DNA gyrase inhibition assays are necessary to demonstrate fluoroquinolone resistance secondary to gyrB mutations in Mycobacterium tuberculosis.

The main mechanism of fluoroquinolone (FQ) resistance in Mycobacterium tuberculosis is mutation in DNA gyrase (GyrA(2)GyrB(2)), especially in gyrA. However, the discovery of unknown mutations in gyrB whose implication in FQ resistance is unclear has become more frequent. We investigated the impact on FQ susceptibility of eight gyrB mutations in M. tuberculosis clinical strains, three of which were previously identified in an FQ-resistant strain. We measured FQ MICs and also DNA gyrase inhibition by FQs in order to clarify the role of these mutations in FQ resistance. Wild-type GyrA, wild-type GyrB, and mutant GyrB subunits produced from engineered gyrB alleles by mutagenesis were overexpressed in Escherichia coli, purified to homogeneity, and used to reconstitute highly active gyrase complexes. MICs and DNA gyrase inhibition were determined for moxifloxacin, gatifloxacin, ofloxacin, levofloxacin, and enoxacin. We demonstrated that the eight substitutions in GyrB (D473N, P478A, R485H, S486F, A506G, A547V, G551R, and G559A), recently identified in FQ-resistant clinical strains or encountered in M. tuberculosis strains isolated in France, are not implicated in FQ resistance. These results underline that, as opposed to phenotypic FQ susceptibility testing, the DNA gyrase inhibition assay is the only way to prove the role of a DNA gyrase mutation in FQ resistance. Therefore, the use of FQ in the treatment of tuberculosis (TB) patients should not be ruled out only on the basis of the presence of mutations in gyrB.

Potential drug-drug interactions and risk of unplanned hospitalization in older patients with cancer: A survey of the prospective ELCAPA (ELderly CAncer PAtients) cohort.

BACKGROUND: Because of comorbidities and polypharmacy, older patients with cancer have a greater risk of iatrogenic events. We aimed to characterize potential drug-drug interactions (PDIs) and the risk of unplanned hospitalization in older patients with cancer treated with antineoplastic agents (ANAs). METHODS: We analyzed all older patients (≥70 years) from the prospective ELCAPA cohort referred for geriatric assessment (2007-2014) prior to treatment with ANA at Henri Mondor Hospital (Créteil, France). PDIs were identified using Lexicomp®, and Theriaque® for French medications. Factors associated with PDIs, and association between PDIs and unplanned hospitalization in the 6 months following geriatric assessment were analyzed using ordered multivariate logistic regression (MLR). RESULTS: We included 442 patients (median [interquartile range] age: 77 years [74-80]); number of medications/patient/day: 6 [3-8]); ECOG-PS ≤ 2: 79%; metastasis: 70%). Most patients had a digestive tract cancer (colorectal: 22%; upper digestive tract: 23%). We identified 1742 PDIs; 76.5% of patients had ≥1 PDI; 13% of the PDIs involved an ANA. In a multivariate analysis, cardiovascular disorders (ischemic heart disease, heart failure, atrial fibrillation and/or arterial hypertension) were independently associated with PDIs (p < .001, after adjustment for polypharmacy and tumor site/stage). A high number of PDIs between two daily medications was independently associated with the risk of unplanned hospitalization (adjusted-odds ratio [95% confidence interval] per PDI: 1.05 [1.00;1.11], p = .05), while polypharmacy was not. CONCLUSION: Patients with cardiovascular comorbidities were more likely to have a PDI. A higher number of PDIs may be an independent risk factor for early unplanned hospitalization.

Immediate hypersensitivity reaction to pegylated liposomal doxorubicin: management and outcome in four patients.

Hypersensitivity reactions (HSR) to pegylated liposomal doxorubicin (PLD; Caelyx®) have been reported, and symptoms usually resolve with drug withdrawal. However, the risk of relapse of severe HSR and prevention remain poorly described. To report the management and outcome in four patients with HSR due to PLD. Patient characteristics, premedication regimen, rate of infusion, time between onset and HSR, clinical manifestations, and management were documented. A first cycle of PLD was received for cutaneous T-cell lymphoma (n = 3) and Kaposi sarcoma (n = 1). The drug was diluted in 250 mL 5% glucose and administered over one hour (4.17 mL dilution/min, i.e. 0.6 mg PLD/min for 1.8 m2 body surface area [BSA]). Grade 3 HSR occurred in the first minutes in the four patients. Because of the absence of alternative treatment for the underlying disease, PLD was resumed. Premedication was reinforced with 300 mg oral ranitidine and 50 mg hydroxyzine the night before and the morning of infusion. The rate of infusion was 1 mL dilution/min (0.14 mg PLD/min for 1.8 m2 BSA) for the first 15 minutes. No HSR occurred in three patients. In contrast, severe symptoms appeared in the first seconds of resumption in one patient. To minimise HSR to PLD, an initial reduced rate of infusion of 0.1-0.2 mg of PLD/min is warranted. In the event of HSR, alternative therapy must be privileged, and if necessary, careful re-challenge with PLD may be attempted, however relapse of HSR may occur.

Safety analysis of occupational exposure of healthcare workers to residual contaminations of cytotoxic drugs using FMECA security approach.

Handling cytotoxic drugs is associated with chemical contamination of workplace surfaces. The potential mutagenic, teratogenic and oncogenic properties of those drugs create a risk of occupational exposure for healthcare workers, from reception of starting materials to the preparation and administration of cytotoxic therapies. The Security Failure Mode Effects and Criticality Analysis (FMECA) was used as a proactive method to assess the risks involved in the chemotherapy compounding process. FMECA was carried out by a multidisciplinary team from 2011 to 2016. Potential failure modes of the process were identified based on the Risk Priority Number (RPN) that prioritizes corrective actions. Twenty-five potential failure modes were identified. Based on RPN results, the corrective actions plan was revised annually to reduce the risk of exposure and improve practices. Since 2011, 16 specific measures were implemented successively. In six years, a cumulative RPN reduction of 626 was observed, with a decrease from 912 to 286 (-69%) despite an increase of cytotoxic compounding activity of around 23.2%. In order to anticipate and prevent occupational exposure, FMECA is a valuable tool to identify, prioritize and eliminate potential failure modes for operators involved in the cytotoxic drug preparation process before the failures occur.