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...

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The authors provide evidence-based guidance on treating human brucellosis, and discuss the future clinical trials that would help address the controversies surrounding treatment.

OR DECADES, INFECTIVE ENDOCARditis (IE) caused by Staphylococcus aureus has been viewed primarily as a community-acquired disease, especially associated with injection drug use. [1][2][3][4][5][6][7] In contrast, patients with nosocomial or intravascular catheterassociated S aureus bacteremia were considered to be at low risk for IE. 5,6,[8][9][10][11] S aureus IE is relatively infrequent at any individual institution, and observations of its characteristics were based primarily upon relatively small samples, 1,3,6,9,[12][13][14] single-center experiences, 5,6,8,9,[13][14][15][16] or retrospectively identified patients. 2,7,8,15,16 Patient characteristics, treatment practices, and outcomes in these single-center studiesoftendifferedconsiderably.Moreover, because no large, prospectively col-See also pp 3022 and 3061.

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...