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Background: Extended-spectrum beta-lactamase (ESBL) and carbapenemase (KPC+)-producing bacteria, such as multidrug-resistant (MDR) strains of Klebsiella pneumoniae, have increased substantially. The reduced antibiotic options encourage the development of complementary therapies such as antimicrobial photodynamic inactivation (aPDI). APDI uses photosensitizer (PS) compounds that utilize light energy to produce reactive oxygen species that nonspecifically kill bacteria. Methodology: The aPDI activity of PSRu-L2, and PSRu-L3, was determined by serial micro dilutions exposing K. pneumoniae to 17 µW/cm2 of light. PS interaction with cefotaxime was determined on a collection of 118 clinical isolates of K. pneumoniae. To characterize the mode of action of aPDI, the bacterial response to oxidative stress was measured by RT-qPCR. Also, the cytotoxicity on mammalian cells was assessed by trypan blue exclusion.

Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure–activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains.

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

The aim of this study was to investigate the antibacterial activity, antibiotic-associated synergy, and anti-biofilm activity of the ruthenium complex, cis-[RuCl2 (dppb) (bqdi)]2+ (RuNN). RuNN exhi...

The prevalence of multidrug resistant bacterial diseases is a major global health risk. Multidrug resistant bacterial diseases are prevalent, and the need for novel methods of treatment is essential to the preservation of public health. Annually foodborne pathogens cause 1.35 million infections and 26,500 hospitalizations in the United States alone. Foodborne pathogens such as Salmonella spp. are a major threat to public health. Bacteriophages offer a unique method for the treatment of these multidrug resistant bacteria. We studied the infection dynamics of a potential mono-phage therapy of Salmonella typhimurium under various pathophysiological conditions. Furthermore, we determined the resistance dynamics of Salmonella typhimurium against P22 phage treatment. We also determined synergy with antibiotics such as ampicillin and kanamycin. This research helps to further define and show the versatility of bacteriophages as potential novel treatment methods.

Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms. IMPORTANCE Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria. We examined the mechanism of action and synergy of these three antibacterials and proposed a mechanistic basis for their synergy. Our results highlight much-needed mechanistic information necessary to advance this combination as a potential therapy.

Combination therapy of bacteriophage and antibiotics offers promise to treat multiple drug resistant bacterial infections through phage antibiotic synergy. However, its usage requires careful assessment as most antibiotics with mechanisms dependent upon inhibiting cell growth through interfering bacterial protein synthesis machinery were found to have an antagonistic effect on phage activity.

Introduction This review summarizes single vs dual antibiotic cement literature, evaluating for synergistic activity with dual antibiotics. Methods A systematic review was performed for literature regarding dual antibiotics in cement, identifying 13 studies to include for review. Results Many in vitro studies reported higher elution from cement and/or improved bacteria inhibition with dual antibiotics, typically at higher dosages with a manual mixing technique. Limited clinical data from hip hemiarthroplasties and spacers demonstrated that dual antibiotics were associated with improved infection prevention and higher intra-articular antibiotic concentrations. Conclusion In addition to broader pathogen coverage, several studies document synergy of elution and increased antibacterial activity when dual antibiotics are added to cement. Limited clinical evidence suggests that dual antibiotic cement may be associated with reduced infection rates.

Nontuberculous mycobacteria (NTM) are ubiquitous microbes belonging to the Mycobacterium genus. Among all NTM pathogens, M. avium is one of the most frequent agents causing pulmonary disease, especially in immunocompromised individuals and cystic fibrosis patients. Recently, we reported the first ad hoc designed M. avium efflux pump inhibitor (EPI; 1b) able to strongly boost clarithromycin (CLA) MIC against different M. avium strains. Since the 3-phenylquinolone derivative 1b suffered from toxicity issues toward human macrophages, herein we report a two-pronged medicinal chemistry workflow for identifying new potent and safe NTM EPIs. Initially, we followed a computational approach exploiting our pharmacophore models to screen FDA approved drugs and in-house compounds to identify "ready-to-use" NTM EPIs and/or new scaffolds to be optimized in terms of EPI activity. Although nicardipine 2 was identified as a new NTM EPI, all identified molecules still suffered from toxicity issues. Therefore, based on the promising NTM EPI activity of 1b, we undertook the design, synthesis, and biological evaluation of new 3-phenylquinolones differently functionalized at the C6/C7 as well as N1 positions. Among the 27 synthesized 3-phenylquinolone analogues, compounds 11b, 12b, and 16a exerted excellent NTM EPI activity at concentrations below their CC50 on human cells, with derivative 16a being the most promising compound. Interestingly, 16a also showed good activity in M. avium-infected macrophages both alone as well as in combination with CLA. The antimycobacterial activity observed for 16a only when tested in the ex vivo model suggests a high therapeutic potential of EPIs against M. avium, which seems to need functional efflux pumps to establish intracellular infections.

Increasingly, clinical infections are becoming recalcitrant or completely resistant to antibiotics treatment and multidrug resistance is rising alarmingly. Patients suffering from infections that used to be treated successfully by antibiotic regimens are running out of the treatment options. Bacteriophage (phage) therapy, long practiced in parts of Eastern Europe and the states of the former Soviet Union, is now being reevaluated as a treatment option complementary to and synergistic with antibiotic treatments. We discuss some current studies that have addressed synergistic killing activity between phages and antibiotics, the issues of treatment order and antibiotic class, and point to considerations that will have to be addressed by future studies. Overall, co-treatments with phages and antibiotics promise to extend the utility of antibiotics in current use. Nevertheless, a lot of work, both basic and clinical, remains to be done before such co-treatments become routine options in the hospital setting.

Endocarditis is a rare but serious manifestation of Listeria monocytogenes (LM). However, the optimal treatment strategy for LM endocarditis has yet to be established. Current antibiotic strategies for listeriosis include penicillin G or ampicillin (AMP) monotherapy, or AMP + gentamicin combination therapy which is often favored for endocarditis. The primary objective of our investigation was to assess the utility of AMP + ceftriaxone (CRO) and AMP + daptomycin (DAP) against LM, modeling less nephrotoxic antibiotic combinations traditionally used to manage resistant enterococcal endocarditis. Here we report a case of LM endocarditis, review the world literature, and evaluate alternative treatment strategies for listeriosis utilizing in vitro and ex vivo studies. The combination of AMP + CRO and AMP + DAP were each noted to have synergistic activity against a LM endocarditis isolate. Additionally, co-incubation of the isolate with sub-lethal concentrations of antibiotics (AMP, CRO, DAP, AMP + CRO or AMP + DAP) sensitized the bacterium to whole blood killing while pretreatment with CRO and DAP (at 1/4 MIC) sensitized the bacterium to neutrophil killing. However, these effects did not reflect potentiation of antibiotic activity to human cathelicidin peptide LL-37, which is abundant in neutrophils and highly active against LM. Interestingly, AMP pretreatment of the LM endocarditis isolate resulted in increased DAP binding to the bacterium when assessed by fluorescence microscopy. These in vitro and ex vivo studies suggest further investigation of combination therapy using AMP + CRO or AMP + DAP as an alternative treatment for LM infection is warranted.

© 2014 Liu, Lu, Mueller, Turnbull, Burke, Schlothauer, Carter, Whitchurch and Harry. Skin infections caused by antibiotic resistant Staphylococcus aureus are a significant health problem worldwide; often associated with high treatment cost and mortality rate. Complex natural products like New Zealand (NZ) manuka honey have been revisited and studied extensively as an alternative to antibiotics due to their potent broad-spectrum antimicrobial activity, and the inability to isolate honey-resistant S. aureus. Previous studies showing synergistic effects between manuka-type honeys and antibiotics have been demonstrated against the growth of one methicillin-resistant S. aureus (MRSA) strain. We have previously demonstrated strong synergistic activity between NZ manukatype honey and rifampicin against growth and biofilm formation of multiple S. arueus strains. Here, we have expanded our investigation using multiple S. aureus strains and four different antibiotics commonly used to treat S. aureus-related skin infections: rifampicin, oxacillin, gentamicin and clindamycin. Using checkerboard microdilution and agar diffusion assays with S. aureus strains including clinical isolates and MRSA we demonstrate that manuka-type honey combined with these four antibiotics frequently produces a synergistic effect. In some cases when synergism was not observed, there was a significant enhancement in antibiotic susceptibility. Some strains that were highly resistant to an antibiotic when present alone become sensitive to clinically-achievable concentrations when combined with honey. However, not all of the S. aureus strains tested responded in the same way to these combinational treatments. Our findings support the use of NZ manuka-type honeys in clinical treatment against S. aureus-related infections and extend their potential use as an antibiotic adjuvant in combinational therapy. Our data also suggest that manuka-type honeys may not work as antibiotic adjuvants for all strains of S. aureus, and this may help determine the mechanistic processes behind honey synergy.

Patients with cystic fibrosis (CF) suffer from chronic bacterial infection of the airways, and many patients are infected with multiresistant bacteria. Combination antibiotic susceptibility tests, or antibiotic synergy tests, are in vitro tests that have been developed to allow clinicians to choose combinations of antibiotics that should be more effective at killing, or inhibiting, multiresistant bacterial pathogens. Only one randomised controlled clinical trial has been performed to determine whether combination antibiotic susceptibility testing leads to an improved clinical outcome for patients with acute pulmonary exacerbations of CF. The results of this clinical trial were disappointing - treatment based on combination antibiotic susceptibility testing was no more effective than treatment based on conventional culture and sensitivity testing. The adoption of antibiotic synergy testing as routine practice for patients with CF would be costly and would not be justified as there is insufficient evidence to suggest that the routine use of these tests improves clinical outcomes.

Combination of antibiotics in order to achieve antimicrobial synergy is often necessary in the treatment of infections due to resistant bacterial strains. Therefore, several in-vitro test systems have been developed with the purpose of predicting in-vivo action of antibiotics, and the fractional inhibitory concentration (FIC) index has been used to interpret results obtained in different test systems. Using these systems it seems that only antibiotic synergy in vitro is predictive of the results of treatment. It is therefore of interest to have an in-vivo test system that makes it possible to describe antibiotic interaction in detail. Animal infection models such as the foreign body model system enable the measurement of many parameters at the site of infection, such as bactericidal effect (BE) and antibiotic concentrations. A new calculation of drug interaction is suggested in which the measurements used are the BE and the time during which the MIC is exceeded, for the individual drugs and the combination. This calculation enables us to penetrate into observed antibiotic efficacy in vivo to find out whether an observed high BE is due to real synergy or simply to optimal pharmacokinetics of antibiotics at the site of infection.

▴ Aaron SD, Vandemheen KL, Ferris W, et al . Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial. Lancet2005;366:463–71 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Patients with cystic fibrosis (CF) are often colonised with multiresistant organisms. In vitro data suggest that bactericidal activity may result from antibiotic synergy even if species are resistant to individual agents on routine resistance testing. Simultaneously testing the bactericidal activity of two or more antibiotics (multiple combination bactericidal antibiotic testing, MCBT) is one approach that has been suggested to … [1]: {openurl}?query=rft.jtitle%253DLancet%26rft.stitle%253DLancet%26rft.aulast%253DAaron%26rft.auinit1%253DS.%2BD.%26rft.volume%253D366%26rft.issue%253D9484%26rft.spage%253D463%26rft.epage%253D471%26rft.atitle%253DCombination%2Bantibiotic%2Bsusceptibility%2Btesting%2Bto%2Btreat%2Bexacerbations%2Bof%2Bcystic%2Bfibrosis%2Bassociated%2Bwith%2Bmultiresistant%2Bbacteria%253A%2Ba%2Brandomised%252C%2Bdouble-blind%252C%2Bcontrolled%2Bclinical%2Btrial.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0140-6736%252805%252967060-2%26rft_id%253Dinfo%253Apmid%252F16084254%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1016/S0140-6736(05)67060-2&link_type=DOI [3]: /lookup/external-ref?access_num=16084254&link_type=MED&atom=%2Fthoraxjnl%2F60%2F11%2F915.atom [4]: /lookup/external-ref?access_num=000231022300027&link_type=ISI

The in vitro activities of three aminoglycosides [Schering 21420 (a 1N-HAPA derivative of gentamicin B), amikacin and gentamicin] plus carbenicillin or piperacillin were tested against 16 clinical iso

Current methods of measuring bactericidal antibiotic synergy are particularly susceptible to error because of their use of arbitrary endpoints and criteria; their results are not easily tested for statistical significance and the procedures require considerable time and effort. A single-stage method is described in which bacteria are exposed to antibiotics for a short period and then transferred twice to drug-free medium by means of a filter membrane. The results are available the next day in the form of survival counts which can be compared statistically. In an examination of 21 strains of faecal streptococcus exposed to penicillin and gentamicin the bactericidal synergy observed was smoothly variable, a finding with a bearing on the management of infections with this organism, in that the recognition of strains showing an intermediate degree of synergy is possible.

Thirty-two human isolates of enterococci were tested for antibiotic synergy by using penicillin and one of six aminoglycosides. Three methods were used: synergy screen, microdilution checkerboard, and time-kill curves. The synergy screen accurately predicted synergy for gentamicin-penicillin combinations, and this synergy was later confirmed by time-kill curves. The microdilution checkerboard method suffered from inherent variation, and agreement with time-kill curves ranged from 92% (twofold reduction in minimum inhibitory concentration) to 4.2% (fourfold reduction in minimum inhibitory concentration). We suggest that enterococci be screened for synergy (i.e., presence or absence of high-level resistance) by using the criterion of growth or no growth in the presence of 2,000 microgram of an aminoglycoside per ml. The microdilution checkerboard test for synergy is not recommended.

Due to the increase in antimicrobial resistance, strategies such as antimicrobial stewardship programs (ASP) have been developed to improve the clinical results, decrease the adverse effects and the development of resistances and ensure cost-effective therapies. Fosfomycin has a unique mechanism of action against Gram-positive and Gram-negative bacteria. Cross-resistance is uncommon; however, fosfomycin should be used in combination in severe infections to avoid selecting resistant mutations. Fosfomycin's oral formulation facilitates sequential treatment, has low toxicity and high tissue penetration, even in the central nervous system and bone. Fosfomycin is active against resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin- resistant enterococci and penicillin-resistant Streptococcus pneumoniae, as well as against resistant Gram-negative bacteria such as extended-spectrum beta-lactamase-producing and carbapenemase-producing enterobacteria. Fosfomycin is therefore useful for cases of persistent bacteremia, skin and soft tissue infections, as a glycopeptide-sparing and carbapenem-sparing drug for healthcare-associated infections and for polymicrobial infections. Published studies have demonstrated the synergy between fosfomycin and beta-lactams, daptomycin and glycopeptides against MSSA and MRSA; with linezolid in biofilm-associated infections and with aminoglycosides and colistin against Gram-negative bacteria, providing a nephroprotective effect.