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, includ...

Most current fluoroquinolone-resistant E. coli clinical isolates, and the largest share of multidrug-resistant isolates, represent a highly clonal subgroup that likely originated from a single rapidly expanded and disseminated ST131 strain. Focused attention to this strain will be required to control the fluoroquinolone and multidrug-resistant E. coli epidemic.

With the expanded use of fluoroquinolones for the treatment of community-acquired respiratory infections and reports of tendon injury linked to the use of these agents, we reviewed the literature to investigate the frequency and strength of this association. Ninety-eight case reports were available for review. The incidence of tendon injury associated with fluoroquinolone use is low in a healthy population but increases in patients who have renal dysfunction, who are undergoing hemodialysis, or who have received renal transplants. Pefloxacin and ciprofloxacin were most frequently implicated, but tendon injury was reported with most fluoroquinolones. The median duration of fluoroquinolone treatment before the onset of tendon injury was 8 days, although symptoms occurred as early as 2 hours after the first dose and as late as 6 months after treatment was stopped. Up to one-half of patients experienced tendon rupture, and almost one-third received long-term corticosteroid therapy. Tendon injury associated with fluoroquinolone use is significant, and risk factors such as renal disease or concurrent corticosteroid use must be considered when these agents are prescribed.

Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spect...

Vancomycin utilisation has increased dramatically in the last 10 years due to the increasing clinical significance of infections with methicillin-resistant staphylococci. Recent studies have focused on characterising the disposition of vancomycin in patients and assessing the relationship between serum concentrations and therapeutic as well as adverse effects. Although vancomycin is not appreciably absorbed from the intact gastrointestinal tract, several recent case reports have documented the attainment of therapeutic and potentially toxic vancomycin serum concentrations following oral administration to patients with pseudomembranous colitis. The disposition of parenterally administered vancomycin has been best characterised by a triexponential model. The half-life of the initial phase (t1/2 pi) is approximately 7 minutes, that of the second phase (t1/2 alpha) is approximately 0.5 to 1 hour, while the terminal elimination half-life (t1/2 beta) ranges from 3 to 9 hours in subjects with normal renal function. The volume of the central compartment (Vc) in adults is approximately 0.15 L/kg while the steady-state volume of distribution (Vdss) ranges from 0.39 to 0.97 L/kg. More than 80% of a vancomycin dose is excreted unchanged in the urine within 24 hours after administration, and the concentration of vancomycin in liver tissue and bile has been reported to be at or below detection limits. Vancomycin renal clearance approximates 0.5 to 0.8 of simultaneously determined creatinine or 125I-iothalamate clearances, suggesting that the primary route of renal excretion is glomerular filtration. Recently, non-renal factors such as hepatic conjugation have been proposed as an important route of vancomycin elimination. However, these data are difficult to reconcile with other studies showing minimal non-renal clearance of vancomycin in subjects with end-stage renal disease. As yet, the disposition of vancomycin in patients with hepatic disease has not been adequately defined. Only limited data are available regarding the concentrations of vancomycin in biological fluids other than plasma. The penetration of vancomycin into cerebrospinal fluid (CSF) in patients with and without meningitis has been quite variable. Although early studies suggested that adequate CSF concentrations may not be achieved in subjects with uninflamed meninges, more recent investigations have reported contradictory results. Therapeutic concentrations of vancomycin, i.e. greater than 2.5 mg/L, have, however, been reported in ascitic, pericardial, pleural and synovial fluids. Tissue concentrations of vancomycin have exceeded simultaneous serum concentrations in heart, kidney, liver and lung sp

The extent to which clonal spread contributes to emerging antimicrobial resistance in Escherichia coli is incompletely defined. To address this question within a recent, nationally representative strain collection, three established drug-resistant E. coli clonal groups (i.e., clonal group A, E. coli O15:K52:H1, and sequence type 131 [ST131]) were sought among 199 E. coli urine isolates recovered from across Canada from 2002 to 2004, with stratification by resistance to trimethoprim-sulfamethoxazole (TS) and fluoroquinolones (FQs). The isolates' clonal backgrounds, virulence genotypes, and macrorestriction profiles were assessed. The three clonal groups were found to account for 37. 2% of isolates overall, but accounted for 0% of TS-susceptible (TS-S) and FQ-susceptible (FQ-S) isolates, 20% of TS-resistant (TS-R) and FQ-S isolates, 60% of TS-S and FQ-R isolates, and 68% of TS-R and FQ-R isolates (P < 0.001). E. coli ST131, the most prevalent clonal group, accounted for 23.1% of isolates overall and for 44% of the FQ-R isolates.Nearly all ST131 isolates were FQ-R (96%) but, notably, cephalosporin susceptible (98%). Although the distinctive virulence profiles of the FQ-R clonal group isolates were less extensive than those of the susceptible isolates, they were significantly more extensive than those of the other FQ-R isolates. These findings indicate that among the E. coli urine isolates studied, resistance to TS and FQs has a prominent clonal component, with the O15:K52:H1 clonal group and especially E. coli ST131 being the major contributors. These clonal groups appear to be more virulent than comparably resistant isolates, possibly contributing to their success as emerging multi-drug-resistant pathogens.

Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC). Little is known about the potential for relebactam or vaborbactam to select for resistance; however, inactivation of the porin protein OmpK36 in K. pneumoniae has been reported to confer resistance to both imipenem-relebactam and meropenem-vaborbactam. The addition of relebactam significantly improves the activity of imipenem against most species of Enterobacteriaceae [by lowering the minimum inhibitory concentration (MIC) by 2- to 128-fold] depending on the presence or absence of β-lactamase enzymes. Against Pseudomonas aeruginosa, the addition of relebactam also improves the activity of imipenem (MIC reduced eightfold). Based on the data available, the addition of relebactam does not improve the activity of imipenem against Acinetobacter baumannii, Stenotrophomonas maltophilia and most anaerobes. Similar to imipenem-relebactam, the addition of vaborbactam significantly (2- to > 1024-fold MIC reduction) improves the activity of meropenem against most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzymes. Limited data suggest that the addition of vaborbactam does not improve the activity of meropenem against A. baumannii, P. aeruginosa, or S. maltophilia. The pharmacokinetics of both relebactam and vaborbactam are described by a two-compartment, linear model and do not appear to be altered by the co-administration of imipenem and meropenem, respectively. Relebactam's approximate volume of distribution (V ) and elimination half-life (t) of ~ 18 L and 1.2-2.1 h, respectively, are similar to imipenem. Likewise, vaborbactam's V and t of ~ 18 L and 1.3-2.0 h, respectively, are comparable to meropenem. Like imipenem and meropenem, relebactam and vaborbactam are both primarily renally excreted, and clearance correlates with creatinine clearance. In vitro and in vivo pharmacodynamic studies have reported bactericidal activity for imipenem-relebactam and meropenem-vaborbactam against various Gram-negative β-lactamase-producing bacilli that are not inhibited by their respective carbapenems alone. These data also suggest that pharmacokinetic-pharmacodynamic parameters correlating with efficacy include time above the MIC for the carbapenems and overall exposure for their companion β-lactamase inhibitors. Phase II clinical trials to date have reported that imipenem-relebactam is as effective as imipenem alone for treatment of complicated intra-abdominal infections and complicated uri...

, 19 medical centers collected 4,180 isolates recovered from clinical specimens from patients in intensive care units (ICUs) in Canada. The 4,180 isolates were collected from 2,292 respiratory specimens (54.8%), 738 blood specimens (17.7%), 581 wound/tissue specimens (13.9%), and 569 urinary specimens (13.6%). The 10 most common organisms isolated from 79.5% of all clinical specimens were methicillin-susceptible Staphylococcus aureus (MSSA) (16.4%), Escherichia coli (12.8%), Pseudomonas aeruginosa (10.0%), Haemophilus influenzae (7.9%), coagulase-negative staphylococci/Staphylococcus epidermidis (6.5%), Enterococcus spp. (6.1%), Streptococcus pneumoniae (5.8%), Klebsiella pneumoniae (5.8%), methicillin-resistant Staphylococcus aureus (MRSA) (4.7%), and Enterobacter cloacae (3.9%). MRSA made up 22.3% (197/884) of all S. aureus isolates (90.9% of MRSA were health care-associated MRSA, and 9.1% were community-associated MRSA), while vancomycin-resistant enterococci (VRE) made up 6.7% (11/255) of all enterococcal isolates (88.2% of VRE had the vanA genotype). Extended-spectrum ␤-lactamase (ESBL)-producing E. coli and K. pneumoniae occurred in 3.5% (19/536) and 1.8% (4/224) of isolates, respectively. All 19 ESBL-producing E. coli isolates were PCR positive for CTX-M, with bla CTX-M-15 occurring in 74% (14/19) of isolates. For MRSA, no resistance against daptomycin, linezolid, tigecycline, and vancomycin was observed, while the resistance rates to other agents were as follows: clarithromycin, 89.9%; clindamycin, 76.1%; fluoroquinolones, 90.1 to 91.8%; and trimethoprim-sulfamethoxazole, 11.7%. For E. coli, no resistance to amikacin, meropenem, and tigecycline was observed, while resistance rates to other agents were as follows: cefazolin, 20.1%; cefepime, 0.7%; ceftriaxone, 3.7%; gentamicin, 3.0%; fluoroquinolones, 21.1%; piperacillin-tazobactam, 1.9%; and trimethoprim-sulfamethoxazole, 24.8%. Resistance rates for P. aeruginosa were as follows: amikacin, 2.6%; cefepime, 10.2%; gentamicin, 15.2%; fluoroquinolones, 23.8 to 25.5%; meropenem, 13.6%; and piperacillin-tazobactam, 9.3%. A multidrug-resistant (MDR) phenotype (resistance to three or more of the following drugs: cefepime, piperacillin-tazobactam, meropenem, amikacin or gentamicin, and ciprofloxacin) occurred frequently in P. aeruginosa (12.6%) but uncommonly in E. coli (0.2%), E. cloacae (0.6%), or K. pneumoniae (0%). In conclusion, S. aureus (MSSA and MRSA), E. coli, P. aeruginosa, H. influenzae, Enterococcus spp., S. pneumoniae, and K. pneumoniae are the most common isolates recovered from clinical specimens in Canadian ICUs. A MDR phenotype is common for P. aeruginosa isolates in Canadian ICUs.