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The path of most resistance
Set against the backdrop of an antibiotic apocalypse in near future London. Rosa Scott, a brilliant and obsessive surgeon becomes Surgeon X, a vigilante doctor who uses experimental surgery and black market drugs to treat patients. But as Surgeon X, Rosa soon develops a godlike-complex, deciding who will live and who will die. Ultimately, she believes that to survive in this compromised world her own warped moral code is the one she must follow--even if it endangers those closest to her.
Book
Antimicrobial Resistance in Bacteria: Mechanisms, Evolution, and Persistence
In recent years, we have seen antimicrobial resistance rapidly emerge at a global scale and spread from one country to the other faster than previously thought. Superbugs and multidrug-resistant bacteria are endemic in many parts of the world. There is no question that the widespread use, overuse, and misuse of antimicrobials during the last 80 years have been associated with the explosion of antimicrobial resistance. On the other hand, the molecular pathways behind the emergence of antimicrobial resistance in bacteria were present since ancient times. Some of these mechanisms are the ancestors of current resistance determinants. Evidently, there are plenty of putative resistance genes in the environment, however, we cannot yet predict which ones would be able to be expressed as phenotypes in pathogenic bacteria and cause clinical disease. In addition, in the presence of inhibitory and sub-inhibitory concentrations of antibiotics in natural habitats, one could assume that novel resistance mechanisms will arise against antimicrobial compounds. This review presents an overview of antimicrobial resistance mechanisms, and describes how these have evolved and how they continue to emerge. As antimicrobial strategies able to bypass the development of resistance are urgently needed, a better understanding of the critical factors that contribute to the persistence and spread of antimicrobial resistance may yield innovative perspectives on the design of such new therapeutic targets.
Journal Article
A new antibiotic selectively kills Gram-negative pathogens
The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens
1
,
2
. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds
3
,
4
. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s
2
. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on
Photorhabdus
symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of
Photorhabdus
isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
Bacterial symbionts of animals may contain antibiotics that are particularly suitable for development into therapeutics; one such compound, darobactin, is active against important Gram-negative pathogens both in vitro and in animal models of infection.
Journal Article
Species-specific activity of antibacterial drug combinations
The spread of antimicrobial resistance has become a serious public health concern, making once-treatable diseases deadly again and undermining the achievements of modern medicine
1
,
2
. Drug combinations can help to fight multi-drug-resistant bacterial infections, yet they are largely unexplored and rarely used in clinics. Here we profile almost 3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in six strains from three Gram-negative pathogens—
Escherichia coli
,
Salmonella enterica
serovar Typhimurium and
Pseudomonas aeruginosa
—to identify general principles for antibacterial drug combinations and understand their potential. Despite the phylogenetic relatedness of the three species, more than 70% of the drug–drug interactions that we detected are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies. Overall, antagonisms are more common than synergies and occur almost exclusively between drugs that target different cellular processes, whereas synergies are more conserved and are enriched in drugs that target the same process. We provide mechanistic insights into this dichotomy and further dissect the interactions of the food additive vanillin. Finally, we demonstrate that several synergies are effective against multi-drug-resistant clinical isolates in vitro and during infections of the larvae of the greater wax moth
Galleria mellonella
, with one reverting resistance to the last-resort antibiotic colistin.
Screening pairwise combinations of antibiotics and other drugs against three bacterial pathogens reveals that antagonistic and synergistic drug–drug interactions are specific to microbial species and strains.
Journal Article
Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity
Background
Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D).
Aim
To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility.
Methods
Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods.
Results
Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (
n
= 37) or placebo (
n
= 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase,
Clostridium difficile
was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008–1 µg/mL] and rifampin (MIC range 0.004–0.25 µg/mL). Following double-blind rifaximin treatment,
Staphylococcus
isolates remained susceptible to rifaximin at all visits (MIC
50
range ≤0.06–32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested.
Conclusions
In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics.
ClinicalTrials.gov Identifier
NCT01543178.
Journal Article
Combination of pre-adapted bacteriophage therapy and antibiotics for treatment of fracture-related infection due to pandrug-resistant Klebsiella pneumoniae
A 30-year-old bombing victim with a fracture-related pandrug-resistant
Klebsiella pneumoniae
infection after long-term (>700 days) antibiotic therapy is treated with a pre-adapted bacteriophage along with meropenem and colistin, followed by ceftazidime/avibactam. This salvage therapy results in objective clinical, microbiological and radiological improvement of the patient’s wounds and overall condition. In support, the bacteriophage and antibiotic combination is highly effective against the patient’s
K. pneumoniae
strain in vitro, in 7-day mature biofilms and in suspensions.
In this case study of a patient with fracture-related pandrug-resistant Klebsiella pneumoniae infection after long-term antibiotic therapy, the authors use a combination therapy of pre-adapted bacteriophage and antibiotics resulting in clinical, microbiological and radiological improvement.
Journal Article
Antibiotic collateral sensitivity is contingent on the repeatability of evolution
Antibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of collateral sensitivities, wherein evolution under a first drug induces susceptibility to a second. Here, we report that sequential drug regimens derived from in vitro evolution experiments may have overstated therapeutic benefit, predicting a collaterally sensitive response where cross-resistance ultimately occurs. We quantify the likelihood of this phenomenon by use of a mathematical model parametrised with combinatorially complete fitness landscapes for
Escherichia coli
. Through experimental evolution we then verify that a second drug can indeed stochastically exhibit either increased susceptibility or increased resistance when following a first. Genetic divergence is confirmed as the driver of this differential response through targeted and whole genome sequencing. Taken together, these results highlight that the success of evolutionarily-informed therapies is predicated on a rigorous probabilistic understanding of the contingencies that arise during the evolution of drug resistance.
The evolution of resistance to an antibiotic can render bacteria more susceptible, or more resistant, to a second antibiotic. Here, Nichol et al. provide evidence that the final outcome can be fairly stochastic and depends on the shape of the evolutionary fitness landscape.
Journal Article
Government policy interventions to reduce human antimicrobial use: A systematic review and evidence map
Growing political attention to antimicrobial resistance (AMR) offers a rare opportunity for achieving meaningful action. Many governments have developed national AMR action plans, but most have not yet implemented policy interventions to reduce antimicrobial overuse. A systematic evidence map can support governments in making evidence-informed decisions about implementing programs to reduce AMR, by identifying, describing, and assessing the full range of evaluated government policy options to reduce antimicrobial use in humans.
Seven databases were searched from inception to January 28, 2019, (MEDLINE, CINAHL, EMBASE, PAIS Index, Cochrane Central Register of Controlled Trials, Web of Science, and PubMed). We identified studies that (1) clearly described a government policy intervention aimed at reducing human antimicrobial use, and (2) applied a quantitative design to measure the impact. We found 69 unique evaluations of government policy interventions carried out across 4 of the 6 WHO regions. These evaluations included randomized controlled trials (n = 4), non-randomized controlled trials (n = 3), controlled before-and-after designs (n = 7), interrupted time series designs (n = 25), uncontrolled before-and-after designs (n = 18), descriptive designs (n = 10), and cohort designs (n = 2). From these we identified 17 unique policy options for governments to reduce the human use of antimicrobials. Many studies evaluated public awareness campaigns (n = 17) and antimicrobial guidelines (n = 13); however, others offered different policy options such as professional regulation, restricted reimbursement, pay for performance, and prescription requirements. Identifying these policies can inform the development of future policies and evaluations in different contexts and health systems. Limitations of our study include the possible omission of unpublished initiatives, and that policies not evaluated with respect to antimicrobial use have not been captured in this review.
To our knowledge this is the first study to provide policy makers with synthesized evidence on specific government policy interventions addressing AMR. In the future, governments should ensure that AMR policy interventions are evaluated using rigorous study designs and that study results are published.
PROSPERO CRD42017067514.
Journal Article
Resist or perish: Fate of a microbial population subjected to a periodic presence of antimicrobial
The evolution of antimicrobial resistance can be strongly affected by variations of antimicrobial concentration. Here, we study the impact of periodic alternations of absence and presence of antimicrobial on resistance evolution in a microbial population, using a stochastic model that includes variations of both population composition and size, and fully incorporates stochastic population extinctions. We show that fast alternations of presence and absence of antimicrobial are inefficient to eradicate the microbial population and strongly favor the establishment of resistance, unless the antimicrobial increases enough the death rate. We further demonstrate that if the period of alternations is longer than a threshold value, the microbial population goes extinct upon the first addition of antimicrobial, if it is not rescued by resistance. We express the probability that the population is eradicated upon the first addition of antimicrobial, assuming rare mutations. Rescue by resistance can happen either if resistant mutants preexist, or if they appear after antimicrobial is added to the environment. Importantly, the latter case is fully prevented by perfect biostatic antimicrobials that completely stop division of sensitive microorganisms. By contrast, we show that the parameter regime where treatment is efficient is larger for biocidal drugs than for biostatic drugs. This sheds light on the respective merits of different antimicrobial modes of action.
Journal Article