NB type treated with GBT were significantly higher than those of patients with the FC type. Additionally, the C-NB type could be treated with oral medications alone.

A Unique Case of Community Acquired Proteus mirabilis Meningitis.

Proteus mirabilis, a gram-negative bacterium commonly known for causing urinary tract infections (UTI) can rarely present with central nervous system (CNS) infections. Proteus mirabilis CNS infections are usually encountered in the neonatal and infantile period and occasionally cause brain abscesses. It is an uncommon cause of adult CNS infection. We report the first case of a community-acquired Proteus mirabilis meningitis (PMM) in a patient with Proteus mirabilis UTI, urolithiasis, and bacteremia. Risk factors for gram-negative bacillary meningitis (GNBM) include extremes of age, cancer history, diabetes mellitus, UTI, and nosocomial exposure, with the latter being a more prominent cause of PMM. Compromise of the anatomical defense against CNS infections whether accidental or neurosurgical is another important cause, and approximately two-thirds of reported cases of PMM have occurred after neurosurgical procedures. PMM patients develop fever, altered consciousness, and have an acute clinical course. Antimicrobials that can be used for treatment include third-generation cephalosporins, ciprofloxacin, imipenem/ cilastatin, aztreonam, and intraventricular aminoglycosides. Despite appropriate antibiotic therapy outcomes are poor with severe neurological deficit and death commonly resulting. Nosocomial infections can be drug-resistant and multiple antibiotics should be started while awaiting culture results. Literature review reveals that treatment with intraventricular aminoglycosides when attempted has shown bacteriological cure indicating this can be an important treatment approach. Due to the acute clinical course and high morbidity and mortality, we recommend starting multiple antibiotics with different mechanisms of action as soon as the disease is suspected. Our patient was initially started on ceftriaxone, vancomycin, acyclovir, and ampicillin for UTI and meningoencephalitis. The antibiotics were later consolidated to cefepime based on blood, urine and, cerebrospinal fluid cultures growing pan-sensitive Proteus mirabilis. Her clinical condition continued to worsen and ciprofloxacin was added. However, due to the progressive decline in her condition, the family elected for inpatient hospice care and intraventricular aminoglycosides were not attempted.

Chitinase 3-like-1 is a therapeutic target that mediates the effects of aging in COVID-19.

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.