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The bactericidal activity of vancomycin and telavancin was compared against 4 clinical methicillin-resistant Staphylococcus aureus isolates recently recovered from cancer patients, using minimum bactericidal concentration (MBC):MIC ratios and time-kill studies. All 4 isolates were susceptible to both agents based on individual MIC values. The 2 methodologies for assessing bactericidal activity produced variable results. Telavancin appeared to have somewhat better bactericidal activity than vancomycin based on narrower MBC:MIC ratios. However, based on the results of the time-kill studies, neither agent demonstrated reliable bactericidal activity (defined as a ≥3 log 10 reduction of the starting inoculum at the end of 24 hours) against these organisms. These findings might be of some therapeutic importance in certain clinical settings and/or specific patient populations (such as febrile neutropenic patients) in whom potent bactericidal activity is either desired or preferred. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to determine the antibiotic resistance profile, clonal relation and efficacy of antibiotic combinations in nosocomial multidrug resistant (MDR) Acinetobacter baumannii. Materials and Methods: Antibiotic susceptibilities of 84 MDR A. baumannii against tigecycline (TGC), colistin (CL), amikacin (AK), ciprofloxacin (CIP), meropenem (MR), moxifloxacin (MXF), rifampicin (RF) were determined by microdilution method. Clonal relationship was investigated by genotyping using AP-PCR and antibiotyping. Interactions of antibiotic combinations were tested against clonally unrelated strains by the checkerboard (CB) method. The efficacy of the best combinations was also assesed on a selected isolate by the time-kill (TK) method. Results: CIP, RF, MXF, MR, AK resistance was found as 90.47%; 47.62%; 22.62%; 58.33%; 50% respectively; however; CL and TGC were not ascertained. The isolates were distinguished as 25 different antibiotypes and 15 varied molecular patterns. The best synergistic effect was detected in combinations of CL with RF (100%) and MR (100%), in combinations of TGC with RF (53%) against clonally unrelated 15 MDR A. baumannii isolates by the CB method. While CL-RF and CL-MR showed synergy by TK method like CB, on the other hand TGC-RF indicated additive interactions by TK. Conclusion: In this study, both synergy tests showed that CL in combination with RF would be a good option in MDR A. baumannii. [ABSTRACT FROM AUTHOR]

Introduction: Gram-negative multi-drug resistance is an emerging threat among pediatric patients with cystic fibrosis (CF). Ceftolozane/tazobactam (C/T) is an extended-spectrum cephalosporin/beta-lactamase inhibitor combination that has been shown to maintain activity against MDR P. aeruginosa isolates. The understanding of C/T effectiveness in pediatric patients is extremely limited. Minimum inhibitory concentration (MIC) testing and time-kill analyses were performed to better understand the antimicrobial susceptibility and potential role of C/T. Methods: Non-duplicate clinical respiratory MDR P. aeruginosa isolates ( n = 5) from four pediatric CF patients were identified. MICs were determined for these isolates using CLSI broth microdilution methods. Time-kill analyses were performed using multiples of C/T alone, and combinations of C/T 2× and 8× the MIC with 30 mg/L tobramycin or 80 mg/L amikacin for all isolates. Cell counts were determined by serial dilution plating. Results: Isolates had variable susceptibilities to C/T (range 0.5-8 mg/L), tobramycin (range 2 to >64 mg/L) and amikacin (range 8 to >256 mg/L). Time-kill analyses revealed an average of 0.71 (range −0.6 to 4.4), 1.50 (range 0.8-2.0) and 2.1 (range 1.2-3.4) log-kill at 4×, 8× and 16× the C/T MIC, respectively. At a tobramycin MIC of 32 mg/L, combination therapy showed synergistic benefit when the isolate was C/T susceptible. C/T and amikacin combination therapy showed synergistic activity at an amikacin MIC >256 mg/L when C/T MIC was 2 mg/L (4.7 log-kill at 2× C/T MIC and 4.0 log-kill at 8× C/T MIC). Conclusion: C/T appears to be a promising treatment option for treatment of MDR P. aeruginosa in pediatric CF patients, both alone and in combination with tobramycin or amikacin. Interestingly, the benefit of C/T combination therapy with amikacin may be more pronounced than with the addition of tobramycin. Further evaluation of such combination regimens in pediatric CF patients is warranted. [ABSTRACT FROM AUTHOR]

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Shigellosis is an important cause of worldwide morbidity and mortality among young children and old people for which treatment with antimicrobial agents is limited. Hence, the need for curative potentials obtainable from medicinal plants becomes inevitable. This study was carried out to assess the antibacterial potentials of crude methanolic extract of the stem bark of Acacia mearnsii against some selected bacteria of clinical importance in shigellosis. The bacteria were inhibited by the extract to produce concentration dependent inhibition zones. The extract exhibited a varied degree of antibacterial activity against all the tested isolates. The MIC values for Gram negative (0.0391–0.3125) mg/mL and those of Gram positive bacteria (0.0781–0.625) mg/mL indicated that the Gram negative bacteria were more inhibited by the extract than the Gram positive bacteria. Average log reduction in viable cell count in time-kill assay ranged between −2.456 Log10 to 2.230 Log10 cfu/mL after 4 h of interaction, and between −2.921 Log10 and 1.447 Log10 cfu/mL after 8 h interaction in 1× MIC and 2× MIC of the extract. The study provided scientific justification for the use of the crude methanolic extract from the stem bark of A. mearnsii in shigellosis. The degree of the antibacterial activity indicated that the crude extract is a potential source of bioactive compounds that could be useful for the development of new antimicrobial agents capable of decreasing the burden of drug resistance and cost of management of diseases of clinical and public health importance in South Africa.

There is an urgent need for new antibiotics to treat hospital- and community-associated methicillin-resistant Staphylococcus aureus (MRSA) infections. Previous work has indicated that both terrestrial and marine-derived members of the napyradiomycin class possess potential anti-staphylococcal activities. These compounds are unique meroterpenoids with unusual levels of halogenation. In this paper we report the evaluation of two previously described napyradiomycin derivatives, A80915A (1) and A80915B (2) produced by the marine-derived actinomycete, Streptomyces sp. strain CNQ-525, for their specific activities against contemporary and clinically relevant MRSA. Reported are studies of the in vitro kinetics of these chemical scaffolds in time-kill MRSA assays. Both napyradiomycin derivatives demonstrate potent and rapid bactericidal activity against contemporary MRSA strains. These data may help guide future development and design of analogs of the napyradiomycins that could potentially serve as useful anti-MRSA therapeutics.

Crude extracts of three actinomycetes species belonging to Saccharopolyspora (TR 046 and TR 039) and Actinosynnema (TR 024) genera were screened for antibacterial activities against a panel of several bacterial strains. The extracts showed antibacterial activities against both gram-negative and gram-positive test bacteria with inhibition zones ranging from 8 to 28 mm (TR 046); 8 to15 mm (TR 039); and 10 to 13 mm (TR 024). The minimum inhibitory concentrations ranged from 0.078 to 10 mg/mL (TR 046); 5 to >10 mg/mL (TR 039); and 1.25 to 5 mg/mL (TR 024). Time-kill studies revealed that crude extract of TR 046 showed strong bactericidal activity against Bacillus pumilus (ATCC14884), reducing the bacterial load by 104 cfu/mL and 102 cfu/mL at 4× MIC and 2× MIC, respectively, after 6 h of exposure. Similarly, against Proteus vulgaris (CSIR 0030), crude extract of TR 046 achieved a 0.9log10 and 0.13log10 cfu/mL reduction at 5 mg/mL (4× MIC) and 1.25 mg/mL (2× MIC) after 12 h of exposure. The extract was however weakly bactericidal against two environmental bacterial strains (Klebsiella pneumoniae and Staphylococcus epidermidis); and against Pseudomonas aeruginosa (ATCC 19582): the extract showed bacteriostatic activities at all concentrations tested. These freshwater actinomycetes appear to have immense potential as a source of new antibacterial compound(s).

Aerococcus urinae can cause severe infections (bacteraemia and endocarditis) that are associated with high mortality. However, data on the bactericidal and synergistic activity for clinically implemented antibiotics are scarce. Time–kill analyses were performed on two clinical isolates (AU1 and AU2) and the reference strain ATCC 700306 for penicillin (PG), ceftriaxone (CRO), gentamicin (GEN), daptomycin (DAP) and their combinations. AU1 and AU2 were CRO-resistant (MICs, 2 µg/mL) and ATCC 700306 was high-level GEN-resistant (MIC, 512 µg/mL), whereas all strains were PG- and DAP-susceptible (MICs, ≤0.125 and ≤1 µg/mL, respectively). CFU counts were determined at various time points from 0 to 48 h. All experiments were performed at 0.5×, 1×, 2× and 4× MIC. PG and CRO were not bactericidal for all strains, whereas DAP exhibited bactericidal activity at all concentrations for AU2 and ATCC 700306. The combination of PG or CRO with GEN was bactericidal for AU1 and AU2 at antibiotic concentrations ≥1× MIC. Bactericidal synergism was detected for PG or CRO combined with GEN in the two clinical isolates. PG plus CRO showed non-bactericidal synergism for ATCC 700306. DAP with GEN was synergistic at 1× MIC for AU1, whereas the killing activity of DAP was too pronounced to detect potential synergism in AU2. The combination of PG or CRO with GEN is synergistic and bactericidal. Moreover, these in vitro data suggest that DAP may represent a potential bactericidal treatment alternative against A. urinae . This finding could be important for the treatment of patients with a β-lactam allergy or renal insufficiency. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of interaction between methanol leaf extract of Spondias mombin and amoxicillin on diarrheagenic Escherichia coli (DEC). Methods: Cold methanol extraction of Spondias mombin leaf and its phytochemical screening were carried out. Isolated, characterized and identified strains of enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), and enterohemorrhagic E. coli (EHEC) from watery stool, mucoid bloody stool and watery bloody stool of diarrheal patients, respectively, were confirmed and typed by conventional and molecular methods. The minimum inhibitory concentration (MIC) and ? MIC at which the extract and amoxicillin interacted were determined. Results: Spondias mombin extract showed remarkable antibacterial activity at extract concentration of 50 - 200 mg/mL with a mean zone of inhibition (MZ) = 11.1 and activity index (AI) of 0.8 - 1.1. MIC of 12.5 mg/mL was observed for both ETEC and EIEC while it was 6.25 mg/mL for EHEC. The extract showed synergistic interaction at various concentrations (50 - 200, 12.5 and 6.25 mg/mL, respectively) with amoxycillin against ETEC, EHEC and EIEC. Synergy across a wide range of concentrations compared favourably with the ? MIC and MIC of both extract and amoxycillin for ETEC. The extract contained moderate levels of alkaloids, flavonoids and tannins, as well as a lot of saponins, and low levels of phenol. The activity of the extract of Spondias mombin compares well with that of amoxicillin with AI = 1 in some cases. Conclusion: A synergistic interaction between the leaf extract of S. mombin and amoxicillin confirms the extract as potential antibacterial agent but further studies are required to ascertain this. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the in vitro synergism of three-drug combinations against Mycobacterium tuberculosis (levofloxacin/linezolid/ethambutol, levofloxacin/amikacin/ethambutol and levofloxacin/linezolid/amikacin) using the time–kill curves method. In total, 8 multidrug-resistant and 12 drug-susceptible M. tuberculosis isolates were used. Minimum inhibitory concentrations (MICs) of the isolates for each drug were determined by the proportions method. Time–kill curves were studied for the three combinations proposed over 14 days using two different protocols. In protocol 1, 0.5× MIC for each drug was used. In protocol 2, 0.5× MIC for levofloxacin and linezolid and 0.25× MIC for amikacin and ethambutol were used. The MICs for all of the isolates studied were 0.5 mg/L for levofloxacin and linezolid and 2.5 mg/L for ethambutol and amikacin. All of the combinations displayed an additive activity compared with the most active individual drug. In conclusion, these results demonstrate that the three combinations tested were equally effective against M. tuberculosis isolates. The study of antituberculous combinations using in vitro methods is an excellent first step to predict their effect in clinical development phases as well as to test new regimens of the antituberculous drugs currently available. [ABSTRACT FROM AUTHOR]

Carbapenemase-producing Enterobacteriaceae (CPE) cause serious infections and are associated with high mortality in part due to limited treatment options. The in vitro activities of the new aminoglycoside plazomicin and comparators were evaluated against a collection of 164 CPE (VIM-1, n = 125; KPC-2, n = 34; OXA-48, n = 4; and IMP-22, n = 1). MIC 90 values of gentamicin, tobramycin and amikacin were 256, 64 and 16 mg/L, respectively. Plazomicin exhibited an MIC range of 0.12–4 mg/L with MIC 50 and MIC 90 values of 0.25 and 1 mg/L. The MICs of plazomicin did not correlate with the other aminoglycoside MICs, with the resistance phenotype or with the carbapenemase harboured. Chequerboard experiments against 10 carbapenemase-producing Klebsiella pneumoniae isolates showed that combinations of plazomicin with colistin yielded synergy against 60% of the strains. Synergy of plazomicin with meropenem or fosfomycin was detected against 20% and 25% of the isolates, respectively. Using time–kill methodology, the interactions of plazomicin at 2×, 1× and 0.5× MIC with meropenem, colistin, fosfomycin or tigecycline at steady-state concentrations against two K. pneumoniae carrying the VIM-1 enzyme were investigated. Bactericidal activity was evident for both isolates at 2× MIC of plazomicin. Synergy was observed when plazomicin was combined with meropenem, colistin or fosfomycin against both isolates, whilst the combination with tigecycline resulted in indifference. Antagonism was not observed for any of the combinations tested. The results of this study suggest that plazomicin may address the need for new therapeutic options for the treatment of infections due to CPE. [ABSTRACT FROM AUTHOR]

Background: The antimicrobial activity of Mul-1867, a novel synthetic compound, was tested against 18 bacterial strains, including clinical isolates and reference strains from culture collections. Methods: The minimal inhibitory concentration (MICs) and minimal bactericidal concentration (MBCs) were determined by using the broth macrodilution method. The kinetics of the inhibitory effects of Mul-1867 against biofilm-growing microorganisms was assessed at time-kill test in vitro against 48-h-old biofilms of Staphylococcus aureus and Escherichia coli. Transmission electron microscopy analyses was conducted to examine cell disruption. Results: A comparative assessment of the antimicrobial activities of Mul-1867 and chlorhexidine digluconate (CHG), used as a control antimicrobial, indicated that Mul-1867 was significantly more effective as a disinfectant than CHG. Mul-1867 showed potent antimicrobial activities against all the tested bacteria (MIC: 0.03-0.5 μg/mL). Furthermore, MBC/MIC ratio of Mul-1867 for all tested strains was less than or equal to 4. Time-kill studies showed that treatment with Mul-1867 (0.05-2 %) reduced bacterial numbers by 2.8-4.8 log10 colony forming units (CFU)/mL within 15-60 s. Bactericidal activity of Mul-1867 was confirmed by morphological changes revealed by TEM suggested that the killing of bacteria was the result of membrane disruption. Conclusion: Overall, these data indicated that Mul-1867 may be a promising antimicrobial for the treatment and prevention of human infections. [ABSTRACT FROM AUTHOR]

Objectives: Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. Our objective was to conduct combination MIC and time-kill experiments to evaluate BL synergy with daptomycin against enterococci. Methods: Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill experiments. Daptomycin at 0.5×MIC was used in combination with BL at biological free concentration. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labelled daptomycin (BoDipy) experiments. Results: Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill experiments, ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial reduction at 24 h was greater for daptomycin+ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin+cefazolin or cefotaxime (P<0.001). In BoDipy daptomycin experiments, ceftaroline enhanced daptomycin binding most compared with all other agents (P<0.001). Conclusions: The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the in vitro effects of combining kanamycin and metronidazole against resistant bacteria. Methods: The influence of combining kanamycin and metronidazole against Gram-positive and Gramnegative bacteria was assessed by agar diffusion, checkerboard and time-kill assays. Results: The test isolates were highly resistant, with minimum inhibitory concentration (MIC) ranging between 15.63 and >250 μg/ml for kanamycin, and 15.63 and 125 μg/ml for metronidazole. The antibacterial combinations resulted in drastic decrease in MIC with increased antibacterial activity that indicated synergistic interaction against all the bacteria except Acinetobacter calcaoceuticus UP, Enterobacter cloacae ATCC 13047 and Shigella flexneri KZN. Fractional inhibitory concentration index (FICI) showed synergy ranging from 0.31 to 0.50, additive interaction with FICI ranging from 0.53 to 1.25 and absence of antagonistic interaction. Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Bacillus cereus ATCC 10702, Enterobacter cloacae ATCC 13047, Klebsiella pneumoniae ATCC 10031, Acinetobacter calcoaceuticus UP and Micrococcus luteus were totally eliminated by the antibacterial combinations within 24 h of incubation. The lack of antagonism between these antibacterial agents in checkerboard and time-kill assays suggest that kanamycin may be effective in both monotherapy and combination therapy. Conclusion: The study indicates the potential beneficial value of combining kanamycin and metronidazole in the treatment of microbial infections in clinical settings. [ABSTRACT FROM AUTHOR]

Candida albicans remains the most common fungal pathogen. This species is closely related to 2 phenotypically similar cryptic species, Candida dubliniensis and Candida africana . This study aims to compare the antifungal activities of echinocandins against 7 C. albicans , 5 C. dubliniensis , and 2 C. africana strains by time–kill methodology. MIC values were similar for the 3 species; however, differences in killing activity were observed among species, isolates, and echinocandins. Echinocandins produced weak killing activity against the 3 species. In all drugs, the fungicidal endpoint (99.9% mortality) was reached at ≤31 h with ≥0.5 μg/mL for anidulafungin in 4 C. albicans and 1 C. dubliniensis , for caspofungin in 1 C. albicans and 2 C. dubliniensis , and for micafungin in 4 C. albicans and 1 C. dubliniensis . None of echinocandins showed lethality against C. africana . Identification of these new cryptic species and time–kill studies would be recommendable when echinocandin treatment fails. [ABSTRACT FROM AUTHOR]

With the increasing emergence of antibiotic resistances old antibiotics became a valuable source to find agents suitable to address this problem. More than 20 years after the last report, our purpose was to re-evaluate the in vitro antibacterial activity of the topical agent primycin against current important bacterial pathogens. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of primycin were tested in comparison with agents widely applied topically, and with those of mupirocin and vancomycin, the topical and the non-topical gold-standard anti-MRSA agents. Primycin was ineffective (MIC > 64 μg/ml) against all the Gram-negative isolates tested. On the other hand, all the tested Gram-positive isolates were susceptible with MIC 90 values of 0.06 μg/ml for staphylococci and 0.5–1 μg/ml for enterococci, streptococci, and P. acnes isolates, including all the multiresistant strains. Against MRSA isolates primycin showed slightly higher activity than mupirocin, and inhibited the mupirocin-resistant strains also. MBC 90 values ranged from 0.25 to 2 μg/ml for the investigated Gram-positive species. The bactericidal effect proved to be concentration-dependent in time-kill experiments. Spontaneous resistant mutants did not emerge in single-step mutation experiments and the resistance development was very slow by serial passaging. Passaged S. aureus strains showing increased primycin MIC values exhibited elevated vancomycin and daptomycin MIC values also. Though elucidation of the mechanisms behind warrants further investigations, these correlations can be related to development of vancomycin-intermediate phenotype. From the point of view of medical practice it is noteworthy that the increased primycin MIC values remained far below the concentration accessible by local application of the agent. These data make primycin a remarkable object of further investigations as well as a promising candidate for topical application against multiresistant Gram-positive pathogens. [ABSTRACT FROM AUTHOR]

The antimicrobial effect of chitosan and synthetic chitosan derivatives has been confirmed on many Gram-positive and Gram-negative bacteria and fungi. The tests were carried out on pathogenic microorganisms, so the mechanism and concentration dependence of the inhibitory effect of chitosan were revealed. We conducted our tests on a probiotic strain, Lactobacillus plantarum . Commercially available chitosan derivatives of different molecular weights were added to L. plantarum suspension in increasing concentrations. The minimum inhibitory concentration (MIC) value of chitosan was determined and confirmed the viability decreasing effect at concentrations above the MIC with a time-kill assay. The release of bacterium cell content was measured at 260 nm after treatment with 0.001-0.1% concentration chitosan solution. An increase in the permeability of the cell membrane was observed only with the 0.1% treatment. The interaction was also investigated by zeta potential measurement, and the irreversible interaction and concentration dependence were established in all concentrations. The interaction of fluorescein isothiocyanate (FITC) labeled low molecular weight chitosan and bacterial cells labeled with membrane dye (FM ® 4-64) was confirmed by confocal microscopy. In conclusion, the inhibitory effect of chitosan was verified on a probiotic strain, which is an undesirable effect in probiotic preparations containing chitosan additives, while the inhibitory effect experienced with pathogenic strains is beneficial.

• Cu 2 Zn 1.75 Mo 3 O 12 NPs were synthesized via novel method for the first time. • Morphological and structural properties of products were investigated. • Cu 2 Zn 1.75 Mo 3 O 12 NPs have tremendous antibacterial activity. • The probable mechanism of antibacterial activity of Cu 2 Zn 1.75 Mo 3 O 12 NPs was provided. Using nanomaterials in the field of antibacterial chemotherapy has received a lot of attention since nanomaterials have attractive properties that can be effective in overcoming problems in this area. This work introduces Cu 2 Zn 1.75 Mo 3 O 12 nanoparticles (NPs) as an operative antibacterial agent for the first time. In this work, the facile and simple ultrasonic method was applied to preparation Cu 2 Zn 1.75 Mo 3 O 12 NPs. XRD, EDS mapping, TEM, FT-IR and SEM were used to investigate the structural and morphological properties of samples. The results revealed that Cu 2 Zn 1.75 Mo 3 O 12 NPs have remarkable antibacterial properties. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and zone of inhibition of Cu 2 Zn 1.75 Mo 3 O 12 were measured 78.125 µg/ml, 312.5 µg/ml, and 30 mm respectively. Better performance of Cu 2 Zn 1.75 Mo 3 O 12 NPs is due to the presence of zinc in the structure, which improves the reactive oxygen species (ROS)-based photocatalytic and ion release mechanisms. So, this work introduces Cu 2 Zn 1.75 Mo 3 O 12 NPs as an attractive option for antibacterial applications. [ABSTRACT FROM AUTHOR]

The in vitro broth microdilution testing method for telavancin, a lipoglycopeptide active against S. aureus , was revised in 2014 to include polysorbate-80 in the test media. This study evaluates the bactericidal activity of telavancin against S. aureus in media containing polysorbate-80 by in vitro time-kill analysis alongside relevant comparators. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this study was to conduct a pharmacokinetic and pharmacodynamic evaluation of high (320/1600 mg) and standard (160/800 mg) doses of trimethoprim/sulfamethoxazole and linezolid in outpatients with mild diabetic foot infections (DFIs). Methods Both viable skin/soft tissue from the infection site and serum were obtained at various times after antibiotic administration from 18 patients (6 per study group) being treated with linezolid, standard doses of trimethoprim/sulfamethoxazole or high doses of trimethoprim/sulfamethoxazole during a follow-up clinic visit. These samples were assayed for drug concentrations by liquid chromatography in tandem with mass spectrometry. Patient sera were also utilized in time–kill assays against two strains of Staphylococcus aureus and three strains of β-haemolytic streptococci. Results The mean tissue/serum ratio for linezolid was 0.46 (range, 0.18–0.71). The mean tissue/serum ratio for trimethoprim was 1.2 (range, 0.3–4.5) for both standard and high doses, and 0.23 (range, 0.1–0.46) and 0.36 (range, 0.14–1.28) for standard and high doses of sulfamethoxazole, respectively. Linezolid exhibited inhibitory activity in time–kill assays against strains of S. aureus (0.45 ± 0.5 log10 cfu/mL) and β-haemolytic streptococci (2.2 ± 0.6 log10 cfu/mL), while trimethoprim/sulfamethoxazole exhibited bactericidal (>3 log kill) activity against all of these isolates. These findings were consistent for each sampling time and for high as well as standard doses of trimethoprim/sulfamethoxazole. Conclusions This pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with DFIs as well as bactericidal activity in serum against strains of S. aureus and β-haemolytic streptococci. [ABSTRACT FROM PUBLISHER]

Objectives: The objectives of this study were to investigate: (1) the antibacterial activity of two antibacterial monomers, dimethylaminododecyl methacrylate (DMADDM) and dimethylammoniumethyl dimethacrylate (DMAEDM), against eight different species of oral pathogens for the first time; (2) the cytotoxicity of DMAEDM and DMADDM. Methods: DMAEDM and DMADDM were synthesized by reacting a tertiary amine group with an organo-halide. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against eight species of bacteria were tested. Time-kill determinations were performed to examine the bactericidal kinetics. Cytotoxicity of monomers on human gingival fibroblasts (HGF) was assessed using a methyl thiazolyltetrazolium assay and live/ dead viability assay. Results: DMADDM showed strong bactericidal activity against all bacteria, with MIC of 1.2- 9.8 μ0g/mL. DMAEDM had MIC of 20-80 μg/mL. Time-kill determinations indicated that DMADDM and DMAEDM had rapid killing effects against eight species of bacteria, and eliminated all bacteria in 30 min at the concentration of 4-fold MBC. Median lethal concentration for DMADDM and DMAEDM was between 20 and 40 μg/mL, which was 20-fold higher than 1-2 μg/mL for BisGMA control. Conclusions: DMAEDM and DMADDM were tested in time-kill assay against eight species of oral bacteria for the first time. Both were effective in bacteria-inhibition, but DMADDM had a higher potency than DMAEDM. Different killing efficacy was found against different bacteria species. DMAEDM and DMADDM had much lower cytotoxicity than BisGMA. Therefore, DMADDM and DMAEDM are promising for use in bonding agents and other restorative/ preventive materials to combat a variety of oral pathogens [ABSTRACT FROM AUTHOR]

Multidrug-resistant (MDR) Klebsiella pneumoniae is a top-prioritized Gram-negative pathogen with a high incidence in hospital-acquired infections. Polymyxins have resurged as a last-line therapy to combat Gram-negative "superbugs", including MDR K. pneumoniae . However, the emergence of polymyxin resistance has increasingly been reported over the past decades when used as monotherapy, and thus combination therapy with non-antibiotics (e.g., metabolites) becomes a promising approach owing to the lower risk of resistance development. Genome-scale metabolic models (GSMMs) were constructed to delineate the altered metabolism of New Delhi metallo-β-lactamase- or extended spectrum β-lactamase-producing K. pneumoniae strains upon addition of exogenous metabolites in media. The metabolites that caused significant metabolic perturbations were then selected to examine their adjuvant effects using in vitro static time-kill studies. Metabolic network simulation shows that feeding of 3-phosphoglycerate and ribose 5-phosphate would lead to enhanced central carbon metabolism, ATP demand, and energy consumption, which is converged with metabolic disruptions by polymyxin treatment. Further static time-kill studies demonstrated enhanced antimicrobial killing of 10 mM 3-phosphoglycerate (1.26 and 1.82 log 10  CFU/ml) and 10 mM ribose 5-phosphate (0.53 and 0.91 log 10  CFU/ml) combination with 2 mg/L polymyxin B against K. pneumoniae strains. Overall, exogenous metabolite feeding could possibly improve polymyxin B activity via metabolic modulation and hence offers an attractive approach to enhance polymyxin B efficacy. With the application of GSMM in bridging the metabolic analysis and time-kill assay, biological insights into metabolite feeding can be inferred from comparative analyses of both results. Taken together, a systematic framework has been developed to facilitate the clinical translation of antibiotic-resistant infection management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chung, Abdul Rahim, Mahamad Maifiah, Hawala Shivashekaregowda, Zhu and Wong.)

Background: Carbapenems are the treatment of choice for multidrug-resistant (MDR) and extensively drug-resistant (XDR)  Acinetobacter baumannii  infections, but the emergence of carbapenem-resistant  A. baumannii  (CRAB) has rendered it ineffective in the vast majority of cases. Combination therapy has grown in popularity over the last decade; this study aims to analyze  A.baumannii  growth kinetics after exposure to meropenem and ampicillin-sulbactam compared with meropenem and amikacin antibiotic combinations in clinically relevant concentrations.  Methods:  This experimental laboratory study was conducted on the  A. baumannii  ATCC 19606 isolate and three clinical isolates that were intermediate or resistant to tested antibiotics. Meropenem and ampicillin-sulbactam, as well as meropenem and amikacin, were tested at four different concentrations against isolates. Turbidity measurements were taken at predetermined time points of 0, 1, 2, 4, 6, 8, and 24 hours following exposure; bacterial concentration was enumerated using the agar plate method, with the results plotted in a time-kill curve.   Results: A bactericidal effect was achieved in isolates that were intermediate to ampicillin-sulbactam and resistant to meropenem after the administration of meropenem and ampicillin-sulbactam combination with a concentration of 4 µg/ml and 16/8 µg/ml, respectively. The combination of meropenem and ampicillin-sulbactam demonstrated bacteriostatic activity against isolates that were resistant to both antibiotics. Isolates treated with resistant antibiotics showed an increased growth rate compared to the growth control.  Conclusion:  The combination of meropenem and ampicillin-sulbactam could be a promising combination therapy in treating CRAB infections. The mechanism and degree of antibiotic resistance in the isolates affect the efficacy of antibiotic combinations; further research is needed to corroborate the findings of this study., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Rivani E et al.)

The global health concern of antimicrobial resistance has harnessed research interest to find new classes of antibiotics to combat disease-causing pathogens. In our studies, 3-halobenzo[b]thiophene derivatives were synthesized and tested for their antimicrobial activities using the broth microdilution susceptibility method. The 3-halo substituted benzo[b]thiophenes were synthesized starting from 2-alkynyl thioanisoles using a convenient electrophilic cyclization methodology that utilizes sodium halides as the source of electrophilic halogens when reacted along with copper(II) sulfate. This environmentally benign methodology is facile, uses ethanol as the solvent, and results in 3-halo substituted benzo[b]thiophene structures in very high yields. The cyclohexanol-substituted 3-chloro and 3-bromobenzo[b]thiophenes resulted in a low MIC of 16 µg/mL against Gram-positive bacteria and yeast. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) properties of the compounds were determined. The compounds with the lowest MIC values showed excellent drug-like properties with no violations to Lipinski, Veber, and Muegge filters. The time-kill curve was obtained for cyclohexanol-substituted 3-chlorobenzo[b]thiophenes against Staphylococcus aureus, which showed fast bactericidal activity at MIC. [ABSTRACT FROM AUTHOR]

Abstract: LCB01-0062, a novel oxazolidinone, has potent antibacterial activity against clinical isolates of Gram-positive bacteria. The in vitro activity of LCB01-0062 was compared with that of linezolid, oxacillin, erythromycin, ciprofloxacin, vancomycin and quinupristin/dalfopristin. Among the tested agents, LCB01-0062 showed the most potent antibacterial activity against meticillin-resistant Staphylococcus aureus, meticillin-resistant coagulase-negative staphylococci and vancomycin-resistant enterococci. LCB01-0062 was 4–8-fold more active than linezolid, the first oxazolidinone drug, against Gram-positive bacteria. The time–kill curves of LCB01-0062 were analysed at concentrations of 0.5×, 1×, 2×, 4× and 8× the minimum inhibitory concentration against S. aureus strains. LCB01-0062 showed bacteriostatic activity during 24h. LCB01-0062 was also more effective than linezolid against S. aureus in a systemic mouse model of infection. [Copyright &y& Elsevier]

Zanthoxylum limonella Alston is commonly used plant in Thailand for flavoring of foods and in traditional medicine. In this study, we investigated the crude essential oil, the distilled fractions thereof and the three pure major compounds of the oil from Z. limonella fruits for antibacterial activities against several bacteria including multi-drug resistant bacteria. The essential oil fractions 1 and II, and sabinene, the major compound of fractions I (54%) and II (41%), showed antibacterial activity against both Gram-positive and Gram-negative bacteria tested, except Pseudomonas aeruginosa. The crude oil showed higher antibacterial activity than sabinene against all tested bacteria, suggesting the presence of potent minor compound(s) with an additive effect, or less potent compound(s) with a synergistic effect among the components of the crude oil. The essential oil showed a potent killing effect, achieving a complete elimination of Staphylococcus aureus and Escherichia coli within a 9-minute exposure to a two-fold minimal bactericidal concentration level, while the multi-drug resistant bacteria, methicillin-resistant S. aureus and the extended- spectrum β-lactamase-producing E.coli, were completely eradicated within 90 minutes at the same dose. This is the first report on the essential oil from Z. limonella fruits against multi-drug resistant bacteria. The essential oil has potential uses in food preservation and as an antiseptic for medical use. [ABSTRACT FROM AUTHOR]

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Shigellosis is an important cause of worldwide morbidity and mortality among young children and old people for which treatment with antimicrobial agents is limited. Hence, the need for curative potentials obtainable from medicinal plants becomes inevitable. This study was carried out to assess the antibacterial potentials of crude methanolic extract of the stem bark of Acacia mearnsii against some selected bacteria of clinical importance in shigellosis. The bacteria were inhibited by the extract to produce concentration dependent inhibition zones. The extract exhibited a varied degree of antibacterial activity against all the tested isolates. The MIC values for Gram negative (0.0391-0.3125) mg/mL and those of Gram positive bacteria (0.0781-0.625) mg/mL indicated that the Gram negative bacteria were more inhibited by the extract than the Gram positive bacteria. Average log reduction in viable cell count in time-kill assay ranged between -2.456 Log10 to 2.230 Log10 cfu/mL after 4 h of interaction, and between -2.921 Log10 and 1.447 Log10 cfu/mL after 8 h interaction in 1x MIC and 2x MIC of the extract. The study provided scientific justification for the use of the crude methanolic extract from the stem bark of A. mearnsii in shigellosis. The degree of the antibacterial activity indicated that the crude extract is a potential source of bioactive compounds that could be useful for the development of new antimicrobial agents capable of decreasing the burden of drug resistance and cost of management of diseases of clinical and public health importance in South Africa. [ABSTRACT FROM AUTHOR]

Treatment of invasive Candida krusei infections can be difficult due to its intrinsic fluconazole resistance and its reduced susceptibility to amphotericin B and flucytosine. Caspofungin (CAS) acts on a different cellular target, and its combination with voriconazole (VOR) or amphotericin B (AmB) appears promising. We evaluated the activity of CAS, VOR and AmB alone and in combination at 1/4, 1, 4xMIC concentrations by time-kill method against 30 C. krusei isolates. All isolates were susceptible to CAS and VOR; AmB MICs were 2 μg/ml for 50% of isolates by broth microdilution. CAS showed a fast killing activity at all concentrations; it was fungistatic at 1/4xMICs and fungicidal at 1-4xMICs in general. VOR displayed a concentration-independent fungistatic activity against all isolates. AmB exhibited a concentration-dependent activity; it was fungistatic at 1/4-1xMIC and fungicidal at 4xMIC. The most common interaction was indifference for both combinations. Frequency of synergic interaction for the VOR + CAS combination was 66.7% at 1/4xMIC after 48 h. The best results for CAS + AmB combination were obtained at 4xMIC in the first 4-8 h; synergic interaction was detected for 20 isolates (66.7%) at 4xMIC after 4 h. Consequently, VOR and CAS alone have been found effective, and high AmB MICs are remarkable against clinical C. krusei isolates in vitro. The combinations of CAS with VOR or AmB have exhibited promising results. [ABSTRACT FROM AUTHOR]

There is an urgent need for new antibiotics to treat hospital- and community-associated methicillin-resistant Staphylococcus aureus (MRSA) infections. Previous work has indicated that both terrestrial and marine-derived members of the napyradiomycin class possess potential anti-staphylococcal activities. These compounds are unique meroterpenoids with unusual levels of halogenation. In this paper we report the evaluation of two previously described napyradiomycin derivatives, A80915A (1) and A80915B (2) produced by the marine-derived actinomycete, Streptomyces sp. strain CNQ-525, for their specific activities against contemporary and clinically relevant MRSA. Reported are studies of the in vitro kinetics of these chemical scaffolds in time-kill MRSA assays. Both napyradiomycin derivatives demonstrate potent and rapid bactericidal activity against contemporary MRSA strains. These data may help guide future development and design of analogs of the napyradiomycins that could potentially serve as useful anti-MRSA therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Antibiotic combinations including tigecycline have not been studied against Klebsiella pneumoniae carbapenemase (KPC)-producing pathogens. Tigecycline alone and combined with colistin and meropenem was tested against eight genetically unrelated KPC-producing clinical strains of Enterobacteriaceae (four K. pneumoniae, two Escherichia coli, one Enterobacter cloacae and one Serratia marcescens) by time–kill assay. Tigecycline displayed a concentration-independent bacteriostatic activity in seven strains and bactericidal activity in one strain. Colistin showed bactericidal activity at 4× the minimum inhibitory concentration (MIC) in three strains and was bacteriostatic for the remaining strains and concentrations. Meropenem was bactericidal in three strains and bacteriostatic in five strains. The tigecycline+meropenem combination was not bactericidal against the four K. pneumoniae strains and was non-synergistic against all eight strains. Tigecycline+colistin was bactericidal against all strains at most time intervals and concentrations and was also synergistic at 1× and 2× MIC against most strains up to 4–8h and at 4× MIC up to 24h against all strains. These findings suggest that, at most drug concentrations, tigecycline, colistin and meropenem as single agents do not exhibit efficient bactericidal activity against most of the KPC-producing strains. Tigecycline alone might be a therapeutic option for infections caused by KPC-producers when bacteriostatic activity is adequate or combined with colistin when bactericidal activity is necessary. Additional in vivo tests are warranted to assess better the killing kinetics of tigecycline combinations against KPC-producers. [Copyright &y& Elsevier]