An experimental test of host’s life history traits modulation in response to cuckoo parasitism risk

Hosts can counteract parasites through defences based on resistance and/or tolerance. The mechanistic basis of tolerance, which involve defensive mechanisms minimizing parasite damage after a successful parasitic attack, remains poorly explored in the study of cuckoo-host interactions. Here, we experimentally explore the possibility that the risk of great spotted cuckoo Clamator glandarius parasitism may induce tolerance defences in magpie Pica pica hosts through plasticity in life-history traits. We predict that magpies exposed to auditory cues indicating high parasitism risk will more likely exhibit resistance and/or modify their life-history traits to minimize parasitism costs (i.e. tolerance) compared to magpies under low parasitism risk. We found that manipulating the perceived parasitism risk did not affect host resistance (i.e. rejection of parasitic eggs) nor host life-history traits. Unexpectedly, host's egg volume increased over the season in nests exposed to auditory cues of control non-harmful hoopoes Upupa epops. Our results do not provide support for inducible defences (either based on resistance or tolerance) in response to risk of parasitism in magpie hosts. Even so, we encourage studying plastic expression of breeding strategies in response to risk of cuckoo parasitism to achieve a better understanding of the mechanistic basis of tolerance defences.This work was supported by the Spanish Ministry of Education and Science/FEDER (Projects CGL2011-27561/BOS and CGL2014-56769-P to D. P. and J.M.A.). D.P. was supported by the Government of Extremadura while writing (contract number TA13002). M.E.G. was supported by the Spanish Ministry of Economy and Competitiveness (grant number BES-2012-051898).

MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network.

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core published documents and guidelines have been reviewed, including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities

Threatened reef corals of the world

10.1371/journal.pone.0034459PLoS ONE73

Clinical standards for the dosing and management of TB drugs

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on ‘best practice´ for dosing and management of TB drugs. METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants. RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified. CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care

Clinical standards for the dosing and management of TB drugs

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care

Meropenem-clavulanate has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis

Aims and objectives: With the relentless increase in multidrug- and extensively-drug resistant tuberculosis (MDR/XDR-TB), new treatment strategies are necessary. Favorable results have been reported by combining a β-lactam antibiotic and a β-lactamase inhibitor. The β-lactamase encoded by the blaC gene of Mycobacterium tuberculosis (MTB) is the major mechanism of resistance to β-lactam antibiotics (e.g., penicillin). Meropenem, a β-lactam antibiotic of the carbapenem group, is a relatively weak substrate for the β-lactamase of MTB. The β-lactamase inhibitor clavulanate irreversibly inactivates the β-lactamase encoded by the blaC gene, thus making the combination of meropenem and clavulanate an interesting treatment alternative for MTB. However, very few isolates of MTB have been tested for this drug combination and few clinical reports exist. Thus, the present study investigates the in vitro activity of meropenem-clavulanate for drug-resistant MTB isolates, including MDR/XDR-TB. Methods: The minimum inhibitory concentration (MIC) distribution of meropenem-clavulanate was determined using Middlebrook 7H10, including MDR and XDR strains of MTB (n = 68). Meropenem was prepared in a stock solution with a final concentration range of 0.002–512 mg/L. Clavulanate was added at a fixed concentration of 64 mg/L, to avoid a decline of the β-lactamase to insufficient levels during the experiment. All isolates were evaluated after three weeks of growth. The pan-susceptible strain H37Rv was used as a control. Results: There was a Gaussian MIC-distribution between 0.125 and 2 mg/L of meropenem-clavulanate (expressed as the concentration of meropenem), but four isolates had very high MIC levels (16 and 32 mg/L), which is likely to be out of reach in clinical doses ([Figure 1). The susceptibility of the isolates to meropenem-clavulanate was not correlated to the level of resistance to first- or second-line anti-tuberculous drugs. The MIC of the pan-susceptible control strain H37Rv was 1 mg/L of meropenem, when combined with clavulanate.{Figure 1} Conclusions: The present study shows that meropenem-clavulanate has low MICs against MTB in vitro, including MDR and XDR-TB isolates. Meropenem has good tissue penetration and low protein-binding, but requires an intravenous access and is relatively expensive. Meropenem-clavulanate may be a treatment option in selected cases of MDR/XDR-TB, although further clinical studies are warranted

Meropenem-Clavulanic Acid Has High In Vitro Activity against Multidrug-Resistant Mycobacterium tuberculosis

We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB.Funding Agencies|Swedish Society of Medicine [SLS 169241]; Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation (Oscar II Jubilee Foundation); Swedish Society of Antimicrobial Chemotherapy; Research Council of Southeast Sweden (FORSS)</p

Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis

We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC(0-24)/MIC) using greater than= 25 as a potential target, the cumulative fraction response was greater than= 90% at doses of greater than= 2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.Funding Agencies|Swedish Society of Medicine [SLS 169241]; Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation (Oscar II Jubilee Foundation); Swedish Society of Antimicrobial Chemotherapy</p