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\"In 1943, Albert Schatz, a young American PhD student, worked on a wartime project in microbiology professor Selman Waksman's lab, searching for an antibiotic to fight infections on the front lines and at home. On his eleventh experiment on a common bacterium found in farmyard soil, Schatz discovered streptomycin, the first effective cure for tuberculosis, at that time the world's leading killer disease. As director of Schatz's reserach, Waksman took credit for the discovery, belittled Schatz's work, and secretly enriched himself with royalties from the streptomycin patent filed by Merck. In [1950, and in] an unprecedented lawsuit, young Schatz sued Waksman, was awarded the title of 'co-discoverer', and a share of the royalties. But two years later, Professor Waksman alone was awarded the Nobel Prize. Schatz disappeared into academic obscurity. ...\"--Book jacket.

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. 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. 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. 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. WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.

Data on treatments for bubonic plague are limited. In this open-label, randomized, controlled trial in Madagascar, ciprofloxacin monotherapy was noninferior to a standard aminoglycoside–ciprofloxacin regimen.

Background Bubonic plague is the primary manifestation of infection with Yersinia pestis , accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. Methods A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague ‘seasons’. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. Discussion If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. Trial registration ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019

It has become increasingly clear that low levels of antibiotics present in many environments can select for resistant bacteria, yet the evolutionary pathways for resistance development during exposure to low amounts of antibiotics remain poorly defined. Here we show that Salmonella enterica exposed to sub-MIC levels of streptomycin evolved high-level resistance via novel mechanisms that are different from those observed during lethal selections. During lethal selection only rpsL mutations are found, whereas at sub-MIC selection resistance is generated by several small-effect resistance mutations that combined confer high-level resistance via three different mechanisms: (i) alteration of the ribosomal RNA target ( gidB mutations), (ii) reduction in aminoglycoside uptake ( cyoB , nuoG , and trkH mutations), and (iii) induction of the aminoglycoside-modifying enzyme AadA ( znuA mutations). These results demonstrate how the strength of the selective pressure influences evolutionary trajectories and that even weak selective pressures can cause evolution of high-level resistance. Mutational antibiotic resistance can emerge under either high or low antibiotic levels. Here, the authors show several small-effect resistance mutations are combined to confer high-level resistance in Salmonella enterica exposed to sub-MIC levels of streptomycin.

Most bacteria use an indirect pathway to generate aminoacylated glutamine and/or asparagine tRNAs. Clinical isolates of Mycobacterium tuberculosis with increased rates of error in gene translation (mistranslation) involving the indirect tRNA-aminoacylation pathway have increased tolerance to the first-line antibiotic rifampicin. Here, we identify that the aminoglycoside kasugamycin can specifically decrease mistranslation due to the indirect tRNA pathway. Kasugamycin but not the aminoglycoside streptomycin, can limit emergence of rifampicin resistance in vitro and increases mycobacterial susceptibility to rifampicin both in vitro and in a murine model of infection. Moreover, despite parenteral administration of kasugamycin being unable to achieve the in vitro minimum inhibitory concentration, kasugamycin alone was able to significantly restrict growth of Mycobacterium tuberculosis in mice. These data suggest that pharmacologically reducing mistranslation may be a novel mechanism for targeting bacterial adaptation. A bacterium called Mycobacterium tuberculosis is responsible for nearly 98% of cases of tuberculosis, which kills more people worldwide than any other infectious disease. This is due, in part, to the time it takes to cure individuals of the disease: patients have to take antibiotics continuously for at least six months to eradicate M. tuberculosis in the body. Bacteria, like all cells, make proteins using instructions contained within their genetic code. Cell components called ribosomes are responsible for translating these instructions and assembling the new proteins. Sometimes the ribosomes produce proteins that are slightly different to what the cell’s genetic code specified. These ‘incorrect proteins’ may not work properly so it is generally thought that cells try to prevent the mistakes from happening. However, scientists have recently found that the ribosomes in M. tuberculosis often assemble incorrect proteins. The more mistakes the ribosomes let happen, the more likely the bacteria are to survive when they are exposed to rifampicin, an antibiotic which is often used to treat tuberculosis infections. This suggests that it may be possible to make antibiotics more effective against M. tuberculosis by using them alongside a second drug that decreases the number of ribosome mistakes. Chaudhuri, Li et al. investigated the effect of a drug called kasugamycin on M. tuberculosis when the bacterium is cultured in the lab, and when it infects mice. The experiments found that Kasugamycin decreased the number of incorrect proteins assembled by the M. tuberculosis bacterium. When the drug was present, rifampicin also killed M. tuberculosis cells more efficiently. Furthermore, in the mice but not the cell cultures, kasugamycin alone was able to restrict the growth of the bacteria. This implies that M. tuberculosis cells may use ribosome mistakes as a strategy to survive in humans and other hosts. When it was given with rifampicin, kasugamycin caused several unwanted side effects in the mice, including weight loss; this may mean that the drug is currently not suitable to use in humans. Further studies may be able to find safer ways to decrease ribosome mistakes in M. tuberculosis, which could speed up the treatment of tuberculosis.

Mycobacterium tuberculosis periprosthetic joint infection (TBPJI) is a rare complication of hip/knee joint arthroplasty. The outcomes of hip/knee TBPJI treatment are still unreported. The objective of this study was to investigate the outcomes of hip/knee TBPJI following treatment with two-stage exchange arthroplasty. From 2003 to 2013, 11 patients with TBPJI (six hips and five knees) were treated with two-stage exchange arthroplasty at our institution. We collected and analyzed variables including demographic data, comorbidities, microbiological data, duration of symptoms, and types of antibiotic used in bone cement. At the most recent follow-up, the success rate of two-stage exchange arthroplasty was 63.3% (7 of 11). All five knee treatments resulted in infection eradication and successful prosthesis reimplantation. However, only two hip TBPJI treatments resulted in successful outcomes; two patients died and two experienced chronic infection. Overall, secondary bacterial infections were common in patients with TBPJI (5 of 11 cases, 45.5%). Streptomycin in bone cement increased the success rate (83.33% vs. 40%). More than one third of the patients treated with two-stage exchange arthroplasty for TBPJI showed infection relapse or uncontrolled infection. Streptomycin-loaded interim cement spacers appeared to help ensure successful treatment. Routine M. tuberculosis culture is recommended when treating TBPJI in areas of high tuberculosis prevalence.

Buruli Ulcer (BU) is a tropical infectious skin disease that is currently treated with 8 weeks of intramuscular streptomycin and oral rifampicin. As prolonged streptomycin administration can cause both oto- and nephrotoxicity, we evaluated its long term toxicity by following-up former BU patients that had received either 4 or 8 weeks of streptomycin in addition to other drugs between 2006 and 2008, in the context of a randomized controlled trial. Former patients were retrieved in 2012, and oto- and nephrotoxicity were determined by audiometry and serum creatinine levels. Data were compared with baseline and week 8 measurements during the drug trial. Of the total of 151 former patients, 127 (84%) were retrieved. Ototoxicity was present in 29% of adults and 25% of children. Adults in the 8 week streptomycin group had significantly higher hearing thresholds in all frequencies at long term follow-up, and these differences were most prominent in the high frequencies. In children, no differences between the two treatment arms were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2.4% of patients at long term follow-up. Prolonged streptomycin administration in the adult study subjects caused significant persistent hearing loss, especially in the high frequency range. Nephrotoxicity was also present in both adults and children but appeared to be transient. Streptomycin should be given with caution especially in patients aged 16 or older, and in individuals with concurrent risks for renal dysfunction or hearing loss.

Allergic asthma rates have increased steadily in developed countries, arguing for an environmental aetiology. To assess the influence of gut microbiota on experimental murine allergic asthma, we treated neonatal mice with clinical doses of two widely used antibiotics—streptomycin and vancomycin—and evaluated resulting shifts in resident flora and subsequent susceptibility to allergic asthma. Streptomycin treatment had little effect on the microbiota and on disease, whereas vancomycin reduced microbial diversity, shifted the composition of the bacterial population and enhanced disease severity. Neither antibiotic had a significant effect when administered to adult mice. Consistent with the ‘hygiene hypothesis’, our data support a neonatal, microbiota‐driven, specific increase in susceptibility to experimental murine allergic asthma. Allergic asthma rates are increasing in developed countries, arguing for an environmental aetiology. Profound changes in gut microbiota are reported in response to treatment in early life with the widely used antibiotic vancomycin, influencing asthma susceptibility.

Bacteria commonly live in dense and genetically diverse communities associated with surfaces. In these communities, competition for resources and space is intense, and yet we understand little of how this affects the spread of antibiotic-resistant strains. Here, we study interactions between antibiotic-resistant and susceptible strains using in vitro competition experiments in the opportunistic pathogen Pseudomonas aeruginosa and in silico simulations. Selection for intracellular resistance to streptomycin is very strong in colonies, such that resistance is favoured at very low antibiotic doses. In contrast, selection for extracellular resistance to carbenicillin is weak in colonies, and high doses of antibiotic are required to select for resistance. Manipulating the density and spatial structure of colonies reveals that this difference is partly explained by the fact that the local degradation of carbenicillin by β-lactamase-secreting cells protects neighbouring sensitive cells from carbenicillin. In addition, we discover a second unexpected effect: the inducible elongation of cells in response to carbenicillin allows sensitive cells to better compete for the rapidly growing colony edge. These combined effects mean that antibiotic treatment can select against antibiotic-resistant strains, raising the possibility of treatment regimes that suppress sensitive strains while limiting the rise of antibiotic resistance. We argue that the detailed study of bacterial interactions will be fundamental to understanding and overcoming antibiotic resistance.