Recent advances in COVID-19-induced liver injury: causes, diagnosis, and management.

Since the start of the pandemic, considerable advancements have been made in our understanding of the effects of SARS-CoV-2 infection and the associated COVID-19 on the hepatic system. There is a broad range of clinical symptoms for COVID-19. It affects multiple systems and has a dominant lung illness depending on complications. The progression of COVID-19 in people with pre-existing chronic liver disease (CLD) has also been studied in large multinational groups. Notably, SARS-CoV-2 infection is associated with a higher risk of hepatic decompensation and death in patients with cirrhosis. In this review, the source, composition, mechanisms, transmission characteristics, clinical characteristics, therapy, and prevention of SARS-CoV-2 were clarified and discussed, as well as the evolution and variations of the virus. This review briefly discusses the causes and effects of SARS-CoV-2 infection in patients with CLD. As part of COVID-19, In addition, we assess the potential of liver biochemistry as a diagnostic tool examine the data on direct viral infection of liver cells, and investigate potential pathways driving SARS-CoV-2-related liver damage. Finally, we explore how the pandemic has had a significant impact on patient behaviors and hepatology services, which may increase the prevalence and severity of liver disease in the future. The topics encompassed in this review encompass the intricate relationships between SARS-CoV-2, liver health, and broader health management strategies, providing valuable insights for both current clinical practice and future research directions.

Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N-(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies.

In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt to improve their biological availability and antiviral activity. Next, both cytotoxicity and anti-SARS-CoV-2 activities of the examined compounds loaded EMLs (F3a-g) were assessed in Vero E6 cells via MTT assay to calculate the CC50 and inhibitory concentration 50 (IC50) values. The most potent 3e-loaded EMLs (F3e) elicited a selectivity index of 18 with an IC50 value of 0.73 µg/mL. Moreover, F3e was selected for further elucidation of a possible mode of action where the results showed that it exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition. Besides, molecular docking and MD simulations towards the SARS-CoV-2 Mpro were performed. Finally, a structure-activity relationship (SAR) study focussed on studying the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide in addition to compound contraction on SARS-CoV-2 activity.HighlightsEmulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g).The most potent 3e-loaded EMLs (F3e) showed an IC50 value of 0.73 µg/mL against SARS-CoV-2.F3e exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition.Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA calculations were performed.Structure-activity relationship (SAR) study was discussed to study the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide on the anti-SARS-CoV-2 activity.

Combination therapy between prophylactic and therapeutic human papillomavirus (HPV) vaccines with special emphasis on implementation of nanotechnology.

Human papillomavirus (HPV) is the most prevalent sexually transmitted disease in the world. Even though preventive vaccines against HPV are effective, the effective treatment of HPV infections is much less satisfactory due to multi-drug resistance and secondary adverse effects. Nanotechnology was employed for the delivery of anti-cancer drugs to increase the effectiveness of the treatment and minimize the side effects. Nanodelivery of both preventive and therapeutic HPV vaccines has also been studied to boost vaccine efficacy. Overall, such developments suggest that the nanoparticle-based vaccine might emerge as the most cost-effective way to prevent and treat HPV cancer, assisted or combined with another nanotechnology-based therapy. This review focuses on the current knowledge on pathogenesis and vaccines against HPV, highlighting the current value and perspective regarding the widespread diffusion of HPV vaccines-based nanomaterials. The ongoing advancements in the design of vaccines-based nanomaterials are expanding their therapeutic roles against HPV.

Calli Essential Oils Synergize with Lawsone against Multidrug Resistant Pathogens.

The fast development of multi-drug resistant (MDR) organisms increasingly threatens global health and well-being. Plant natural products have been known for centuries as alternative medicines that can possess pharmacological characteristics, including antimicrobial activities. The antimicrobial activities of essential oil (Calli oil) extracted from the Calligonum comosum plant by hydro-steam distillation was tested either alone or when combined with lawsone, a henna plant naphthoquinone, against MDR microbes. Lawsone showed significant antimicrobial activities against MDR pathogens in the range of 200-300 µg/mL. Furthermore, Calli oil showed significant antimicrobial activities against MDR bacteria in the range of 180-200 µg/mL, Candida at 220-240 µg/mL and spore-forming Rhizopus fungus at 250 µg/mL. Calli oil's inhibition effect on Rhizopus, the major cause of the lethal infection mucormycosis, stands for 72 h, followed by an extended irreversible white sporulation effect. The combination of Calli oil with lawsone enhanced the antimicrobial activities of each individual alone by at least three-fold, while incorporation of both natural products in a liposome reduced their toxicity by four- to eight-fold, while maintaining the augmented efficacy of the combination treatment. We map the antimicrobial activity of Calli oil to its major component, a benzaldehyde derivative. The findings from this study demonstrate that formulations containing essential oils have the potential in the future to overcome antimicrobial resistance.

Monte Carlo simulation analysis of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit-isolated methicillin-resistant Staphylococcus aureus.

The aim of the present study was to compare the potential of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) targets against methicillin-resistant Staphylococcus aureus isolates collected from intensive care unit (ICU) settings. Monte Carlo simulations were carried out to simulate the PK/PD indices of the investigated antimicrobials. The probability of target attainment (PTA) was estimated at minimum inhibitory concentration values ranging from 0.03 to 32 µg/mL to define the PK/PD susceptibility breakpoints. The cumulative fraction of response (CFR) was computed using minimum inhibitory concentration data from the Canadian National Intensive Care Unit study. Analysis of the simulation results suggested the breakpoints of 4 µg/mL for ceftobiprole (500 mg/2 h t.i.d.), 0.25 µg/mL for dalbavancin (1000 mg), 0.12 µg/mL for daptomycin (4 mg/kg q.d. and 6 mg/kg q.d.) and tigecycline (50 mg b.i.d.), and 2 µg/mL for linezolid (600 mg b.i.d.) and vancomycin (1 g b.i.d. and 1.5 g b.i.d.). The estimated CFR were 100, 100, 70.6, 88.8, 96.5, 82.4, 89.4, and 98.3% for ceftobiprole, dalbavancin, daptomycin (4 mg/kg/day), daptomycin (6 mg/kg/day), linezolid, tigecycline, vancomycin (1 g b.i.d.) and vancomycin (1.5 g b.i.d.), respectively. In conclusion, ceftobiprole and dalbavancin have the highest probability of achieving their requisite PK/PD targets against methicillin-resistant Staphylococcus aureus isolated from ICU settings. The susceptibility predictions suggested a reduction of the vancomycin breakpoint to 1 µg/mL.

Investigating the superiority of chitosan/D-alpha-tocopheryl polyethylene glycol succinate binary coated bilosomes in promoting the cellular uptake and anti-SARS-CoV-2 activity of polyphenolic herbal drug candidate.

The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 23 full factorial designs to improve solubility and intestinal permeability of CUR, hence boosting its anti-SARS-CoV-2 activity. Eight experimental runs were attained considering three independent variables: soybean phosphatidylcholine amount (mg) (SPC amount), bile salt amount (mg) (BS amount), and TPGS amount (mg). The optimum formula (F4) exhibited EE % (88.5 ± 2.4 %), PS (181.5 ± 21.6 nm), and ZP (-34.5 ± 3.7 mV) with desirability value = 0.739 was picked as an optimum formula. Furthermore, the optimum formula (F4) was extra coated with chitosan (CS) to improve permeability and anti-SAR-CoV-2 activity. Caco-2 cell uptake after 2 hr revealed the superiority of CS-F4 and F4 by 6 and 5 folds relative to CUR dispersion, respectively. Furthermore, CS-F4 exhibited a significantly higher anti-SARS-CoV-2 activity with IC50 (0.24 µg/ml) by 8.3 times than F4 (1.99 µg/ml). Besides, the mechanistic study demonstrated that the two formulae imparted antiviral activity by inhibiting the spike protein by virucidal potentialities. In addition, the conducted molecular docking and MD simulations towards the SARS-CoV-2 Mpro enzyme confirmed the interaction of CUR with key residues of the virus enzymes. Based on the preceded, CS-F4 could be assumed to be used to effectively eradicate SARS-CoV-2 infection.

Assessment of the activity of ceftaroline against clinical isolates of penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae with elevated MICs of ceftaroline using an in vitro pharmacodynamic model.

OBJECTIVES: This study assessed the pharmacodynamics of ceftaroline against penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae with elevated MICs of ceftaroline using an in vitro pharmacodynamic model. METHODS: Nine isolates of S. pneumoniae, including one penicillin-susceptible isolate, one penicillin-intermediate isolate and seven penicillin-resistant isolates, were tested. The pharmacodynamic model was inoculated with a concentration of 1 × 10(6) cfu/mL and ceftaroline was dosed twice daily (at 0 and 12 h) to simulate the fC(max) (maximum free concentration in serum) and t(1/2) (half-life in serum) obtained after 600 mg intravenous doses every 12 h (fC(max), 16 mg/L; t(1/2), 2.6 h). Ceftaroline was compared with ceftriaxone dosed once daily to simulate the fC(max) and t(1/2) obtained after a 1 g dose (fC(max), 18 mg/L; t(1/2), 8.0 h). Samples were collected over 24 h to assess viable growth and possible changes in ceftaroline MICs over time. RESULTS: Ceftaroline fT(>MIC) (time of free serum concentration over the MIC) of 100% (ceftaroline MICs, ≤ 0.5 mg/L) was bactericidal (≥ 3 log(10) killing) against all isolates at 6 h and completely eradicated all organisms at 12 and 24 h. No bacterial regrowth occurred over the study period and no changes in ceftaroline MICs were observed. Upon ceftriaxone exposure, S. pneumoniae isolates with ceftriaxone MICs of 0.12 and 0.25 mg/L were eradicated, but isolates with ceftriaxone MICs of 1-8 mg/L resulted in initial bacterial reduction at 6 h with organism regrowth at 12 h and no reduction in organism concentration, relative to the starting inoculum, at 24 h. CONCLUSIONS: Ceftaroline fT(>MIC) of 100% (ceftaroline MICs, ≤ 0.5 mg/L) was bactericidal (≥ 3 log(10) killing) and eradicated all S. pneumoniae at 12 and 24 h with no regrowth.

Intensification of resveratrol cytotoxicity, pro-apoptosis, oxidant potentials in human colorectal carcinoma HCT-116 cells using zein nanoparticles.

Resveratrol (RSV), a non-flavonoid stilbene polyphenol, possesses anti-carcinogenic activities against all the major stages of cancer. Zein nanoparticles (ZN NPs) have been utilized successfully in delivery of variant therapeuticals by virtue of their histocompatible nature. The goal of this work was to comparatively explore the antiproliferative, pro-apoptotic and oxidative stress potentials of RSV-ZN NPs versus RSV against human colorectal carcinoma HCT-116 cells. ZN-RSV NPs were developed and assayed for particle size analysis and RSV diffusion. The selected formula obtained 137.6 ± 8.3 nm as mean particle size, 29.4 ± 1.8 mV zeta potential, 92.3 ± 3.6% encapsulation efficiency. IC50 of the selected formula was significantly lower against HCT-116 cells versus Caco-2 cells. Also, significantly enhanced cellular uptake was generated from RSV-ZN NPs versus free RSV. Enhanced apoptosis was concluded due to increased percentage cells in G2-M and pre-G1 phases. The pro-apoptotic potential was explained by caspase-3 and cleaved caspase-3 increased mRNA expression in addition to NF-κB and miRNA125b decreased expression. Biochemically, ZN-RSV NPs induced oxidative stress as demonstrated by enhanced reactive oxygen species (ROS) generation and endothelial nitric oxide synthase (eNOS) isoenzyme increased levels. Conclusively, ZN-RSV NPs obtained cell cycle inhibition supported with augmented cytotoxicity, uptake and oxidative stress markers levels in HCT-116 tumor cells in comparison with free RSV. These results indicated intensified chemopreventive profile of RSV due to effective delivery utilizing ZN nano-dispersion against colorectal carcinoma HCT-116 cells.

Ceftaroline pharmacodynamic activity versus community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus, heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus using an in vitro model.

BACKGROUND: This study assessed the pharmacodynamics of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA), heteroresistant (h) vancomycin-intermediate S. aureus (hVISA), VISA and vancomycin-resistant S. aureus (VRSA) using an in vitro model. METHODS: Two methicillin-susceptible S. aureus (MSSA), one community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, one hVISA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 × 106 cfu/mL and ceftaroline dosed every 12 h (at 0 and 12 h) to simulate the ƒC(max) and t(½) obtained after administering 600 mg intravenously every 12 h (ƒC(max), 16 mg/L; t(½), 2.6 h). Samples were collected over 24 h to assess viable growth and changes in ceftaroline MIC over time. RESULTS: Ceftaroline ƒT(> MIC) of ≥ 92% (ceftaroline MICs, ≤ 1 mg/L) was bactericidal (≥ 3 log10 killing) against MSSA, CA-MRSA, HA-MRSA, hVISA, VISA and VRSA at 12 and 24 h. No bacterial regrowth occurred over the study period and no change in ceftaroline MIC was observed. CONCLUSIONS: Ceftaroline ƒT(> MIC) of ≥ 92% (ceftaroline MICs, ≤ 1 mg/L) was bactericidal (≥ 3 log10 killing) against MSSA, CA-MRSA, HA-MRSA, hVISA, VISA and VRSA at 12 and 24 h.

Global dynamics of SARS-CoV-2 clades and their relation to COVID-19 epidemiology.

Expansion of COVID-19 worldwide increases interest in unraveling genomic variations of novel SARS-CoV-2 virus. Metadata of 408,493 SARS-CoV-2 genomes submitted to GISAID database were analyzed with respect to genomic clades and their geographic, age, and gender distributions. Of the currently known SARS-CoV-2 clades, clade GR was the most prevalent worldwide followed by GV then GH. Chronological analysis revealed expansion in SARS-CoV-2 clades carrying D614G mutations with the predominance of the newest clade, GV, in the last three months. D614G clades prevail in countries with more COVID-19 cases. Of them, the clades GH and GR were more frequently recovered from severe or deceased COVID-19 cases. In contrast, G and GV clades showed a significantly higher prevalence among asymptomatic patients or those with mild disease. Metadata analysis showed higher (p < 0.05) prevalence of severe/deceased cases among males than females and predominance of GR clade in female patients. Furthermore, severe disease/death was more prevalent (p < 0.05) in elderly than in adults/children. Higher prevalence of the GV clade in children compared to other age groups was also evident. These findings uniquely provide a statistical evidence on the adaptation-driven evolution of SARS-CoV-2 leading to altered infectivity, virulence, and mortality.

Pharmacodynamic activity of ceftobiprole compared with vancomycin versus methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA) using an in vitro model.

BACKGROUND: This study compared the pharmacodynamics of ceftobiprole and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) using an in vitro model. METHODS: Two methicillin-susceptible S. aureus (MSSA), two community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 x 10(6) cfu/mL and ceftobiprole dosed every 8 h (at 0, 8 and 16 h) to simulate the fC(max) and t(1/2) obtained after 500 mg intravenous (iv) every 8 h dosing (fC(max,) 30 mg/L; t(1/2,) 3.5 h). Vancomycin was dosed every 12 h (at 0 and 12 h) to simulate fC(max) and t(1/2) obtained after 1 g iv every 12 h dosing (fC(max), 20 mg/L; t(1/2), 8 h). Samples were collected over 24 h to assess viable growth. RESULTS: Ceftobiprole T > MIC of > or =100% (ceftobiprole MICs, < or =2 mg/L) was bactericidal (> or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin fAUC(24)/MIC of 340 (vancomycin MIC, 1 mg/L for MSSA and MRSA) resulted in a 1.8-2.6 log(10) reduction in colony count at 24 h. Vancomycin fAUC(24)/MIC of 85-170 (vancomycin MIC, 2-4 mg/L for VISA) resulted in a 0.4-0.7 log(10) reduction at 24 h. Vancomycin fAUC(24)/MIC of 5.3 (vancomycin MIC, 64 mg/L for VRSA) resulted in a limited effect. CONCLUSIONS: Ceftobiprole T > MIC of > or =100% (ceftobiprole MICs, < or =2 mg/L) was bactericidal (> or =3 log(10) killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin was bacteriostatic against MSSA, MRSA and VISA, while demonstrating no activity against VRSA.

The impact of Catechol-O-methyl transferase knockdown on the cell proliferation of hormone-responsive cancers.

Estrogen (E2) plays a central role in the development and progression of hormone-responsive cancers. Estrogen metabolites exhibit either stimulatory or inhibitory roles on breast and prostate cells. The catechol metabolite 4-hydroxyestradiol (4-OHE2) enhances cell proliferation, while 2-methoxyestradiol (2 ME) possesses anticancer activity. The major metabolizing enzyme responsible for detoxifying the deleterious metabolite 4-OHE2 and forming the anticancer metabolite 2 ME is Catechol-O-Methyl Transferase (COMT). The current work investigated the relationship between the expression level of COMT and the cell proliferation of hormone-responsive cancers. The results showed that COMT silencing enhanced the cell proliferation of ER-α positive cancer cells MCF-7 and PC-3 but not the cells that lack ER-α expression as MDA-MB231 and DU-145. The data generated from our study provides a better understanding of the effect of COMT on critical signaling pathways involved in the development and progression of breast cancer (BC) and prostate cancer (PC) including ER-α, p21cip1, p27kip1, NF-κB (P65) and CYP19A1. These findings suggest that COMT enzyme plays a tumor suppressor role in hormone receptor-positive tumors which opens the door for future studies to validate COMT expression as a novel biomarker for the prediction of cancer aggressiveness and treatment efficacy.

Pharmacodynamic activity of ertapenem versus multidrug-resistant genotypically characterized extended-spectrum beta-lactamase-producing Escherichia coli using an in vitro model.

BACKGROUND: This study assessed the pharmacodynamic activity of ertapenem against multidrug-resistant (MDR) genotypically characterized extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli using an in vitro model. METHODS: Six ESBL-producing E. coli with the CTX-M-15 genotype were studied. All six strains were MDR (defined as resistance to third-generation cephalosporins and > or = two other unrelated antimicrobial classes). The in vitro pharmacodynamic model was inoculated with 1 x 10(6) cfu/mL, and ertapenem was dosed once daily at 0 and 24 h to simulate free (f) Cmax and t(1/2) obtained after a standard 1 g intravenous once-daily dose in healthy volunteers (fCmax, 15 mg/L; t(1/2), 4 h). Sampling was performed over 48 h to assess viable growth and resistance selection. RESULTS: Ertapenem T(>MIC) > or = 98% (ertapenem MICs < or = 0.25 mg/L) resulted in bactericidal (> or = 3 log(10) killing) activity at 6, 12, 24 and 48 h against all strains. Eradication of organisms from the in vitro model (below the level of detection) occurred at 2 h followed by slow regrowth of the majority of the strains (5 of 6) over 12, 24 and 48 h time points. Despite limited regrowth, ertapenem achieved a bactericidal effect against all strains (all time points) over the 48 h study period. CONCLUSIONS: Ertapenem was rapidly bactericidal (in approximately 2 h) against MDR ESBL (CTX-M-15)-producing E. coli (ertapenem MICs < or = 0.25 mg/L) when simulating free drug after 1 g intravenous once-daily dosing. This bactericidal activity was maintained over the 48 h experimental period with only minor regrowth, which was not associated with MIC increase from baseline.

Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin.

Ceftobiprole, an investigational cephalosporin, is currently in phase III clinical development. Ceftobiprole is a broad-spectrum cephalosporin with demonstrated in vitro activity against Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant S. epidermidis, penicillin-resistant S. pneumoniae, Enterococcus faecalis, Gram-negative bacilli including AmpC-producing Escherichia coli and Pseudomonas aeruginosa, but excluding extended-spectrum beta-lactamase-producing strains. Like cefotaxime, ceftriaxone, ceftazidime, and cefepime, ceftobiprole demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. In single-step and serial passage in vitro resistance development studies, ceftobiprole demonstrated a low propensity to select for resistant subpopulations. Ceftobiprole, like cefepime, is a weak inducer and a poor substrate for AmpC beta-lactamases.Ceftobiprole medocaril, the prodrug of ceftobiprole, is converted by plasma esterases to ceftobiprole in <30 minutes. Peak serum concentrations of ceftobiprole observed at the end of a single 30-minute infusion were 35.5 mug/mL for a 500-mg dose and 59.6 mug/mL for a 750-mg dose. The volume of distribution of ceftobiprole is 0.26 L/kg ( approximately 18 L), protein binding is 16%, and its serum half-life is approximately 3.5 hours. Ceftobiprole is renally excreted ( approximately 70% in the active form) and systemic clearance correlates with creatinine clearance, meaning that dosage adjustment is required in patients with renal dysfunction. Ceftobiprole has a modest post-antibiotic effect (PAE) of approximately 0.5 hours for MRSA and a longer PAE of approximately 2 hours for penicillin-resistant pneumococci. Ceftobiprole, when administered intravenously at 500 mg once every 8 hours (2-hour infusion), has a >90% probability of achieving f T(>MIC) (free drug concentration exceeds the minimum inhibitory concentration [MIC]) for 40% and 60%, respectively, of the dosing interval for isolates with ceftobiprole MIC < or =4 and < or =2 mg/L, respectively.Currently, only limited clinical trial data are published for ceftobiprole. In a phase III trial, 784 patients with Gram-positive skin infections were randomized to treatment with either ceftobiprole 500 mg or vancomycin 1 g, each administered twice daily for 7-14 days; 93.3% of patients were clinically cured with ceftobiprole compared with 93.5% receiving vancomycin, and the eradication rate for MRSA infections was 91.8% for ceftobiprole compared with 90% for vancomycin. A phase III, randomized, double-blind, multicenter trial compared ceftobiprole 500 mg every 8 hours with vancomycin 1 g every 12 hours plus ceftazidime 1 g every 8 hours in patients with complicated skin and skin structure infections. Of the 828 patients enrolled, 31% had diabetic foot infections, 30% had abscesses, and 22% had wounds. No difference in clinical cure was reported in the clinically evaluable, intent-to-treat and microbiologically evaluable populations with cure rates of 90.5%, 81.9%, and 90.8%, respectively, in the ceftobiprole-treated patients and 90.2%, 80.8%, and 90.5%, respectively, in the vancomycin plus ceftazidime-treated group. Microbiologic eradication of Gram-positive cocci meticillin-susceptible S. aureus (MSSA) [ceftobiprole 91% vs vancomycin plus ceftazidime 92%] and MRSA (ceftobiprole 87% vs vancomycin plus ceftazidime 80%), as well as Gram-negative bacilli, E. coli (ceftobiprole 89% vs vancomycin plus ceftazidime 92%), and P. aeruginosa (ceftobiprole 87% vs vancomycin plus ceftazidime 100%), was not significantly different between groups. Similar cures rates in the microbiologically evaluable population occurred in both groups for Panton-Valentine leukocidin (PVL)-positive MSSA and PVL-positive MRSA.Currently, ceftobiprole has completed phase III trials for complicated skin and skin structure infections due to MRSA and nosocomial pneumonia due to suspected or proven MRSA; phase III trials are also ongoing in community-acquired pneumonia. Ceftobiprole has so far demonstrated a good safety profile in preliminary studies with similar tolerability to comparators. The broad-spectrum activity of ceftobiprole may allow it to be used as monotherapy in situations where a combination of antibacterials might be required. Further clinical studies are needed to determine the efficacy and safety of ceftobiprole and to define its role in patient care.

Comparative review of the carbapenems.

The carbapenems are beta-lactam antimicrobial agents with an exceptionally broad spectrum of activity. Older carbapenems, such as imipenem, were often susceptible to degradation by the enzyme dehydropeptidase-1 (DHP-1) located in renal tubules and required co-administration with a DHP-1 inhibitor such as cilastatin. Later additions to the class such as meropenem, ertapenem and doripenem demonstrated increased stability to DHP-1 and are administered without a DHP-1 inhibitor. Like all beta-lactam antimicrobial agents, carbapenems act by inhibiting bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins (PBPs). Carbapenems are stable to most beta-lactamases including AmpC beta-lactamases and extended-spectrum beta-lactamases. Resistance to carbapenems develops when bacteria acquire or develop structural changes within their PBPs, when they acquire metallo-beta-lactamases that are capable of rapidly degrading carbapenems, or when changes in membrane permeability arise as a result of loss of specific outer membrane porins. Carbapenems (imipenem, meropenem, doripenem) possess broad-spectrum in vitro activity, which includes activity against many Gram-positive, Gram-negative and anaerobic bacteria; carbapenems lack activity against Enterococcus faecium, methicillin-resistant Staphylococcus aureus and Stenotrophomonas maltophilia. Compared with imipenem, meropenem and doripenem, the spectrum of activity of ertapenem is more limited primarily because it lacks activity against Pseudomonas aeruginosa and Enterococcus spp. Imipenem, meropenem and doripenem have in vivo half lives of approximately 1 hour, while ertapenem has a half-life of approximately 4 hours making it suitable for once-daily administration. As with other beta-lactam antimicrobial agents, the most important pharmacodynamic parameter predicting in vivo efficacy is the time that the plasma drug concentration is maintained above the minimum inhibitory concentration (T>MIC). Imipenem/cilastatin and meropenem have been studied in comparative clinical trials establishing their efficacy in the treatment of a variety of infections including complicated intra-abdominal infections, skin and skin structure infections, community-acquired pneumonia, nosocomial pneumonia, complicated urinary tract infections, meningitis (meropenem only) and febrile neutropenia. The current role for imipenem/cilastatin and meropenem in therapy remains for use in moderate to severe nosocomial and polymicrobial infections. The unique antimicrobial spectrum and pharmacokinetic properties of ertapenem make it more suited to treatment of community-acquired infections and outpatient intravenous antimicrobial therapy than for the treatment of nosocomial infections. Doripenem is a promising new carbapenem with similar properties to those of meropenem, although it appears to have more potent in vitro activity against P. aeruginosa than meropenem. Clinical trials are required to establish the efficacy and safety of doripenem in moderate to severe infections, including nosocomial infections.

Comparative pharmacodynamics of garenoxacin, gemifloxacin, and moxifloxacin in community-acquired pneumonia caused by Streptococcus pneumoniae: a Monte Carlo simulation analysis.

OBJECTIVE: This study used Monte Carlo simulations to assess the potential for attainment of pharmacodynamic targets with the fluoroquinolones garenoxacin, gemifloxacin, and moxifloxacin against Streptococcus pneumoniae in serum and epithelial lining fluid (ELF) from hospitalized patients with community-acquired pneumonia (CAP). METHODS: Data on the free AUC over 24 hours (fAUC(0-24)), a measure of drug exposure, were derived from previously described population pharmacokinetic models for therapeutic doses of the 3 fluoroquinolones. MIC distribution data for S pneumoniae were obtained from the Canadian Respiratory Organism Susceptibility Study. These data were used to produce the ratio of fAUC(0-24) to the MIC(90) (fAUC(0-24)/MIC(90)), a pharmacodynamic predictor of bacterial eradication. Monte Carlo simulations were used to analyze the potential for garenoxacin 400 mg QD, gemifloxacin 320 mg QD, and moxifloxacin 400 mg QD to achieve target fAUC(0-24)/MIC(90) ratios of 30, 40, 100, and 120 against S pneumoniae in serum and ELF from hospitalized patients with CAP. Target ratios of 30 and 40 were used to assess the probability of bacterial eradication, while ratios of 100 and 120 were used to assess the probability of preventing development of resistance. RESULTS: Monte Carlo simulations indicated that all 3 fluoroquinolones had a high probability (>90%) of attaining target fAUC(0-24)/MIC(90) ratios of 30 and 40 against S pneumoniae in both serum and ELF. Garenoxacin 400 mg QD was associated with a >95% probability of achieving target fAUC(0-24)/MIC(90) ratios of 100 and 120 in both serum and ELF. Both gemifloxacin 320 mg QD and moxifloxacin 400 mg QD were associated with high probabilities of attaining fAUC(0-24)/MIC(90) ratios of 100 and 120 in ELF (>95%); the probability of gemifloxacin and moxifloxacin attaining these targets in serum ranged from 78.3% to 88.0%. CONCLUSION: Based on these simulations, garenoxacin 400 mg QD, gemifloxacin 320 mg QD, and moxifloxacin 400 mg QD appeared likely to achieve target serum and ELF concentrations against S pneumoniae in hospitalized patients with CAP, with a low potential to select for resistance.

Use of pharmacodynamic principles to optimise dosage regimens for antibacterial agents in the elderly.

Throughout most of the world we are witnessing an ever increasing number of aged people as a percentage of the general population. In the coming years, the unique spectrum of infections presented by an elderly population, particularly those in long-term care facilities, will challenge our ability to maintain an effective battery of antibacterials. The pharmacokinetic parameters of most antibacterial agents are altered when assessed in the elderly due in part to non-pathological physiological changes. The inability to clear a drug from the body due to declining lung, kidney/bladder, gastrointestinal and circulatory efficiency can cause accumulation in the body of drugs given in standard dosages. While this may have the potential benefit of achieving therapeutic concentrations at a lower dose, there is also a heightened risk of attaining toxic drug concentrations and an increased chance of unfavourable interactions with other medications. Pharmacodynamic issues in the elderly are related to problems that arise from treating elderly patients who may have a history of previous antibacterial treatment and exposure to resistant organisms from multiple hospitalisations. Furthermore, the elderly often acquire infections in tandem with other common disease states such as diabetes mellitus and heart disease. Thus, it is essential that optimised dosage strategies be designed specifically for this population using pharmacodynamic principles that take into account the unique circumstances of the elderly. Rational and effective dosage and administration strategies based on pharmacodynamic breakpoints and detailed understanding of the pharmacokinetics of antibacterials in the elderly increase the chances of achieving complete eradication of an infection in a timely manner. In addition, this strategy helps prevent selection of drug-resistant bacteria and minimises the toxic effects of antibacterial therapy in the elderly patient.

Plants' Natural Products as Alternative Promising Anti-Candida Drugs.

Candida is a serious life-threatening pathogen, particularly with immunocompromised patients. Candida infections are considered as a major cause of morbidity and mortality in a broad range of immunocompromised patients. Candida infections are common in hospitalized patients and elderly people. The difficulty to eradicate Candida infections is owing to its unique switch between yeast and hyphae forms and more likely to biofilm formations that render resistance to antifungal therapy. Plants are known sources of natural medicines. Several plants show significant anti-Candida activities and some of them have lower minimum inhibitory concentration, making them promising candidates for anti-Candida therapy. However, none of these plant products is marketed for anti-Candida therapy because of lack of sufficient information about their efficacy, toxicity, and kinetics. This review revises major plants that have been tested for anti-Candida activities with recommendations for further use of some of these plants for more investigation and in vivo testing including the use of nanostructure lipid system.

A Review of New Fluoroquinolones : Focus on their Use in Respiratory Tract Infections.

The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.

Comparison of gatifloxacin and levofloxacin administered at various dosing regimens to hospitalised patients with community-acquired pneumonia: pharmacodynamic target attainment study using North American surveillance data for Streptococcus pneumoniae.

This work aimed at determining the target attainment potential of gatifloxacin and levofloxacin in specific age-related patient populations such as elderly (> or =65 years) versus younger (<65 years) hospitalised patients with community-acquired pneumonia (CAP). Previously described population pharmacokinetic models of gatifloxacin and levofloxacin administration in patients with serious CAP were utilised to simulate gatifloxacin and levofloxacin pharmacokinetics. Pharmacokinetic simulations and susceptibility data for Streptococcus pneumoniae from the ongoing national surveillance study, Canadian Respiratory Organism Susceptibility Study (CROSS), were then used to produce pharmacodynamic indices of free-drug area under the curve over 24h relative to the minimum inhibitory concentration (free-drug AUC(0-24)/MIC(all)). Monte Carlo simulations were then used to analyse target attainment both of gatifloxacin and levofloxacin to achieve free-drug AUC(0-24)/MIC(all)> or =30 against S. pneumoniae in patients with CAP. Dosing regimens for gatifloxacin were 400 mg once daily (qd) administered to younger patients (<65 years) and gatifloxacin 200 mg qd to elderly patients (> or =65 years). Dosing regimens for levofloxacin were simulated as 500 mg, 750 mg and 1000 mg qd administered to elderly patients as well as younger patients. Monte Carlo simulations using gatifloxacin 400mg against S. pneumoniae yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 96.6% for all patients, 92.3% for younger patients and 97.7% for elderly patients. When administered to elderly patients, a reduced dose of gatifloxacin 200mg qd could achieve a target attainment potential of 91.4%. Monte Carlo simulation using levofloxacin 500 mg qd yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 92.3% for all patients, 95.7% for elderly patients compared with 72.7% for younger patients. Using levofloxacin 750 mg and 1000 mg qd had probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 97.0% and 98.3%, 98.1% and 99.2%, and 90.1% and 95.2% for all patients, elderly patients and younger patients, respectively. The probability of achieving free-drug AUC(0-24)/MIC(all) of 100 was low both with gatifloxacin and levofloxacin, except in the case of elderly patients receiving levofloxacin in a dose of 1000 mg qd (78.5%). We conclude that gatifloxacin and levofloxacin pharmacokinetics in elderly patients with CAP are markedly different from those of younger patients. Higher gatifloxacin/levofloxacin AUC and longer half-life (t(1/2)) values in elderly patients with CAP compared with younger patients provide better pharmacodynamic parameters (free-drug AUC(0-24)/MIC) leading to a higher probability of pharmacodynamic target attainment and improved bacteriological outcome against S. pneumoniae. Gatifloxacin 400mg qd results in a high probability of target attainment and improved bacteriological outcome against S. pneumoniae both in young and elderly CAP patients. However, gatifloxacin administered at a lowered dose of 200 mg qd in elderly patients could still be successful in producing a favourable antibacterial effect. Levofloxacin administered at a dose of 750 mg qd results in a high probability of target attainment and improved bacteriological outcome against S. pneumoniae in all patients with CAP.