Impact of fluoroquinolone administration and gut mucosal colonization on the risk of pre-engraftment bloodstream infections after allogeneic hematopoietic cell transplantation.

Fluoroquinolones (FQ) has been used after allogeneic hematopoietic stem cell transplantation (allo-HCT) for decades. This study on 284 allo-HCT recipients aimed to analyze the impact of FQ on pre-engraftment BSI. A total of 154 patients were colonized with resistant gram-negative bacteria, and 130 patients were not. Colonized patients did not receive FQ (n = 147) except 7 who received FQ as sequential therapy; 98 non-colonized patients received FQ, whereas 32 did not. Gram-negative (p < 0.0001), and ESBL-E BSI (p < 0.0001) were higher in colonized patients receiving FQ. No difference was found in gram-positive BSI (p = 0.452). In multivariate analysis colonized patients with (p < 0.0001) or without FQ (p = 0.007), omission of FQ in non-colonized patients (p = 0.038), and active disease (p = 0.042) were associated with gram-negative BSI, whereas mismatched unrelated donor transplantations - with gram-positive BSI (p = 0.009). Colonized patients with FQ have a higher risk of gram-negative BSI. In non-colonized patients, FQ prophylaxis is effective approach significantly reducing gram-negative BSI risk.

Phenotypic and molecular characterization of fluoroquinolone resistant Pseudomonas aeruginosa isolates in Palestine / Caracterização fenotípica e molecular de isolados de Pseudomonas aeruginosa resistentes a fluoroquinolonas na Palestina

Fluoroquinolones are important antimicrobial agents for the treatment of Pseudomonas infections. A total of 11 isolates of P. aeruginosa were collected from different clinical samples from different medical centers in the North West Bank-Palestine during 2017. In this study, resistance to fluoroquinolones and secretions of β-lactamases were detected by phenotypic methods, while presence of β-lactamase gene sequences and other virulence factors were detected by PCR technique. PCR product for gyrA, parC and parE genes were sequenced for further analyses. The phylogenetic analyses, population diversity indices and haplotypes determination were conducted using computer programs MEGA version 6, DnaSP 5.1001 and median-joining algorithm in the program Network 5, respectively. Results of this study showed that the MIC for ciprofloxacin and norfloxacin had a range of 32-256 µg/ml. In addition, all isolates carried either exoT or exoT and exoY genes, different β-lactamase genes and 82% of these isolates harbored class 1 integrons. Analyses of the gyrA, parC and parE sequences were found to be polymorphic, had high haplotype diversity (0.945-0.982), low nucleotide diversity (0.01225-0.02001) and number of haplotypes were 9 for each gyrA and parE genes and 10 haplotypes for parC gene. The founder haplotypes being Hap-1 (18%), Hap-2 (27.3%) and Hap-6 (9.1%) for gyrA, parC and parE genes, respectively. Two of ParE haplotypes were detected as indel haplotypes. The Median-joining- (MJ) networks constructed from haplotypes of these genes showed a star-like expansion. The neutrality tests (Tajima’s D test and Fu’s Fs test) for these genes showed negative values. Palestinian fluoroquinolone resistant P. aeruginosa strains showed high MIC level for fluoroquinolones, β-lactamase producers, carried type III secretion exotoxin-encoding genes, most of them [...].

Fluoroquinolonas são agentes antimicrobianos importantes para o tratamento de infecções por Pseudomonas. Um total de 11 bacilos isolados de P. aeruginosa foram coletados de diferentes amostras clínicas provenientes de diferentes centros médicos na Cisjordânia-Palestina durante o ano de 2017. Neste estudo, resistência a fluoroquinolonas e secreções de β-lactamases foram detectadas por métodos fenotípicos, enquanto a presença de sequências do gene β-lactamase e outros fatores de virulência foram detectados pela técnica de PCR (Proteína C-reativa). O produto de PCR para os genes gyrA, parC e parE foram sequenciados para análises posteriores. As análises filogenéticas, os índices de diversidade populacional e a determinação de haplótipos foram realizados utilizando os softwares MEGA versão 6, DnaSP 5.1001 e o algoritmo de junção de mediana do programa Network 5, respectivamente. Os resultados deste estudo mostraram que a MIC para ciprofloxacina e norfloxacina tinha um intervalo de 32-256 µg/ml. Além disso, todos os bacilos isolados carregavam genes exoT ou exoT e exoY, genes de β-lactamase diferentes e 82% desses isolados continham integrons de classe 1. As análises das sequências gyrA, parC e parE foram consideradas polimórficas, com alta diversidade de haplótipos (0,945-0,982), baixa diversidade de nucleotídeos (0,01225-0,02001) e o número de haplótipos foi de 9 para cada gene de gyrA e parE e 10 haplótipos para o gene parC. Os haplótipos fundadores são Hap-1 (18%), Hap-2 (27,3%) e Hap-6 (9,1%) para os genes gyrA, parC e parE, respectivamente. Dois dos haplótipos parE foram detectados como haplótipos InDel. As redes Median-joining (MJ) construídas a partir de haplótipos desses genes mostraram uma expansão semelhante à de uma estrela. Os testes de neutralidade (teste D de Tajima e teste Fs de Fu) para esses genes apresentaram valores negativos. As cepas palestinas de P. aeruginosa resistentes a fluoroquinolonas mostraram alto nível de MIC para [...].

A novel, sensitive, and widely accessible besifloxacin quantification method by HPLC-fluorescence: Application to an ocular pharmacokinetic study.

Besifloxacin has been embraced for the treatment of ocular bacterial infections. While LC-MS/MS has been used in investigating BSF pharmacokinetics, those costly instruments are not universally available and have complicated requirements for operation and maintenance. Additionally, pharmacokinetics of besifloxacin in dose-intense regimens are still unknown. Herein, a new quantification method was developed employing the widely accessible HPLC with fluorescence detection and applied to an ocular pharmacokinetic study with an intense regimen. Biosamples were pre-treated using protein precipitation. Chromatographic separation was achieved on a C18 column using mobile phase of 0.1% trifluoroacetic acid and acetonitrile. To address the weak fluorescence issue of besifloxacin, effects of detection parameters, elution pattern, pH of mobile phase, and reconstitution solvents were investigated. The method was fully validated per US-FDA guidelines and demonstrated precision (<13%), accuracy (91-112%), lower limit of quantification (5 ng/mL), linearity over clinically relevant concentrations (R2 > 0.999), matrix-effects (93-105%), recoveries (95-106%), and excellent selectivity. The method showed agreement with agar disk diffusion assays for in vitro screening and comparable in vivo performance to LC-MS/MS (Deming Regression, y = 1.010x + 0.123, r = 0.997; Bland-Altman analysis, mean difference was -6.3%; n = 21). Pharmacokinetic parameters suggested superior surface-retentive properties of besifloxacin. Maximum concentrations were 1412 ± 1910 and 0.15 ± 0.12 µg/mL; area under the curve was 1,637 and 1.08 µg·h/g; and half-life was 4.9 and 4.1 h; and pharmacokinetic-to-pharmacodynamic ratios were ≥ 409 and ≤ 17.8 against ocular pathogens in tears and aqueous humor, respectively. This readily available method is sensitive for biosamples and practical for routine use, facilitating besifloxacin therapy development.

Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study.

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R2 adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.

Lefamulin efficacy and safety in a pooled phase 3 clinical trial population with community-acquired bacterial pneumonia and common clinical comorbidities.

BACKGROUND: Lefamulin, a first-in-class pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia (CABP), was noninferior to moxifloxacin in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 intravenous-to-oral switch study and the LEAP 2 oral-only study. Using pooled LEAP 1/2 data, we examined lefamulin efficacy/safety overall and within subgroups of patients presenting with comorbidities typical in CABP management. METHODS: In LEAP 1, adults with CABP were randomized to receive intravenous lefamulin (150 mg every 12 h) for 5‒7 days or moxifloxacin (400 mg every 24 h) for 7 days, with optional intravenous-to-oral switch if predefined improvement criteria were met. In LEAP 2, adults with CABP were randomized to receive oral lefamulin (600 mg every 12 h) for 5 days or moxifloxacin (400 mg every 24 h) for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 h after first study drug dose and investigator assessment of clinical response (IACR) at test-of-cure (5‒10 days after last dose). Pooled analyses of the overall population used a 10% noninferiority margin. RESULTS: Lefamulin (n = 646) was noninferior to moxifloxacin (n = 643) for ECR (89.3% vs 90.5%, respectively; difference - 1.1%; 95% CI - 4.4 to 2.2); IACR success rates at test-of-cure were similarly high (≥ 85.0%). High efficacy with both lefamulin and moxifloxacin was also demonstrated across all well-represented patient subgroups, including those with advanced age, diabetes mellitus, a history of cardiovascular diseases (e.g., hypertension, congestive heart failure, or arrhythmia) or chronic lung diseases (e.g., asthma or chronic obstructive pulmonary disease), elevated liver enzymes, or mild-to-moderate renal dysfunction. No new safety signals were identified. CONCLUSIONS: Lefamulin may provide a valuable intravenous/oral monotherapy alternative to fluoroquinolones or macrolides for empiric treatment of patients with CABP, including cases of patients at risk for poor outcomes due to age or various comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov LEAP 1 (NCT02559310; Registration Date: 24/09/2015) and LEAP 2 (NCT02813694; Registration Date: 27/06/2016).

A Case of Pediatric Subcutaneous Abscess Caused by Mycobacterium mageritense Infection.

Soft tissue infections with Mycobacterium mageritense are uncommon. We report the case of a 5-year-old girl who developed a subcutaneous abscess in her right ankle caused by M. mageritense. She had a history of acute encephalopathy and adrenal insufficiency and was hospitalized for acute pancreatitis. During hospitalization, the patient developed fever and tachycardia. Blood culture was positive for gram-positive bacilli. Although initial testing with matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) reported a different organism, a repeat test identified M. mageritense. One month after the positive blood culture, she developed redness and swelling in the right ankle. The pus from the subcutaneous abscess after drainage grew M. mageritense, which was further confirmed by the sequencing of housekeeping genes. Based on sensitivity testing, the patient was treated with tosufloxacin and linezolid. The local inflammatory signs gradually improved on starting the treatment. The antibiotics were administered for 6 months, and she experienced no relapse during the 8 months of follow-up after the completion of therapy. This is the first case report of a pediatric M. mageritense infection, which also highlights an important potential pitfall of MALDI-TOF MS. Further, we observe that the choice of antimicrobials for the treatment of M. mageritense is more limited in children than in adults.

Danofloxacin pharmacokinetics and tissue residues in Bilgorajska geese.

Danofloxacin is a fluoroquinolone developed for veterinary medicine and used in avian species for the treatment of numerous bacterial infections. However, no pharmacokinetic data have been reported in geese. The aim of the study was three-fold: (i) to evaluate the pharmacokinetics of danofloxacin in geese after single oral (PO) and intravenous (IV) administrations; (ii) to define its residue depletion profile in different goose tissues, and (iii) to recreate a multiple-dose simulation in the practical context of large-scale breeding. Twenty-four healthy geese were randomly divided in three groups each composed of eight animals. Group 1 received danofloxacin IV (5 mg/kg) and groups 2 and 3 were treated PO with the same dose. Blood was collected until 24 h (IV; group 1) and 48 h (PO; group 2) after administration. Two animals from group 3 were sacrificed at 6, 10, 24 and 48 h to collect samples of muscle, heart, kidney, liver, and lung. Danofloxacin was quantified in each matrix using a validated high-performance liquid chromatography method with spectrofluorimetric detection and the pharmacokinetic analysis was performed using non-compartmental and compartmental approaches. Danofloxacin showed a moderate elimination half-life (6.61 h), a slow clearance (0.35 mL/g*h) and a large volume of distribution (1.46 mL/g). The peak plasma concentration after PO administration and the time to reach it were 0.96 µg/mL and 1.70 h, respectively. The oral bioavailability was moderate (58%). Higher residue concentration was found in liver and kidney, compared to the other tissues. If the AUC(0-24) value found in the present study is included in the pharmacokinetic/pharmacodynamic index (AUC(0-24)/MIC) for the prediction of fluoroquinolones' efficacy, danofloxacin seems to be effective in geese against gram-negative bacteria with a minimum inhibitory concentration (MIC) < 0.076 µg/mL and against S. pneumoniae with a MIC < 0.29 µg/mL after a single PO dose of 5 mg/kg. Liver and kidney showed the highest drug tissue penetration value, with an explorative withdrawal time of 2.6 and 3.8 days, respectively. A practical multiple-dose regimen simulation does not lead to significant plasma drug accumulation.

Association of prior fluoroquinolone treatment with survival outcomes of immune checkpoint inhibitors in Asia.

WHAT IS KNOWN AND OBJECTIVE: Gut microbiota plays an important role in shaping immune responses. Several studies have reported that antibiotics may alter gut microbiota diversity and compromise the therapeutic response to immune checkpoint inhibitors (ICIs). Nevertheless, the impact of a specific class of antibiotics on ICIs therapy is still not known. The aim of this study was to analyse the influence of antibiotics on the clinical outcomes of non-small cell lung cancer (NSCLC) patients treated with ICIs and to compare the effects of fluoroquinolones vs. other broad-spectrum antibiotics. METHODS: This retrospective cohort study (n = 340) analysed data from Chang Gung Research Database, which comprises work from seven medical institutions in Taiwan. Patients with NSCLC who received ICIs between January 2016 and March 2019 were evaluated. The data of patients who received antibiotics (ie fluoroquinolone) within 30 days prior to ICIs therapy were analysed. Overall survival (OS) was the goal of our study and was calculated from the time the ICIs therapy start. Survival analysis was estimated using the Kaplan-Meier and Cox statistics. RESULTS: A total of 340 patients were identified for analysis. Of the 340 patients, only over one third (38%) of patients received antibiotics 30 days prior to ICI therapy. These patients exhibited a shorter OS compared with those not receiving antibiotics (median OS, 266 days vs. 455 days; hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.1-8.1, p = 0.003). In this study, 127 out of 128 patients who were exposed to antibiotics had received at least one broad-spectrum antibiotic. We observed patients who had received fluoroquinolone had a shorter OS compared with those receiving other broad-spectrum antibiotics (median OS, 121 days vs. 370 days; HR, 1.582; 95% CI 1.007-2.841; p = 0.047). WHAT IS NEW AND CONCLUSION: Antibiotic treatment, especially fluoroquinolone, prior to ICIs therapy was associated with poorer clinical efficacy in NSCLC patients. Antibiotics should not be withheld when there is a clear need for them despite the possibility of interfering with the microbiome, which may, in turn, adversely affect the ICI's effectiveness. However, one should consider avoiding the use of fluoroquinolones antibiotics.

Effects of ABCB1, UGT1A1, and UGT1A9 Genetic Polymorphisms on the Pharmacokinetics of Sitafloxacin Granules in Healthy Subjects.

Sitafloxacin, a new fluoroquinolone, has strong antibacterial activity. We evaluated the effects of sitafloxacin granules in single-dose and multidose cohorts and the effects of ABCB1, UGT1A1, and UGT1A9 genetic polymorphisms on the pharmacokinetics (PK) of sitafloxacin in healthy subjects. The single-dose study included 3 fasted cohorts receiving 50, 100, and 200 mg of sitafloxacin granules and 1 cohort receiving 50 mg of sitafloxacin granules with a high-fat meal. The multidose study included 1 cohort receiving 100 mg of sitafloxacin granules once daily for 5 days. PK parameters were calculated using noncompartmental parameters based on concentration-time data. The genotypes for ABCB1, UGT1A1, and UGT1A9 single-nucleotide polymorphisms were determined using Sanger sequencing. Subsequently, the association between sitafloxacin PK parameters and target single-nucleotide polymorphisms was analyzed. Sitafloxacin granules were well tolerated up to 200 and 100 mg in the single-dose and multidose studies, respectively. Sitafloxacin AUC and Cmax increased linearly within the detection range, and a steady state was reached within 3 days after the administration of multiple oral doses. Our findings showed that Cmax was lower in the ABCB1 (rs1045642) mutation group, whereas t1/2 was longer in the UGT1A1 (rs2741049) and UGT1A9 (rs3832043) mutation groups. In conclusion, sitafloxacin granules were safe at single doses and multiple doses up to 200 and 100 mg/day, respectively, with a linear plasma PK profile. However, ABCB1 (rs1045642), UGT1A1 (rs2741049), and UGT1A9 (rs3832043) genetic polymorphisms are likely to influence the Cmax or t1/2 and thereby merit further clinical evaluation.

In vitro toxicity evaluation of lomefloxacin-loaded MCM-41 mesoporous silica nanoparticles.

Lomefloxacin (LF) is interesting as a model molecule from a safety point of view because of its high potential for serious adverse drug effects (i.e. phototoxic reactions). In this study, MCM-41 mesoporous silica nanoparticles (MCM-41) were loaded with lomefloxacin, aiming to overcome the drug's intrinsic cytotoxicity. The good biocompatibility of the empty drug carrier (0.1-1.0 mg/ml) was established by the absence of red blood cell lysis (hemolysis assay). The cytotoxicity of empty MCM-41 and lomefloxacin-loaded MCM-41 (LF-MCM-41) was evaluated by using a battery of in vitro cytotoxicity assays: Alamar blue, lactate dehydrogenase release and reactive oxygen species formation by dichlorofluorescein assay. Three cell cultures models: hepatoma HepG2, fibroblasts L929 and endothelial EA.hy926 cells were used to compare the cytotoxicity and reactive oxygen species formation by free drug, empty MCM-41, and LF-MCM-41. The findings from the study indicated that empty MCM-41 (0.1-1.0 mg/ml) showed a low cytotoxic potential in HepG2, followed by L929 and EA.hy926 cells. Lomefloxacin loading in MCM-41 mesoporous silica nanocarrier reduced the cytotoxicity of the free lomefloxacin, especially in the high concentration (1.0 mg/ml MCM-41, containing 120 µg/ml LF). L929 and EA.hy926 cells were more sensitive to the protective effects of LF-MCM-41, compared to HepG2 cells. The results indicate that an improvement in lomefloxacin safety might be expected after incorporation in an appropriate drug delivery system.

Association Between the Prothrombin Time-International Normalized Ratio and Concomitant Use of Antibiotics in Warfarin Users: Focus on Type of Antibiotic and Susceptibility of Bacteroides fragilis to Antibiotics.

BACKGROUND: The difference in type of antibiotics and susceptibility of Bacteroides fragilis to antibiotics may influence warfarin anticoagulation. However, these influences have not been clarified in clinical settings. OBJECTIVES: This study aimed to investigate association the between the prothrombin time-international normalized ratio (PT-INR) and concomitant use of antibiotics in a real-world population of warfarin users. METHODS: This was a single-center cohort study using data from health records and included patients who received ß-lactams (BLs)/fluoroquinolones (FQs) during ongoing warfarin treatment (2011-2015) at Hamamatsu University Hospital in Japan. Antibiotics were categorized into those to which B fragilis is susceptible (BLsus, FQsus) and those to which it is not (BLnon, FQnon) and into those given orally (BLpo, FQpo) or intravenously (BLiv, FQiv). Outcomes were excessive PT-INR and changes in PT-INR, defined as the ratio (INR ratio) and difference (ΔINR) of maximum PT-INR and baseline PT-INR. Excessive PT-INR was graded as INR ratio of >1.5 or >2.5. RESULTS: A total of 1185 warfarin users were included. The proportion of INR ratio >2.5 in FQiv was higher than in BLiv (95% CI: 1.59-46.5). The proportions with an INR ratio of >1.5 in BLsus and FQsus were higher than in BLnon (1.72-14.1) and FQnon (1.05-9.36), respectively. ΔINR values in FQpo, FQiv, and FQsus were higher than those in BLpo, BLiv, and FQnon, respectively. CONCLUSIONS AND RELEVANCE: Concomitant use of FQs, or of antibiotics to which B fragilis is susceptible is associated with higher risk of excessive anticoagulation. These findings would contribute to safe and proper antibiotic treatment in warfarin users.

A randomized, active-controlled, multicentre clinical trial to evaluate the efficacy and safety of oral sitafloxacin versus levofloxacin in Chinese adults with acute uncomplicated or complicated urinary tract infection.

PURPOSE: To evaluate the efficacy and safety of oral sitafloxacin versus levofloxacin in Chinese adults with acute uncomplicated urinary tract infection (UTI) or complicated UTI. METHODS: In this randomized, active-controlled clinical trial, the patients with acute uncomplicated UTI were randomized to receive sitafloxacin 100-mg once-daily (qd) or levofloxacin 500-mg qd orally for 3-5 days. The patients with complicated UTI were randomized to receive sitafloxacin 100-mg twice daily or levofloxacin 500-mg qd orally for 10-14 days. The primary endpoint was the clinical efficacy at test-of-cure (TOC) visit. RESULTS: At TOC visit, the clinical cure rate was 89.2% (58/65) in sitafloxacin group and 97.1% (68/70) in levofloxacin group for the patients with acute uncomplicated UTI corresponding to the bacterial eradication rate of 97.1% (34/35) and 97.6% (41/42) (all p > .05), respectively. For the patients with complicated UTI, the clinical cure rate was 81.8% (27/33) in sitafloxacin group and 76.9% (20/26) in levofloxacin group corresponding to the bacterial eradication rate of 93.3% (14/15) and 63.6% (7/11) (all p > .05), respectively. Sitafloxacin and levofloxacin showed similar incidence of drug-related adverse events. CONCLUSIONS: Oral sitafloxacin is as effective and safe as levofloxacin in treating acute uncomplicated and complicated UTI. KEY MESSAGE: Oral sitafloxacin showed similar clinical cure rate and bacterial eradication rate as levofloxacin for treatment of complicated and uncomplicated urinary tract infections (UTIs) in a randomized, active-controlled, multicentre clinical trial. Oral sitafloxacin is safe and well-tolerated in treating acute uncomplicated and complicated UTIs in Chinese adults. Sitafloxacin is a promising alternative treatment option for UTIs in adults.

[Antibiotic stewardship - recent developments]. / Aktuelle Entwicklungen im Bereich Antibiotic Stewardship.

Both in hospitals and outpatient settings, fewer fluoroquinolones have been prescribed in Germany in recent years. The consumption of cephalosporins also decreased somewhat in favor of penicillin derivatives. The aminoglycosides, which have only rarely been prescribed, can now be used again as a suitable alternative - but only parenterally - due to their relatively favorable activity and low resistance rates among typical urinary tract infection pathogens. In acute severe infection such as sepsis, addition, e. g. of tobramycin, to a suitable betalactam of a single dose has been discussed as a useful option, but the evidence for such a recommendation is weak. There is little news about the rational use of antibiotics in hematology-oncology patients. In the case of fever and neutropenia, the initial empirical regimens of choice remain piperacillin-tazobactam or a pseudomonas-active carbapenem as monotherapy. These betalactams should be given with extended infusion times, e. g. over 4 hours. Linezolid should be considered as a reserve drug and not be used empirically, but only in targeted therapy. With regard to an alleged penicillin allergy, the risk of true allergic reactions can be differentiated by careful taking of the history; on that ground patient subgroups can be defined that may be re-exposed without further allergological examinations.

Case Study and Attempt of Treatment of Mycobacteriosis Caused by Mycobacterium avium in a Parental Flock of Meat-Breed Pigeons.

Mycobacteriosis caused by Mycobacterium avium subsp. avium was observed in a parental loft of 70 meat-breed pigeons. It was decided to undertake treatment as the birds represented a substantial value to the owner. A multiagent therapy using azithromycin, marbofloxacin, and ethambutol was administered. After 4 mo of therapy, the desired results were not obtained. At the end of treatment, the birds were in poor general condition, with white blood cells above 20 g/L, and after clutching, 2-yr-old and older birds were euthanatized. Overall, postmortem lesions were found in 17 out of 49 necropsied individuals. Slide agglutination tests with a M. avium subsp. avium lysate were conducted in all examined pigeons. In 28 pigeons, blood count was conducted once a month during therapy, while in 24 pigeons, a tuberculin sensitivity test was conducted before the planned euthanatization. The tuberculin sensitivity test did not prove useful in the diagnosis of ill individuals. Slide agglutination yielded positive results in only four birds, all of which also had postmortem lesions. Blood count in a large number of cases allowed distinguishing between ill and healthy individuals, which was used for subsequent selection. The comparison of cultured strains with the (CCG)4-based PCR method showed the variation of M. avium isolates up to a maximum of 30%. The described case proves that the treatment of mycobacteriosis in pigeon flocks is not effective, mainly due to the high resistance to M. avium subsp. avium. In addition, therapy may contribute to an even greater increase in mycobacterial resistance to antibiotics, which may pose a potential risk to public health.

Oral beta-lactam step down in bacteremic E. coli urinary tract infections.

BACKGROUND: Literature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones. METHODS: This multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding. RESULTS: A total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference - 4.2, 95% confidence interval [CI] -10.3 to 1.9%, p = 0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05-1.90, p = 0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes. CONCLUSIONS: Oral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones.

Management of isoniazid-monoresistant tuberculosis (Hr-TB) in Queensland, Australia: a retrospective case series.

OBJECTIVES: Drug-resistance represents a major threat in the fight against tuberculosis. Globally, isoniazid-monoresistant tuberculosis (Hr-TB) is twice as common as multidrug/rifampicin-resistant (MDR/RR)-TB. Recently updated WHO guidelines now recommend treatment of Hr-TB with rifampicin, ethambutol, pyrazinamide and levofloxacin for at least six months. Our primary objective was to define the frequency, treatment and outcomes for Hr-TB in Queensland, Australia. We also sought to determine the frequency of fluoroquinolone use and whether its inclusion improved outcomes. METHODS: Retrospective case series of tuberculosis notifications in Queensland between 2000 and 2017 with at least low-level isoniazid resistance and preserved susceptibility to other first-line oral agents. RESULTS: Hr-TB was identified in 7.2% of all notifications. Where outcomes were assessable (163/198), 76.1% were treated with first-line agents only and 11.0% received at least six months of a fluoroquinolone-containing regimen (consistent with recent WHO guidelines). Favourable outcomes were achieved in 95.7%, comparable to fully susceptible disease (94.9%). Inclusion of a fluoroquinolone did not significantly improve outcomes compared with a regimen containing first-line agents only, although these cases were more likely to have high-level resistance. Previous treatment made an unfavourable outcome more likely. CONCLUSIONS: Hr-TB is prevalent in Queensland. Treatment outcomes in our cohort were comparable to fully susceptible disease. The current WHO-recommended regimen did not confer advantage over an appropriately constructed regimen containing first-line agents only. Our findings suggest that, in a well-resourced setting with good programmatic management, the addition of a fluoroquinolone may not substantially improve outcomes - potentially allowing these agents to be reserved for more extensively resistant disease.