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Background: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions., Methods: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437., Findings: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts., Interpretation: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer., Funding: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac., (© 2020 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Background: Mycobacterium xenopi spinal infections were diagnosed in 1993 in patients who had undergone surgical microdiscectomy for disc hernia, by nucleotomy or microsurgery, in a private hospital. Contaminated tap water, used for rinsing surgical devices after disinfection, was identified as the source of the outbreak. Several cases were recorded in the 4 years after implementation of effective control measures because of the long time between discectomy and case detection. The national health authorities decided to launch a retrospective investigation in patients who were exposed to M xenopi contamination in that hospital., Methods: Mailing and media campaigns were undertaken concurrently to trace exposed patients for spinal infections. Patients were screened by magnetic resonance imaging (MRI), and the scans were reviewed by a radiologist who was unaware of the diagnosis. Suspected cases had discovertebral biopsy for histopathological and bacteriological examination., Findings: Of 3244 exposed patients, 2971 (92%) were informed about the risk of infection and 2454 (76%) had MRI. Overall, 58 cases of M xenopi spinal infection were identified (overall cumulative frequency 1.8%), including 26 by the campaign (mean delay in detection 5.2 years, SD 2.4, range 1-10 years). Multivariate analysis showed that the risk of M xenopi spinal infection was related to nucleotomy and high number of patients per operating session., Interpretation: Failures in hygiene practices could result in an uncontrolled outbreak of nosocomial infection. Patients who have been exposed to an iatrogenic infectious hazard should be screened promptly and receive effective information.

Multidrug resistance proteins (MRPs) such as MRP1, MRP2 and MRP3 are membrane efflux pumps involved in multidrug resistance and handling organic anions. In the present study, MRP activity was investigated in normal mature leucocytes and CD34-positive hematopoietic cells from peripheral blood using the flow cytometric carboxy-2',7'-dichlorofluorescein (CF) efflux assay. Basal and similar cellular exports of CF, an anionic fluorescent dye substrate for MRP1 and MRP2 transporters, were evidenced in lymphocytes whatever their subsets (CD3, CD4, CD8, CD20 and CD56 cells), in CD14 monocytes and in CD15 granulocytes whereas higher CF efflux was found in CD34 cells. Such outwardly-directed transports of CF were inhibited by known blockers of MRP function such as probenecid whereas the P-glycoprotein modulator verapamil did not alter the retention of the dye in the blood leukocytes. Peripheral mature blood leukocytes were moreover found to express MRP1 mRNAs and MRP1 protein as assessed by Northern-blot and Western-blot analyses, whereas MRP2 and MRP3 transcripts were not present or only at very low levels. Mature leukocytes therefore display basal constitutive MRP-related transport activity regardless of cell lineage and likely related to MRP1 expression whereas higher MRP-related efflux can be detected in peripheral CD34 hematopoietic cells.

Analysis of restriction fragment length polymorphism (RFLP), using a DNA probe directed against the insertion sequence IS6110, was applied to strains of Mycobacterium tuberculosis successively isolated from four patients. In order to determine the cause of recurrence in these patients, the RFLP patterns of the corresponding isolated were analyzed. The profils obtained from the strains isolated from each of the patients were identical, thus suggesting that a relapse, rather than an exogenous reinfection with a new strain, was the cause of recurrence. The RFLP patterns of successive isolated remained unchanged during periods of time ranging from 5 months to 7 years, and were not modified after development of rifampin resistance. These results demonstrate the stability of the polymorphism detected by the IS6110 probe. Therefore, RFLP analysis is a powerfull epidemiologic tool to distinguish relapse from exogenous reinfection.

Tuberculosis-control programmes are compromised by the increased frequency of multidrug-resistant strains of Mycobacterium tuberculosis. We used the polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis techniques to establish the molecular basis of resistance in 37 drug-resistant isolates of M tuberculosis, and correlated these findings with clinical and antibiotic-sensitivity data. Resistance to isoniazid was found in 36 strains, 16 of which were also resistant to ethionamide. Of the 36 isoniazid-resistant strains, 23 had mutations in the katG gene, and 5 of these also had mutations in the inhA gene. A further 5 strains had alterations in the inhA locus without the katG gene being mutated. Rifampicin resistance was less frequent (13 strains) and usually associated with isoniazid resistance (11 of 13 strains). Mutations in the rpoB gene were detected for all these rifampicin-resistant isolates. Mutations in the rpsL and rrs genes, associated with streptomycin resistance, were found in 13 of 25 and 2 of 25 streptomycin-resistant strains, respectively. The same chromosomal mutations, or combinations of mutations, were found in strains displaying single or multidrug resistance, from cases of both primary and secondary resistance, and from patients infected with human immunodeficiency virus. Thus, multidrug resistance is not due to a novel mechanism and tuberculosis chemotherapy is not subject to a new threat.

Norfloxacin is a synthetic antibiotic belonging to the fluoroquinolone class. At present, an oral formulation is available and indicated for the treatment of urinary tract infections. Because of the properties of norfloxacin, a 0.3% norfloxacin ophtalmic solution may be used by ophtalmologists. The molecular target of norfloxacin is DNA gyrase that regulates DNA replication. Norfloxacin is a broad spectrum antibiotic. A flurin atome in position 6 is responsible for the broad spectrum of activity as compared with the first generation quinolones. MICs of norfloxacin against Haemophilus influenzae, Neisseria gonorrhoeae, Staphylococcus aureus, Pseudomonas aeruginosa, and enterbacteriaceae are low or intermediate. Norfloxacin is a bactericidal drug of which MBCs are equivalent to or twice as high as MICs against the majority of organisms. The proportion of norfloxacin resistant strains is limited and, at present, no plasmid resistance has been observed. This explains the activity of norfloxacin against clinical isolates whose drug resistance is plasmid-mediated. Norfloxacin resistance is chromosomic, but the mutation rate is low. There is no cross-resistance between quinolones and other classes of drug, with the exception of drug resistance related to changes in the bacterial outer membrane proteins. A low decrease in norfloxacin susceptibility is observed in case of resistance to first generation quinolones. The above-mentioned properties make norfloxacin in ophtalmic solution a first line drug for treatment of superficial ocular infections and a second line drug for treatment of infections due to organisms resistant to other drugs.

In a first experiment mice infected intravenously with 10(6) Mycobacterium tuberculosis were randomly treated either with isoniazid (INH) + rifampicin (RMP) 25 mg/kg or with INH + RMP + pyrazinamide (PZA) or with INH + RMP + PZA + streptomycin (SM). The decrease of the viable counts (CFU) in the lungs was similar with all three regimens. In a second experiment, mice were treated for six months either with INH + RMP 25 mg/kg or INH + RMP 10 mg/kg. After a follow-up of six months, mice were killed and their lungs and spleen cultivated. Positive cultures were obtained in 7.5 p. cent of the mice treated with the high dose of RMP and 36.5 p. cent in the mice treated with the low dose (p less than 0.05). A third experiment demonstrated that, during the first two months of treatment, adding PZA to INH + RMP 10 mg/kg increased significantly the overall effectiveness of INH + RMP 10 mg/kg combination. A fourth experiment demonstrated that after three initial months of INH + RMP 10 mg/kg, RMP alone was as effective as RMP + INH or RMP + INH + PZA. It may be concluded that RMP and PZA are both active on the intracellular population of Mycobacterium tuberculosis and that RMP is the only drug to act on persisting Mycobacterium tuberculosis in extracellular lesions.

The synergy between sulfamethoxazole (SMZ) and trimethoprim (TMP) is studied on 91 methicillin sensitive S. aureus strains (methi.S) and 95 methicillin resistant S. aureus strains (methi.R). In methi.S strains, the MIC 90% of SMZ, TMP and SMZ + TMP (19 SMZ/1 TMP) is respectively 64, 0.5 and 2 mg/l. 98% of methi.S strains have a FIC index less than or equal to 0.6 and only one strain has a FIC index greater than or equal to 0.6. In methi.R strains, the MIC 90% of SMZ, TMP and SMZ + TMP is respectively 256, 0.5 and 4 mg/l. 77% of methi.R strains have a FIC index less than or equal to 0.6. The relationship between FIC index and disc diffusion method is studied: bridging inhibition zone between SMZ 200 mcg disc, and TMP 2.5 micrograms disc and difference of the inhibition diameter between SMZ + TMP disc and TMP 1.25 micrograms disc. There is a good correlation only in methi.S strains in the first method and in methi.S and methi.R strains in the second method.

To evaluate the efficacy of cefuroxime, a second generation cephalosporin, in minimizing the risk of per and postoperative infection complications in patients with urinary tract infection undergoing transurethral surgery, 86 patients (ASA I, II) with persistent urinary tract infection despite antibiotic therapy were studied. A double blind protocol was followed. Patients were randomly assigned to receive 10 minutes before surgery either I.V. cefuroxime (1.5 g) (group C, n = 39) or placebo (group P, n = 47) the incidence of positive peroperative systematic blood cultures was lower in group C (9.7%) than in group P (25.2%) (p less than 0.001). The incidence of postoperative blood cultures taken when clinical septic signs were present, was significantly lower in group C (0%) than in group P (21.7%) (p less than 0.05). However neither the incidences of both postoperative urinary tract infection at the 48th postoperative hour and the clinical signs of bacteraemia including fever nor the average length of hospitalization were significantly different in the 2 groups. This lack of significant clinical benefit was not explained by the pharmacokinetic properties of this antibiotic. Thus, preoperative administration of a single dose of cefuroxime, reduces the incidence of per and postoperative bacteraemias in ASA I-II patients with persistent urinary tract infection.

MIC of ceftriaxone, moxalactam and cefotaxime is determined for 827 strains of Enterobacteriaceae isolated in the Central Laboratory of the Pitié-Salpêtrière Hospital between december 1981 and september 1982. Results are distributed according to the species involved and the pattern of sensitivity (S) and resistance (R) to ampicillin (A), carbenicilline (Ca) and cephalotin (Ct). Among the strains ASCaSCtS and ARCaRCtS cefotaxime and ceftriaxone have the lowest MICs. Among the most sensitive strains ARCaSCtR and ARCaRCtR cefotaxime, ceftriaxone and moxalactam have the similar MICs, whereas among the less sensitive ones moxalactam has the lowest MICs. The latter might be the cephalosporin of choice for the treatment of serious infection due to the less sensitive Enterobacteriaceae. On the other hand, cefotaxime and ceftriaxone might be the cephalosporins of choice for the treatment of serious infections due to the most sensitive Enterobacteriaceae.

This study compares the probability of in vitro activity of amoxicillin-clavulanic acid combination (AMOX-CLA) with those of amoxicillin (AMOX), cephalothin (CEPH), cotrimoxazole (COT) and nalidixic acid (NAL) on the 2 003 strains isolated during the first semester of 1983 in 5 wards of medicine (MED), 2 of gynecology-obstetrics (GYN) and 1 of pediatrics (PED) at the Pitié-Salpêtrière Hospital. As expected, AMOX-CLA was active on most of the strains of S. aureus, E. coli, P. mirabilis, Klebsiella and Bacteroides resistant to AMOX. AMOX-CLA was active on 70 to 86% of all strains, a higher rate than that of AMOX in all situations taken in concert. AMOX-CLA was more often active than AMOX on urinary strains by 17% in MED and GYN, 26% in neonates and 37% in children; it was more often active by 16% on strains isolated from the genital tract and from specimens taken at birth, and by 43% on strains isolated from pus. AMOX-CLA showed the same activity rate as CEPH whatever the infection and was as often active as COT and NAL on urinary strains in MED. On the opposite, activity rates of AMOX-CLA were lower by 6 to 15% than those of COT and NAL on urinary strains in GYN and PED of COT on strains isolated from pus in MED, GYN and PED. Therefore, AMOX-CLA was superior to AMOX in every case, and comparable to CEPH and often COT and NAL, whose use is restricted in pregnant women and neonates owing to side effects.

Intermittent regimens with rifampicin (RMP) for chemotherapy of pulmonary tuberculosis are cheaper and can be usually supervised more easily than daily regimens. They are recommended, specially, in developing countries. The present study is designed to evaluate the reduction of RMP activity as the interval between doses is increased in experimental mouse tuberculosis. The mice are given 10 mg/kg oral doses of RMP once, twice, three times or six times a week. The RMP activity is measured as the decrease of viable counts (cfu) in the spleen of mice. RMP given once a week has no activity neither in combination with isoniazid and streptomycin on a large population of organisms nor alone on a small population. RMP given alone twice a week has an activity slightly better than RMP given once a week. RMP given alone three times a week has a weak but not worthy activity: the mean number of cfu after a three times weekly treatment is significantly lower than the mean number of cfu in control (p less than 0.001) but significantly higher than the mean number of cfu after a six times weekly treatment (p less than 0.001). These experimental results are consistent with the experimental data on the effects of RMP on the RNA polymerase. They are not favourable to the intermittent administration of RMP in the chemotherapy of tuberculosis.