Cumulative clinical experience from over a decade of use of levofloxacin in community-acquired pneumonia: critical appraisal and role in therapy

Levofloxacin is the synthetic L-isomer of the racemic fluoroquinolone, ofloxacin. It interferes with critical processes in the bacterial cell such as DNA replication, transcription, repair, and recombination by inhibiting bacterial topoisomerases. Levofloxacin has broad spectrum activity against several causative bacterial pathogens of community-acquired pneumonia (CAP). Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation such that patients can be conveniently transitioned between these formulations when moving from the inpatient to the outpatient setting. Furthermore, levofloxacin demonstrates excellent safety, and has good tissue penetration maintaining adequate concentrations at the site of infection. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP are well established. Furthermore, a high-dose (750 mg) and short-course (5 days) of once-daily levofloxacin has been approved for use in the US in the treatment of CAP, acute bacterial sinusitis, acute pyelonephritis, and complicated urinary tract infections. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent antibacterial activity, decreases the potential for drug resistance, and has better patient compliance

Comparative Pharmacodynamics of Ceftobiprole, Daptomycin, Linezolid, Telavancin, Tigecycline, and Vancomycin in the Treatment of Methicillin Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e: A Monte Carlo Simulation Analysis

Background/Objectives: Appropriate initial treatment choices for methicillin resistant Staphylococcus aureus (MRSA) infections are very critical. The aim of this study was to compare the ability of Ceftobiprole, Daptomycin, Linezolid, Telavancin, Tigecycline, and Vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) target against clinical MRSA isolates. Methods: Monte Carlo Simulations were performed to simulate the PK/PD indices of the investigated antimicrobials. Population Pharmacokinetic data and Pharmacodynamic indices were integrated into Monte Carlo Simulation routine with 10,000 iterations. Probability of target attainment (PTA) was estimated at MIC values ranging from 0.03-32 μg/ml to define the PK/PD susceptibility breakpoints. Cumulative fraction of response (CFR) was computed using MIC data from the Canadian National Ward (CAN-Ward) study collected in 2007, 2008 and 2009. Results: Analysis of the simulation results suggested the breakpoints of 8μg/ml for Ceftobiprole, 0.12 μg/ml for Daptomycin and Tigecycline, 0.5 μg/ml for Telavancin and 1 μg/ml for Linezolid and Vancomycin. The estimated CFR were 100, 66.5, 84, 89.1, 98.2, 60, 97.5 % for Ceft obiprole, Daptomycin (4mg/kg/day), Daptomycin (6mg/kg/day), Linezolid, Telavancin, Tigecycline, Vancomycin (2gm/day) and Vancomycin (3gm/day), respectively. Conclusions: Ceftobiprole and Telavancin have the highest probability of achieving favorable outcome against MRSA infections. The susceptibility results suggested a further reduction of the vancomycin breakpoint to 1 μg/ml

Pharmacodynamic Activity of Ceftobiprole Compared with Vancomycin versus Methicillin-Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e (MRSA), Vancomycin-Intermediate \u3cem\u3eStaphylococcus aureus\u3c/em\u3e (VISA) and Vancomycin-Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e (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 × 106 cfu/mL and ceftobiprole dosed every 8 h (at 0, 8 and 16 h) to simulate the fCmax and t1/2 obtained after 500 mg intravenous (iv) every 8 h dosing (fCmax, 30 mg/L; t1/2, 3.5 h). Vancomycin was dosed every 12 h (at 0 and 12 h) to simulate fCmax and t1/2 obtained after 1 g iv every 12 h dosing (fCmax, 20 mg/L; t1/2, 8 h). Samples were collected over 24 h to assess viable growth. Results Ceftobiprole T \u3e MIC of ≥100% (ceftobiprole MICs, ≤2 mg/L) was bactericidal (≥3 log10 killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin fAUC24/MIC of 340 (vancomycin MIC, 1 mg/L for MSSA and MRSA) resulted in a 1.8–2.6 log10 reduction in colony count at 24 h. Vancomycin fAUC24/MIC of 85–170 (vancomycin MIC, 2–4 mg/L for VISA) resulted in a 0.4–0.7 log10 reduction at 24 h. Vancomycin fAUC24/MIC of 5.3 (vancomycin MIC, 64 mg/L for VRSA) resulted in a limited effect. Conclusions Ceftobiprole T \u3e MIC of ≥100% (ceftobiprole MICs, ≤2 mg/L) was bactericidal (≥3 log10 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

Assessment of the Activity of Ceftaroline Against Clinical Isolates of Penicillin-Intermediate and Penicillin-Resistant \u3cem\u3eStreptococcus pneumoniae\u3c/em\u3e 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 × 106 cfu/mL and ceftaroline was dosed twice daily (at 0 and 12 h) to simulate the fCmax (maximum free concentration in serum) and t1/2 (half-life in serum) obtained after 600 mg intravenous doses every 12 h (fCmax, 16 mg/L; t1/2, 2.6 h). Ceftaroline was compared with ceftriaxone dosed once daily to simulate the fCmax and t1/2 obtained after a 1 g dose (fCmax, 18 mg/L; t1/2, 8.0 h). Samples were collected over 24 h to assess viable growth and possible changes in ceftaroline MICs over time. Results Ceftaroline fT\u3eMIC (time of free serum concentration over the MIC) of 100% (ceftaroline MICs, ≤0.5 mg/L) was bactericidal (≥3 log10 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\u3eMIC of 100% (ceftaroline MICs, ≤0.5 mg/L) was bactericidal (≥3 log10 killing) and eradicated all S. pneumoniae at 12 and 24 h with no regrowth

Pharmacodynamic Activity of Azithromycin Against Macrolide-Susceptible and Macrolide-Resistant \u3cem\u3eStreptococcus pneumoniae\u3c/em\u3e Simulating Clinically Achievable Free Serum, Epithelial Lining Fluid and Middle Ear Fluid Concentrations

Background: The association between macrolide resistance mechanisms and bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro pharmacodynamic model, assessed azithromycin activity against macrolide-susceptible and -resistant S. pneumoniae simulating clinically achievable free serum (S), epithelial lining fluid (ELF) and middle ear fluid (MEF) concentrations. Materials and methods: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Azithromycin was modelled simulating a dosage of 500 mg/250 mg by mouth, once a day [free S: maximum concentration (Cmax) 0.2 mg/L, t1/2 68 h; free ELF Cmax 1.0 mg/L, t1/2 68 h] and 10 mg/kg by mouth, once a day (free MEF: Cmax 1.0 mg/L, t1/2 68 h) using a one compartment model. Starting inocula were 1 × 106 cfu/mL in Mueller–Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log10 cfu/mL versus initial inoculum). Results: Free azithromycin concentrations in serum, ELF and MEF simulating time above the MIC (T \u3e MIC) of 100% [area under the curve to MIC (AUC0–24/MIC] ≥ 36.7] were bactericidal (≥3 log10 killing) at 24 and 48 h versus macrolide-susceptible S. pneumoniae. Against macrolide-resistant S. pneumoniae, free serum concentrations providing T \u3e MIC of 0% or AUC0–24/MIC ≤ 1.1 demonstrated no bacterial inhibition followed by regrowth at 24 and 48 h, whereas free ELF and MEF providing T \u3e MIC of 0% or AUC0–24/MIC of 4.6 produced a bacteriostatic (0.2–0.5 log10 killing at 24 h) effect with a mef(A) strain with an azithromycin MIC of 2 mg/L. Against mef(A)-positive S. pneumoniae strains with azithromycin MICs ≥ 4 mg/L, no bacterial killing occurred at any time point and rapid regrowth was observed simulating ELF or MEF T \u3e MIC of 0% or AUC0–24/MIC ≤ 2.3. Conclusion: Azithromycin serum, ELF and MEF concentrations rapidly eradicated macrolide-susceptible S. pneumoniae but did not eradicate macrolide-resistant S. pneumoniae regardless of resistance phenotype

Dynamics of extended-spectrum cephalosporin resistance genes in Escherichia coli from Europe and North America

Extended-spectrum cephalosporins (ESCs) are critically important antimicrobial agents for human and veterinary medicine. ESC resistance (ESC-R) genes have spread worldwide through plasmids and clonal expansion, yet the distribution and dynamics of ESC-R genes in different ecological compartments are poorly understood. Here we use whole genome sequence data of Enterobacterales isolates of human and animal origin from Europe and North America and identify contrasting temporal dynamics. AmpC β-lactamases were initially more dominant in North America in humans and farm animals, only later emerging in Europe. In contrast, specific extended-spectrum β-lactamases (ESBLs) were initially common in animals from Europe and later emerged in North America. This study identifies differences in the relative importance of plasmids and clonal expansion across different compartments for the spread of different ESC-R genes. Understanding the mechanisms of transmission will be critical in the design of interventions to reduce the spread of antimicrobial resistance

A Critical Review of Oxazolidinones: An Alternative or Replacement for Glycopeptides and Streptogramins?

OBJECTIVE: To review the available data on the oxazolidinones linezolid and eperezolid. DATA SELECTION: Published reports were obtained by searching MEDLINE for articles published between 1992 and 2000, inclusive. References of published papers were also obtained and reviewed. Abstracts from scientific proceedings were reviewed. DATA EXTRACTION: Due to the limited data available regarding these agents, the criteria for study inclusion were not restrictive. DATA SYNTHESIS: The oxazolidinones (eg, linezolid) are a new antimicrobial class with a unique mechanism of action. They are active against resistant Gram-positive cocci including methicillin-susceptible and -resistant Staphylococcus aureus (MRSA), methicillin-susceptible and -resistant Staphylococccus epidermidis, vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP). Linezolid is active against anaerobes and displays modest activity against fastidious Gram-negative pathogens such as Haemophilus influenzae, but is not active against Enterobacteriaceae. Linezolid is available both orally and parenterally, and has a bioavailability of 100%. Clinical trials comparing linezolid with standard therapy have demonstrated similar bacteriological and clinical cures rates to standard therapy in community- and hospital-acquired pneumonia, uncomplicated and complicated skin and soft tissue infections, and infections caused by MRSA and VRE. Adverse effects have been minor and infrequent; however, platelets should be monitored in patients who have received more than two weeks of linezolid therapy. It is expected that these agents will have a bright future due to their excellent spectrum of activity against antibiotic-resistant Gram-positive organisms, such as MRSA, VRE and PRSP, and their excellent bioavailability. CONCLUSION: The oxazolidinones represent a new class of antimicrobials with a unique mechanism of action. They have excellent activity against susceptible and resistant Gram-positive organisms such as MRSA, methicillin-susceptible S epidermidis, VRE and PRSP, and a good adverse effect profile; they can be administered both intravenously and orally. Their potential use in Canada may be as an intravenous and oral alternative to glycopeptides and streptogramins

Real-life experience with ceftolozane/tazobactam in Canada: results from the CLEAR (Canadian LEadership on Antimicrobial Real-life usage) registry.

Objectives Ceftolozane/tazobactam is a cephalosporin/β-lactamase inhibitor combination with activity against Gram-negative bacilli. We report the use of ceftolozane/tazobactam in Canada using a national registry. Methods The CLEAR registry uses REDCapTM (Research Electronic Data Capture) (online survey, https://is.gd/CLEAR_ceftolozanetazobactam) to capture details associated with clinical use of ceftolozane/tazobactam. Results Data from 51 patients treated in 2020 with ceftolozane/tazobactam are available. Infections treated included hospital-acquired bacterial pneumonia (37.3% of patients), ventilator-associated bacterial pneumonia (15.7%), bone/joint infection (11.8%), complicated intra-abdominal infection (7.8%) and complicated skin and skin structure infection (7.8%). 17.6% of patients had bacteremia and 47.1% were in intensive care. Ceftolozane/tazobactam was primarily used as directed therapy for Pseudomonas aeruginosa infections (92.2% of patients). Ceftolozane/tazobactam was used because of resistance to (86.3%), failure of (11.7%), or adverse effects from (2.0%) previously prescribed antimicrobials. Ceftolozane/tazobactam susceptibility testing was performed on isolates from 88.2% of patients. Ceftolozane/tazobactam was used in combination with another antimicrobial active versus Gram-negative bacilli in 39.2% of patients (aminoglycosides [15.7%], fluoroquinolones [7.8%] and colistin/polymyxin B [7.8%]). The dosage regimen was customized in all patients based on their creatinine clearance. Treatment duration was primarily >10 days (60.8% of patients) with microbiological success in 60.5% and clinical success in 64.4% of patients. 7.8% of patients had adverse effects not requiring drug discontinuation. Conclusions In Canada, ceftolozane/tazobactam is used as directed therapy to treat a variety of severe infections caused MDR P. aeruginosa. It is commonly used in combination with other antimicrobials with relatively high microbiological/clinical cure rates, and an excellent safety profile

Comparative in vitro activity of Meropenem, Imipenem and Piperacillin/tazobactam against 1071 clinical isolates using 2 different methods: a French multicentre study

<p>Abstract</p> <p>Background</p> <p>Meropenem is a carbapenem that has an excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. The major objective of the present study was to assess the <it>in vitro </it>activity of meropenem compared to imipenem and piperacillin/tazobactam, against 1071 non-repetitive isolates collected from patients with bacteremia (55%), pneumonia (29%), peritonitis (12%) and wound infections (3%), in 15 French hospitals in 2006. The secondary aim of the study was to compare the results of routinely testings and those obtained by a referent laboratory.</p> <p>Method</p> <p>Susceptibility testing and Minimum Inhibitory Concentrations (MICs) of meropenem, imipenem and piperacillin/tazobactam were determined locally by Etest method. Susceptibility to meropenem was confirmed at a central laboratory by disc diffusion method and MICs determined by agar dilution method for meropenem, imipenem and piperacillin/tazobactam.</p> <p>Results</p> <p>Cumulative susceptibility rates against <it>Escherichia coli </it>were, meropenem and imipenem: 100% and piperacillin/tazobactam: 90%. Against other <it>Enterobacteriaceae</it>, the rates were meropenem: 99%, imipenem: 98% and piperacillin/tazobactam: 90%. All <it>Staphylococci</it>, <it>Streptococci </it>and anaerobes were susceptible to the three antibiotics. Against non fermeters, meropenem was active on 84-94% of the strains, imipenem on 84-98% of the strains and piperacillin/tazobactam on 90-100% of the strains.</p> <p>Conclusions</p> <p>Compared to imipenem, meropenem displays lower MICs against <it>Enterobacteriaceae</it>, <it>Escherichia coli </it>and <it>Pseudomonas aeruginosa</it>. Except for non fermenters, MICs90 of carbapenems were <4 mg/L. Piperacillin/tazobactam was less active against <it>Enterobacteriaceae </it>and <it>Acinetobacter </it>but not <it>P. aeruginosa</it>. Some discrepancies were noted between MICs determined by Etest accross centres and MICs determined by agar dilution method at the central laboratory. Discrepancies were more common for imipenem testing and more frequently related to a few centres. Overall MICs determined by Etest were in general higher (0.5 log to 1 log fold) than MICs by agar dilution.</p

Managing urinary tract infections

Urinary tract infections (UTI) are common in childhood. Presence of pyuria and bacteriuria in an appropriately collected urine sample are diagnostic of UTI. The risk of UTI is increased with an underlying urological abnormality such as vesicoureteral reflux, constipation, and voiding dysfunction. Patients with acute pyelonephritis are at risk of renal scarring and subsequent complications such as hypertension, proteinuria with and without FSGS, pregnancy-related complications and even end-stage renal failure. The relevance and the sequence of the renal imaging following initial UTI, and the role of antimicrobial prophylaxis and surgical intervention are currently undergoing an intense debate. Prompt treatment of UTI and appropriate follow-up of those at increased risk of recurrence and/or renal scarring are important