Coronavirus disease 19 (COVID-19) is responsible for one of the worst pandemics in human history. The causative virus, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), can invade host cells in multiple organs by binding the angiotensin-converting enzyme (ACE) II expressed on the cell surface. Once inside the host cell, viral replication takes place, leading to cellular disruption and the release of signal molecules that are recognised by the innate immune system. Innate immunity activation leads to the release of proinflammatory cytokines and primes the adaptive immune system. The proinflammatory environment defends against further viral entry and replication. SARS-CoV-2 infection is thought to lead to myocardial injury through several mechanisms. Firstly, direct viral-mediated cellular invasion of cardiomyocytes has been shown in in vitro and histological studies, which is related to cellular injury. Secondly, the proinflammatory state during COVID-19 can lead to myocardial injury and the release of protein remnants of the cardiac contractile machinery. Thirdly, the hypercoagulable state of COVID-19 is associated with thromboembolism of coronary arteries and/or other vascular systems. COVID-19 patients can also develop heart failure; however, the underlying mechanism is much less well-characterised than for myocardial injury. Several questions remain regarding COVID-19-related heart failure, including its potential reversibility, the role of anti-viral medications in its prevention, and the mechanisms underlying heart failure pathogenesis in long COVID-19. Further work is required to improve our understanding of the mechanism of cardiac sequelae in COVID-19, which may enable us to target SARS-CoV-2 and protect patients against longer-lasting cardiovascular complications.

Introduction Assessment of inpatient mortality risk in COVID-19 patients is important for guiding clinical decision-making. High sensitivity cardiac troponin T (hs-cTnT) is a biomarker of cardiac injury associated with a worse prognosis in COVID-19. We explored how hs-cTnT could potentially be used in clinical practice for ruling in and ruling out mortality in COVID-19. Method We tested the diagnostic value of hs-cTnT in laboratory-confirmed COVID-19 patients (≥18 years old) admitted to the Royal Berkshire Hospital (UK) between 1st March and 10th May 2020. A normal hs-cTnT was defined as a value within the 99th percentile of healthy individuals (≤14 ng/L), and an elevated hs-cTnT was defined as >14 ng/L. Adverse clinical outcome was defined as inpatient mortality related to COVID-19. Results A total of 191 COVID-19 patients (62% male; age 66±16 years) had hs-cTnT measured on admission. Of these patients, 124 (65%) had elevated hs-cTnT and 67 (35%) had normal hs-cTnT. On a group level, patients with elevated hs-cTnT had worse inpatient survival (p = 0.0014; Kaplan-Meier analysis) and higher risk of inpatient mortality (HR 5.84 [95% CI 1.29–26.4]; p = 0.02; Cox multivariate regression) compared to patients with normal hs-cTnT. On a per-patient level, a normal hs-cTnT had a negative predictive value of 94% (95% CI: 85–98%) for ruling out mortality, whilst an elevated hs-cTnT had a low positive predictive value of 38% (95% CI: 39–47%) for ruling in mortality. Conclusions In this study cohort of COVID-19 patients, the potential clinical utility of hs-cTnT appears to rest in ruling out inpatient mortality. This finding, if prospectively validated in a larger study, may allow hs-cTnT to become an important biomarker to facilitate admission-avoidance and early safe discharge.

Background: CRB-65 (Confusion; Respiratory rate ≥ 30/min; Blood pressure ≤ 90/60 mmHg; age ≥ 65 years) is a risk score for prognosticating patients with COVID-19 pneumonia. However, a significant proportion of COVID-19 patients have normal chest X-rays (CXRs). The influence of CXR abnormalities on the prognostic value of CRB-65 is unknown, limiting its wider applicability. Methods: We assessed the influence of CXR abnormalities on the prognostic value of CRB-65 in COVID-19. Results: In 589 study patients (71 years (IQR: 57-83); 57% males), 186 (32%) had normal CXRs. On ROC analysis, CRB-65 performed similarly in patients with normal vs. abnormal CXRs for predicting inpatient mortality (AUC 0.67 ± 0.05 vs. 0.69 ± 0.03). In patients with normal CXRs, a CRB-65 of 0 ruled out mortality, NIV requirement and critical illness (intubation and/or ICU admission) with negative predictive values (NPVs) of 94%, 98% and 99%, respectively. In patients with abnormal CXRs, a CRB-65 of 0 ruled out the same endpoints with NPVs of 91%, 83% and 86%, respectively. Patients with low CRB-65 scores had better inpatient survival than patients with high CRB-65 scores, irrespective of CXR abnormalities (all p < 0.05). Conclusions: CRB-65, CXR and CRP are independent predictors of mortality in COVID-19. Adding CXR findings (dichotomised to either normal or abnormal) to CRB-65 does not improve its prognostic accuracy. A low CRB-65 score of 0 may be a good rule-out test for adverse clinical outcomes in COVID-19 patients with normal or abnormal CXRs, which deserves prospective validation.

Background: In COVID-19 patients, lymphocyte-CRP ratio (LCR) is a promising biomarker for predicting adverse clinical outcomes. How well LCR performs compared to conventional inflammatory markers for prognosticating COVID-19 patients remains unclear, which hinders the clinical translation of this novel biomarker. Methods: In a cohort of COVID-19 inpatients, we characterised the clinical applicability of LCR by comparing its prognostic value against conventional inflammatory markers for predicting inpatient mortality and a composite of mortality, invasive/non-invasive ventilation and intensive care unit admissions. Results: Of the 413 COVID-19 patients, 100 (24%) patients suffered inpatient mortality. On Receiver Operating Characteristics analysis, LCR performed similarly to CRP for predicting mortality (AUC 0.74 vs. 0.71, p = 0.049) and the composite endpoint (AUC 0.76 vs. 0.76, p = 0.812). LCR outperformed lymphocyte counts (AUC 0.74 vs. 0.66, p = 0.002), platelet counts (AUC 0.74 vs. 0.61, p = 0.003) and white cell counts (AUC 0.74 vs. 0.54, p < 0.001) for predicting mortality. On Kaplan-Meier analysis, patients with a low LCR (below a 58 cut-off) had worse inpatient survival than patients with other LCR values (p < 0.001). Conclusion: LCR appears comparable to CRP, but outperformed other inflammatory markers, for prognosticating COVID-19 patients. Further studies are required to improve the diagnostic value of LCR to facilitate clinical translation.

Introduction: The ferritin–lymphocyte ratio (FLR) is a novel inflammatory biomarker for the assessment of acute COVID-19 patients. However, the prognostic value of FLR for predicting adverse clinical outcomes in COVID-19 remains unclear, which hinders its clinical translation. Methods: We characterised the prognostic value of FLR in COVID-19 patients, as compared to established inflammatory markers. Results: In 217 study patients (69 years [IQR: 55–82]; 60% males), FLR was weakly correlated with CRP (R = 0.108, p = 0.115) and white cell count (R = −0.144; p = 0.034). On ROC analysis, an FLR cut-off of 286 achieved a sensitivity of 86% and a specificity of 30% for predicting inpatient mortality (AUC 0.60, 95% CI: 0.53–0.67). The negative predictive values of FLR for ruling out mortality, non-invasive ventilation requirement and critical illness (intubation and/or ICU admission) were 86%, 85% and 93%, respectively. FLR performed similarly to CRP (AUC 0.60 vs. 0.64; p = 0.375) for predicting mortality, but worse than CRP for predicting non-fatal outcomes (all p < 0.05). On Kaplan–Meier analysis, COVID-19 patients with FLR values > 286 had worse inpatient survival than patients with FLR ≤ 286, p = 0.041. Conclusions: FLR has prognostic value in COVID-19 patients, and appears unrelated to other inflammatory markers such as CRP and WCC. FLR exhibits high sensitivity and negative predictive values for adverse clinical outcomes in COVID-19, and may be a good “rule-out” test. Further work is needed to improve the sensitivity of FLR and validate its role in prospective studies for guiding clinical management.

In acute coronavirus disease 19 (COVID-19) patients, effective clinical risk stratification has important implications on treatment and therapeutic resource distribution. This article reviews the evidence behind a wide range of biomarkers with prognostic value in COVID-19. Patient characteristics and co-morbidities, such as cardiovascular and respiratory diseases, are associated with increased mortality risk. Peripheral oxygen saturation and arterial oxygenation are predictive of severe respiratory compromise, whereas risk scores such as the 4C-score enable multi-factorial prognostic risk estimation. Blood tests such as markers of inflammation, cardiac injury and d-dimer and abnormalities on electrocardiogram are linked to inpatient prognosis. Of the imaging modalities, lung ultrasound and echocardiography enable the bedside assessment of prognostic abnormalities in COVID-19. Chest radiograph (CXR) and computed tomography (CT) can inform about prognostic pulmonary pathologies, whereas cardiovascular CT detects high-risk features such as coronary artery and aortic calcification. Dynamic changes in biomarkers, such as blood tests, CXR, CT and electrocardiogram findings, can further inform about disease severity and prognosis. Despite the vast volumes of existing evidence, several gaps exist in our understanding of COVID-19 biomarkers. First, the pathophysiological basis on which these markers can foretell prognosis in COVID-19 remains poorly understood. Second, certain under-explored tests such as thoracic impedance assessment and cardiovascular magnetic resonance imaging deserve further investigation. Lastly, the prognostic values of most biomarkers in COVID-19 are derived from retrospective analyses. Prospective studies are required to validate these markers for guiding clinical decision-making and to facilitate their translation into clinical management pathways.

Pseudomonas aeruginosa is a Gram-negative bacterium which is capable of developing a high level of antibiotic resistance. It has been placed on the WHO's critical priority pathogen list and it is commonly found in ventilator-associated pneumonia infections, blood stream infections and other largely hospital-acquired illnesses. These infections are difficult to effectively treat due to their increasing antibiotic resistance and as such patients are often treated with antibiotic combination regimens. METHODS:We conducted a systematic search with screening criteria using the Ovid search engine and the Embase, Ovid Medline, and APA PsycInfo databases. RESULTS:It was found that in many cases the combination therapies were able to match or outperform the monotherapies and none performed noticeably worse than the monotherapies. However, the clinical studies were mostly small, only a few were prospective randomized clinical trials and statistical significance was lacking. CONCLUSIONS:It was concluded that combination therapies have a place in the treatment of these highly resistant bacteria and, in some cases, there is some evidence to suggest that they provide a more effective treatment than monotherapies.

Infections caused by carbapenem-resistant Enterobacterales are difficult to treat. Colistin is the last-resort drug for the treatment of these infections, however colistin resistance has emerged in animals and humans. This study investigated the in vitro efficacy of mefloquine in combination with colistin against 114 antibiotic-resistant Enterobacterales isolates including NDM-1, extended-spectrum beta-lactamase (ESBL) and mcr-1 containing strains from a broad range of origins. The effect of the mefloquine and colistin combination was examined in vitro by chequerboard method and time-kill analysis and in vivo in a murine peritoneal infection model. The fractional inhibitory concentration index (FICI) of the combination indicated that synergy was detected for all NDM-1 and mcr-1 containing strains, 87.5% of ESBL producing Escherichia coli and 97.9% of ESBL producing Klebsiella pneumoniae strains. Time-kill curves demonstrated significant synergistic activity with low concentrations of colistin that were boosted by mefloquine. The combination showed enhanced activity against infection with NDM-1- or mcr-1 containing Enterobacteriaceae in mice at 4 h and 6 h after treatment. These findings suggest that the combination of mefloquine and colistin has the potential for rejuvenating the activity of colistin against multidrug-resistant Enterobacterales. (C) 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Objectives: To investigate the efficacy of zidovudine in combination with carbapenems against NDM-1-producing Enterobacteriaceae. Methods: MICs were determined using the broth microdilution method. The combinatory effects of zidovudine and carbapenems were examined using the chequerboard method and time-kill analysis. Results: We found that the NDM-1-producing strains were resistant to all carbapenems tested. FIC index from chequerboard assay demonstrated that zidovudine synergized with carbapenems against all the NDM-1 strains. Time-kill analysis demonstrated significant synergistic activity when a Low Level of zidovudine was combined with meropenem. Conclusions: Zidovudine in combination with carbapenems produced synergistic activity against NDM-1 Enterobacteriaceae strains in vitro.

The development of optimal treatment regimens in tuberculosis (TB) remains challenging due to the need of combination therapy and possibility of pharmacodynamic (PD) interactions. Preclinical information about PD interactions needs to be used more optimally when designing early bactericidal activity (EBA) studies. In this work, we developed a translational approach which can allow for forward translation to predict efficacy of drug combination in EBA studies using the Multistate Tuberculosis Pharmacometric (MTP) and the General Pharmacodynamic Interaction (GPDI) models informed by in vitro static time‐kill data. These models were linked with translational factors to account for differences between the in vitro system and humans. Our translational MTP‐GPDI model approach was able to predict the EBA 0–2 days , EBA 0–5 days , and EBA 0–14 days from different EBA studies of rifampicin and isoniazid in monotherapy and combination. Our translational model approach can contribute to an optimal dose selection of drug combinations in early TB clinical trials.

Antimicrobial resistance is one of the greatest challenges for humanity. Patients, especially, admitted to the intensive care unit have been exposed to higher risk of healthcare associated infections mostly caused by antibiotic resistance since the imprudent use of antibiotics over the years. The discovery and development of new antibiotics are facing difficulties with the continuous evolution of drug resistance in bacteria, and the reduced investment in R&D for antibiotics from pharmaceutical companies. Novel strategies are urgently needed to control this pandemic threat of antibiotic resistance. Antibiotic combination with two or more drugs may be useful in targeting resistant gram-negative bacteria by producing synergistic effect and enhanced bactericidal activates. In this study, we determined the combination of rifampicin and colistin against Extended Spectrum Beta Lactamase (ESBL), carbapenemase producing and colistin resistant Enterobacteriaceae using chequerboard method and time kill curves. We measured the combination effects based on Fractional Inhibitory Concentration index (FICI) and the efficacy of bacterial reduction comparing to that of single antibiotic. Interestingly, we found that the combination of rifampicin and colistin showed synergistic activities against the tested bacteria, indicating FIC index ≤0.5. The time kill curve shows that the two drugs combination exhibits 99% kill whilst the single antibiotic had no activities. Thus, the combination of rifampicin and colistin demonstrated synergistic activity with reduced MIC and the increased rate of killing against both ESBL and carbapenemsase producing and colistin resistant Enterobacteriaceae.

Antimicrobial susceptibility testing (AST) performed according to defined guidelines is important to identify resistance and to predict the clinical success or failure of specific antibiotic therapy. However, these guidelines do not cover all physiological conditions that can have a tremendous impact on in vivo resistance. In this study, we tested the susceptibility of thirteen mcr-1-positive Escherichia coli strains against colistin, one of the last resort antibiotics for treating multi-drug resistant pathogens, in media recommended for ASTs as well as – physiologically more relevant – in human serum and artificial urine (AU). Minimal inhibitory concentration (MIC) values in heat-inactivated human serum were similar to those in cation-adjusted Mueller-Hinton broth (CAMHB), but reduced in native serum for almost all strains that could grow in this media. In AU MIC values for mcr-1 positive E. coli were increased significantly up to 16-fold compared to that in CAMBH, which did not apply to the colistin-susceptible E. coli strains tested. Although different growth media could affect the MIC of colistin alone, their impact on the synergistic effect of the combination with the antiviral drug azidothymidine was minimal. The higher divalent cation concentration combined with acidic pH values is most likely responsible for the increased MIC values of the mcr-1 harboring E. coli strains tested against colistin in AU compared to that in CAMHB. Antimicrobial susceptibility screening procedures for colistin using CAMHB only could lead to an underestimation of resistance under different physiological conditions. Therefore, not only pharmacokinetic but also pharmacodynamic studies in urine are as important as in serum or plasma.

BACKGROUND:We have previously demonstrated that Mycobacteria tuberculosis chaperonin 60.1 inhibits leucocyte diapedesis and bronchial hyperresponsiveness in a murine model of allergic lung inflammation.METHODS:In the present study, we have investigated the effect of a shorter peptide sequence derived from Cpn 60.1, named IRL201104, on allergic lung inflammation induced by ovalbumin (OVA) in mice and by house dust mite (HDM) in guinea pigs, as well as investigating the action of IRL201104 on human cells in vitro.RESULTS:Pre-treatment of mice or guinea pigs with IRL201104 inhibits the infiltration of eosinophils to the lung, cytokine release, and in guinea pig skin, inhibits allergen-induced vascular permeability. The protective effect of intranasal IRL201104 against OVA-induced eosinophilia persisted for up to 20 days post-treatment. Moreover, OVA-sensitized mice treated intranasally with 20 ng/kg of IRL201104 show a significant increase in the expression of the anti-inflammatory molecule ubiquitin A20 and significant inhibition of the activation of NF-κB in lung tissue. Our results also show that A20 expression was significantly reduced in blood leucocytes and ASM obtained from patients with asthma compared to cells obtained from healthy subjects which were restored after incubation with IRL201104 in vitro, when added alone, or in combination with LPS or TNF-α in ASM.CONCLUSIONS:Our results suggest that a peptide derived from mycobacterial Cpn60.1 has a long-lasting anti-inflammatory and immunomodulatory activity which may help explain some of the protective effects of TB against allergic diseases.

Introduction: Anti-Microbial Resistance (AMR) is a pandemic which threatens modern medicine. There is a lack of effective drug treatment due to the slow pace, high cost and low achievable sales prices of new antibiotic monotherapies. New hope comes in the shape of antibiotic combination therapy, which although used by mother nature, is under-explored and could provide the solution to AMR.Areas covered: We performed a search of Pubmed and Medline using the keywords 'combination therapy', 'antimicrobial resistance' for articles between 1930 and 2019, as supplemented with other relevant references to our knowledge. We have reviewed the theoretical considerations for combination development and examine the existing and future clinical indications of combination therapies. We have discussed the potential of antibiotic combinations to provide therapeutic synergy, rejuvenating the effectiveness of old antibiotics to which the bacteria had developed resistance previously. We have examined the current thinking and evidence on resistance reduction using combination therapies, with a review on toxicity and drug-drug antagonism.Expert opinion: Antibiotic combination therapy, exploiting synergies, old-drug rejuvenation and resistance reduction could provide the solution to AMR. The number of pharmaceutical companies in this area is likely to expand, bringing promising combinations to the bedside, to save millions of lives worldwide.

Proper characterization of drug effects on Mycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure–response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of in vitro and in vivo phenotypic resistance i.e. persisters, using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated based on bacterial cultures grown with and without drug exposure using CFU alone or CFU plus MPN data. Phenotypic resistance and total bacterial number in in vitro natural growth observations, i.e. without drug, was well predicted by the MTP model using only CFU data. Capturing the murine in vivo total bacterial number and persisters during natural growth did however require re-estimation of model parameter using both the CFU and MPN observations implying that the ratio of persisters to total bacterial burden is different in vitro compared to murine in vivo. The evaluation of the in vitro rifampicin drug effect revealed that higher resolution in the persister drug effect was seen using CFU and MPN compared to CFU alone although drug effects on the other bacterial populations were well predicted using only CFU data. The ratio of persistent bacteria to total bacteria was predicted to be different between in vitro and murine in vivo . This difference could have implications for subsequent translational efforts in tuberculosis drug development.

Staphylococcus aureus biofilms are a significant problem in health care settings, partly due to the presence of a nondividing, antibiotic-tolerant subpopulation. Here we evaluated treatment of S. aureus UAMS-1 biofilms with HT61, a quinoline derivative shown to be effective against nondividing Staphylococcus spp. HT61 was effective at reducing biofilm viability and was associated with increased expression of cell wall stress and division proteins, confirming its potential as a treatment for S. aureus biofilm infections.

Future Drug DiscoveryVol. 1, No. 1 InterviewOpen AccessThe future of antibiotics lies in combination treatmentsAnthony CoatesAnthony Coates*Author for correspondence: E-mail Address: talia@roadcommunications.co.uk Helperby Therapeutics, 66 Lincoln's Inn Fields, London, WC2A 3LH Published Online:2 Apr 2019https://doi.org/10.4155/fdd-2019-0012AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: antibioticsantimicrobal resistancecombination therapy Since 1981, Anthony Coates has held a strong research interest in tuberculosis, dormant bacteria and antibiotic discovery and has been an author of over 150 publications on the subject. He is the cofounder of Antibiotic Discovery UK, BEAM (biotechs from Europe innovating in antimicrobial resistance), Antibiotic Discovery Global and Antibiotic Research UK (charity) which promotes the discovery of antibiotics against highly resistant microbes. In addition, he founded the company Helperby Therapeutics, a biopharmaceutical company focused on developing the next generation of combination antibiotics.Following his graduation from St Thomas's Hospital (London, UK), Anthony Coates was awarded a Medical Research Council Research Training Fellowship at the Medical Research Council's TB unit. Working under Prof Denny Mitchison who was part of the first group to undertake randomized clinical trials he developed the first set of monoclonal antibodies against Mycobacterium tuberculosis, gaining an MD for his work.He was appointed Senior Lecturer at the London Hospital Medical School, later moving to St George's University (London, UK) where he was appointed Professor, Chairman of the Department of Medical Microbiology, Director of Public Health Laboratory Service and service delivery unit Leader for Medical Microbiology. Here he remains a Professor of Medical Microbiology.Could you introduce yourself & give a short background to your work in antibiotics?Over 16 years ago, I founded a company called Helperby Therapeutics Group Ltd. Helperby has discovered and is developing a suite of Antibiotic Resistance Breakers (ARBs), which are used in combination with old antibiotics. These combinations can restore the original potency of the old antibiotics, against both Gram-positive and Gram-negative bacteria. One of these combinations (ARB-002) is active against all three of the critical priority pathogens identified by the World Health Organization: Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. Helperby's combinations have unique mechanisms of action and differ from other antibiotics in clinical use. They are highly relevant to major commercially valuable markets and are covered internationally by extensive patents. Helperby has done extensive work to discover and develop new antibiotic combinations. The work is based on the observation that major disease areas like tuberculosis, AIDS and cancer have benefited from combination therapies but that antibiotics continue to be used as single molecule treatments. My collaborator Dr Yanmin Hu and I now have 128 granted Helperby patents for novel combinations which are active against highly resistant bacteria. We have two combinations which have reached the Phase II clinical trial stage and one is Phase II/III ready. Helperby is one of the few companies in the world whose antibiotics are in clinical trials and have the ability to kill all three critical priority pathogens.Could you give us a bit of a background to antimicrobial resistance & why there is a pressing need for new drugs?Antimicrobial resistance (AMR) is one of the most pressing global threats to medicine. Without effective antibiotics, much of the success of modern medicine, such as the levels of unprecedented survival rates from major surgery or chemotherapy treatment, would be severely compromised. The AMR in common bacteria is epidemic. The last of the penicillins, known as carbapenems, are nearly obsolete in countries such as India and Greece. Bacteria which are resistant to carbapenems are also becoming resistant to the last resort, colistin in the aforementioned countries. Without antibiotics, many of us would be dead already and modern medicine would not exist. By 2050, it is predicted that more people will die from resistant microbes than will die from cancer and diabetes combined.For the past 40 years, no new classes of antibiotic against carbapenem-resistant Enterobacteriaceae (CRE), the most dangerous of these resistant bacteria, have been marketed. Helperby Therapeutics is one of a small handful of companies which has a treatment for CRE at the clinical trials stage of development. 'Big Pharma' companies have mostly ruled themselves out of the antibiotics game, favoring a focus on the more incremental increases in innovation in chronic disease areas over the more unpredictable leaps needed to keep up with the development of bacterial mutation. This leaves the fight for antibiotic survival, arguably one of the most urgent fields of drug development, to smaller, more nimble biopharmaceutical companies.You have recently formed a collaboration with Dr Pamela Yeh & her team at University of California, Los Angeles to work on the development of novel antibiotic therapies. What made you decide to form this partnership?The WHO recognizes antimicrobial resistance as one of the most pressing global threats to health. Combining antibiotics is a useful way of boosting bactericidal activity. So, while each antibiotic may not kill a highly resistant bacterium, the combination will do so. Dr Pamela Yeh has made larger combinations, up to five in each case. She has analyzed and noted the phenomenon of emergent synergy, an effect greater than that expected over the independent, individual effects of combining two or more existing antibiotics and their efficacy against pathogenic Escherichia coli. She has found many new, effective combinations that could be useful in designing new treatments for patients with highly resistant bacterial infections. The objective of this collaboration is to take the combination of antibiotics up to the next level.Could you give a summary of what your research together will involve?We will be working closely to explore the commercial opportunity of additional, new, combination therapies, combining our respective data, expertise and research methodology. All new antibiotics face the threat of resistance from increasingly smart bacteria. Using Helperby's combinations, it may be possible to renew old antibiotics over and over again for hundreds of years, rather like renewable energy; an old antibiotic is combined with a new ARB and is developed as a treatment for bacteria resistant to all other antibiotics. Inevitably, within 20–30 years, resistance will arise to this combination, so the same antibiotic is then combined with a second ARB. Again, resistance arises, so the same antibiotic is combined with a third ARB. And so on, again and again. Dr Pamela Yeh's work backs up all the work Helperby has done over the last 16 years by comparing two, three, four and five molecule combinations.What impact do you think this will have on the field of antibiotics?First, it will increase efficacy of antibiotics. Mostly, this is linked with a search for synergy – combinations where the combined effect is greater than the added effects of single therapy. Second, to broaden the spectrum. If the infection pathogen is unknown and there are several possibilities to choose from, a combination can be used to broaden the spectrum. Finally, in my opinion I think this could be the most important breakthrough in the fight against antibiotic resistance. The 'one drug, one target' model has limited viability and there is evidence that combination therapy is the norm in the treatment of many cancers, viral infections such as HIV and tuberculosis treatment. It is a viable alternative to the development of totally new antibiotics that usually take at least 30 years or more to develop. Investing in these combined strategies will keep mankind ahead of antimicrobial resistance and is crucial in order to preserve a world where simple infections do not routinely kill healthy people. This is the first potential long-term renewable solution to the antibiotic crisis.In your opinion, what are the promising strategy/strategies for tackling antimicrobial resistance?The AMR in common bacteria needs new antibiotics, or new antibiotic combinations, to save patients' lives. They need to be well tolerated, safe, and if possible, prevent the emergence of resistance. Of course, other strategies also play their part: irrational use of medicines is a serious global problem, good infection control, publicity about AMR, more effective vaccines, less use of antibiotics in agriculture, fast diagnostic testing, more professionals working in the AMR field, more investment for clinical trials and a much higher unit price. The establishment of an international committee to monitor the impact of antibiotic resistance and provide coordination is required. Joint efforts from patients, prescribers, individuals, international regulators and policy makers are needed to fight against the global spread of antimicrobial resistance. Investing in these combined strategies may keep mankind ahead of antimicrobial resistance. Unfortunately, the epidemic of highly resistant bacteria continues to increase.Interview disclosureThe opinions expressed in this interview are those of A Coates and do not necessarily reflect the views of Future Science Ltd.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/FiguresReferencesRelatedDetailsCited ByAntibacterial Combinations6 April 2021New approaches for targeting drug resistance through drug combinationWelcome to the first issue of Future Drug DiscoveryFrancesca Lake2 July 2019 | Future Drug Discovery, Vol. 1, No. 1 Vol. 1, No. 1 Follow us on social media for the latest updates Metrics Downloaded 0 times History Received 12 March 2019 Accepted 13 March 2019 Published online 2 April 2019 Published in print July 2019 Information© 2019 Anthony CoatesKeywordsantibioticsantimicrobal resistancecombination therapy Interview disclosureThe opinions expressed in this interview are those of A Coates and do not necessarily reflect the views of Future Science Ltd.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download

Bacterial infections remain a leading killer worldwide, which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae are prevalent and extremely difficult to treat. Repurposing existing drugs and improving the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an antiretroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here, we investigated the in vitro and in vivo efficacy of AZT in combination with colistin against antibiotic-resistant Enterobacteriaceae, including strains producing extended-spectrum beta-lactamases (ESBLs) or New Delhi metallo-beta-lactamase 1 (NDM) or carrying mobilized colistin resistance (mcr-1). The MIC was determined using the broth microdilution method. The combined effect of AZT and colistin was examined using the checkerboard method and time-kill analysis. A murine peritoneal infection model was used to test the therapeutic effect of the combination of AZT and colistin. The fractional inhibitory concentration index from the checkerboard assay demonstrated that AZT synergized with colistin against 61% and 87% of ESBL-producing Escherichia coli and Klebsiella pneumoniae strains, respectively, 100% of NDM-1-producing strains, and 92% of mcr-1-producing E. coli strains. Time-kill analysis demonstrated significant synergistic activities when AZT was combined with colistin. In a murine peritoneal infection model, AZT in combination with colistin showed augmented activities of both drugs in the treatment of NDM-1 K. pneumoniae and mcr-1 E. coli infections. The AZT and colistin combination possesses a potential to be used coherently to treat antibiotic-resistant Enterobacteriaceae infections.

BACKGROUND:New antibiotics are urgently needed to treat multi-drug resistant infections; however, production of novel antibiotics is diminishing. Synergistic combination drug therapy to enhance the activity of available antibiotics may improve management of patients with resistant infections.METHODS:Colistin-resistant Klebsiella pneumoniae isolates were collected from inpatients in 10 Greek hospitals and used to study combination activity of colistin plus azidothymidine. Combination activity was evaluated with the sum of fractional inhibitory concentrations (ΣFIC) using the mini checkerboard broth microdilution method.RESULTS:A hundred individual strains were tested. Synergistic activity was noted in 79% (79/100) of isolates and additive activity in the remaining 21% (21/100). ΣFIC50 and ΣFIC90 were 0.28 and 0.56, respectively.CONCLUSION:Colistin with azidothymidine exhibited promising synergistic activity against colistin-resistant Klebsiella pneumoniae isolates warranting further investigation of the combination.