Optimal meropenem concentrations to treat multi-drug resistant Pseudomonas aeruginosa septic shock.

Antimicrob Agents Chemother. 2012 Jan 30;

Authors: Taccone FS, Cotton F, Roisin S, Vincent JL, Jacobs F

Abstract
A patient with septic shock due to extensively-drug resistant (XDR) Pseudomonas aeruginosa was cured by optimizing the meropenem (MEM) regimen to obtain at least 40% of the time between two administrations in which drug levels were four times above the minimal inhibitory concentration (MIC) of the pathogen. As standard drug dose did not achieve these optimal concentrations, MEM regimen was progressively increased up to 12g/day (3g q6h in 3-hour extended infusion), which eventually resulted in sepsis resolution. High MEM dosage may represent a valuable therapeutic option for infection due to MDR strains and drug monitoring would allow rapid regimen adjustment in clinical practice.

PMID: 22290984 [PubMed - as supplied by publisher]

The efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum ?-lactamase producing Enterobacteriaceae.

Antimicrob Agents Chemother. 2012 Jan 30;

Authors: Collins VL, Marchaim D, Pogue JM, Moshos J, Bheemreddy S, Sunkara B, Shallal A, Chugh N, Eiseler S, Bhargava P, Blunden C, Lephart PR, Memon I, Hayakawa K, Odaliz AL, Chopra T, Munoz-Price S, Carmeli Y, Kaye K

Abstract
Ertapenem is active against ESBLs but inactive against Pseudomonas aeruginosa and Acinetobacter baumannii. Due to lack of therapeutic data for ertapenem in treatment of ESBL bloodstream infections (BSI), group 2 carbapenems (e.g. imipenem or meropenem) are often preferred for treatment of ESBLs, although their anti-pseudomonal activity is unnecessary. From 2005-2010, 261 patients with ESBL BSIs were analyzed. Outcomes were equivalent between patients treated with ertapenem and group 2 carbapenems (mortality rates 6% and 18%, p=0.18).

PMID: 22290982 [PubMed - as supplied by publisher]

The efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum ?-lactamase producing Enterobacteriaceae.

Antimicrob Agents Chemother. 2012 Jan 30;

Authors: Collins VL, Marchaim D, Pogue JM, Moshos J, Bheemreddy S, Sunkara B, Shallal A, Chugh N, Eiseler S, Bhargava P, Blunden C, Lephart PR, Memon I, Hayakawa K, Odaliz AL, Chopra T, Munoz-Price S, Carmeli Y, Kaye K

Abstract
Ertapenem is active against ESBLs but inactive against Pseudomonas aeruginosa and Acinetobacter baumannii. Due to lack of therapeutic data for ertapenem in treatment of ESBL bloodstream infections (BSI), group 2 carbapenems (e.g. imipenem or meropenem) are often preferred for treatment of ESBLs, although their anti-pseudomonal activity is unnecessary. From 2005-2010, 261 patients with ESBL BSIs were analyzed. Outcomes were equivalent between patients treated with ertapenem and group 2 carbapenems (mortality rates 6% and 18%, p=0.18).

PMID: 22290982 [PubMed - as supplied by publisher]

The efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum ?-lactamase producing Enterobacteriaceae.

Antimicrob Agents Chemother. 2012 Jan 30;

Authors: Collins VL, Marchaim D, Pogue JM, Moshos J, Bheemreddy S, Sunkara B, Shallal A, Chugh N, Eiseler S, Bhargava P, Blunden C, Lephart PR, Memon I, Hayakawa K, Odaliz AL, Chopra T, Munoz-Price S, Carmeli Y, Kaye K

Abstract
Ertapenem is active against ESBLs but inactive against Pseudomonas aeruginosa and Acinetobacter baumannii. Due to lack of therapeutic data for ertapenem in treatment of ESBL bloodstream infections (BSI), group 2 carbapenems (e.g. imipenem or meropenem) are often preferred for treatment of ESBLs, although their anti-pseudomonal activity is unnecessary. From 2005-2010, 261 patients with ESBL BSIs were analyzed. Outcomes were equivalent between patients treated with ertapenem and group 2 carbapenems (mortality rates 6% and 18%, p=0.18).

PMID: 22290982 [PubMed - as supplied by publisher]

Cethromycin versus clarithromycin for community acquired pneumonia: The comparative efficacy and safety outcomes of two double-blinded, randomized, parallel group, multi-center, multi-national non-inferiority studies.

Antimicrob Agents Chemother. 2012 Jan 30;

Authors: English ML, Fredericks CE, Milanesio NA, Rohowsky N, Xu ZQ, Jenta TR, Flavin MT, Eiznhamer DA

Abstract
Community acquired pneumonia (CAP) continues to be a major health challenge in the US and globally. Factors such as overprescribing and non-compliance with antibiotics have added to the growing antibacterial resistance problem. In addition, several agents available for the treatment of CAP have been associated with serious side effects. Cethromycin is a new ketolide antibiotic that may provide prescribing physicians with an additional agent to supplement a continually limited armamentarium. Two global Phase III non-inferiority studies (CL05-001 and CL06-001) to evaluate cethromycin safety and efficacy were designed and conducted in patients with mild-to-moderate CAP. Study CL05-001 demonstrated 83.1% clinical cure rate in cethromycin group compared with 81.1% in clarithromycin group [95% CI: -4.8%, +8.9%] in the ITT population and 94.0% cethromycin clinical cure rate compared with 93.8% clarithromycin cure rate [95% CI: -4.5%, +5.1%] in the PPc population. Study CL06-001 achieved 82.9% cethromycin clinical cure rate in the ITT population compared with 88.5% clarithromycin cure rate [95% CI: -11.9%, +0.6%], whereas the clinical cure rate in the PPc population was 91.5% in cethromycin group compared with 95.9% in clarithromycin group [95% CI: -9.1%, +0.3%]. Both studies met the primary endpoints for clinical cure rate based on pre-defined, sliding-scale non-inferiority design. Therefore, in comparison with clarithromycin, these two non-inferiority studies demonstrated the efficacy and safety of cethromycin, with encouraging findings of efficacy in subjects with S. pneumoniae bacteremia. No clinically significant adverse events were observed during the studies. Cethromycin may be a potential oral therapy for the outpatient treatment of CAP.

PMID: 22290969 [PubMed - as supplied by publisher]

A prospective observational study comparing three different treatment regimes in patients with Clostridium difficile infection.

Antimicrob Agents Chemother. 2012 Jan 17;

Authors: Wenisch JM, Schmid D, Kuo HW, Allerberger F, Michl V, Tesik P, Tucek G, Laferl H, Wenisch C

Abstract
ObjectiveTo test the effects of the three standard treatment regimens for mild Clostridium difficile infection (CDI) on the risk of complications, sequelae and all-cause death within 30 days after starting treatment.MethodsIn a hospital-based, prospective cohort study the three standard treatment regimens of oral (p.o.) metronidazole 3 × 500 mg/d, intravenous (i.v.) metronidazole 3 × 500 mg/d and oral (p.o.) vancomycin 4 × 250 mg/d, for mild CDI were compared with respect to occurrence of complications, sequelae and all-cause death within 30 days after date of starting treatment. Differences in the incidence of these outcomes were tested by ?2 or Fisher's exact tests. A Poisson regression model was performed to control for possible confounding effects of sex, age and severity of comorbidity categorized according to the Charlson comorbidity index.ResultsThe highest mortality was observed in the metronidazole i.v. group with 38.1% (16/42) compared to 7.4% (9/121) in the metronidazole p.o. group and 9.5% (4/42) in the vancomycin p.o. group (p<0.001). After adjustment for possible effects of sex, age (> 65 years) and severity of comorbidity, the relative risk of 30-day fatal outcome for patients receiving metronidazole i.v. was 4.3 (95%CI 1.92-10; p<0.0001) as compared to patients with metronidazole p.o. and 4.0 (95%CI: 1.31-5.0; p<0.015) compared to patients treated with vancomycin p.o. There were no significant differences in the risk of complications between the three treatment groups.ConclusionThis study generates the hypothesis that treatment with i.v. metronidazole is inferior to the oral alternatives metronidazole and vancomycin.

PMID: 22252830 [PubMed - as supplied by publisher]

Trends in the Susceptibility of Clinically Important Resistant Bacteria to Tigecycline: Results from the Tigecycline In-vitro Surveillance in Taiwan (TIST), 2006-2010.

Antimicrob Agents Chemother. 2011 Dec 27;

Authors: Chen YH, Lu PL, Huang CH, Liao CH, Lu CT, Chuang YC, Tsao SM, Chen YS, Liu YC, Chen WY, Jang TN, Lin HC, Chen CM, Shi ZY, Pan SC, Yang CL, Kung HC, Liu CE, Cheng YJ, Liu JW, Sun W, Wang LS, Ko WC, Yu KW, Chiang PC, Lee MH, Lee CM, Hsu GJ, Hsueh PR

Abstract
The Tigecycline In-vitro Surveillance in Taiwan (TIST), a nationwide, prospective surveillance during 2006 to 2010, collected a total of 7,793 clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA) (n=1,834), penicillin-resistant Streptococcus pneumoniae (PRSP) (n=423), vancomycin-resistant enterococci (VRE) (n=219), extended-spectrum ?-lactamase (ESBL)-producing Escherichia coli (n=1,141), ESBL-producing Klebsiella pneumoniae (n=1,330), Acinetobacter baumannii (n=1,645), and Stenotrophomonas maltophilia (n=903), from different specimens from 20 different hospitals in Taiwan. Minimum inhibitory concentrations (MICs) of tigecycline were determined following the criteria of the US Food and Drug Administration (FDA) and European Committee on Antimicrobial Susceptibility Testing (EUCAST-2011).Among drug-resistant Gram-positive pathogens, all of the PRSP isolates were susceptible to tigecycline (MIC(90), 0.03 ?g/ml) and only one MRSA isolate (MIC(90), 0.5 ?g/ml) and three VRE isolates (MIC(90), 0.125 ?g/ml) were non-susceptible to tigecycline. Among the Gram-negative bacteria, the tigecycline susceptibility rates were 99.65% for ESBL-producing E. coli (MIC(90), 0.5 ?g/ml) and 96.32% for ESBL-producing K. pneumoniae (MIC(90), 2 ?g/ml), when interpreted by FDA criteria, but were 98.7% and 85.8%, respectively, when interpreted by EUCAST-2011 criteria. The susceptibility of A. baumannii (MIC(90), 4 ?g/ml) decreased from 80.9% in 2006 to 55.3% in 2009, but increased to 73.4% in 2010. A bimodal MIC distribution was found among carbapenem-susceptible A. baumannii isolates and an unimodal MIC distribution was found among carbapenem-nonsusceptible A. baumannii isolates. In Taiwan, tigecycline continues to have excellent in vitro activity against several major clinically important drug-resistant bacteria, with the exception of A. baumannii.

PMID: 22203598 [PubMed - as supplied by publisher]

Impact of Carbapenem Resistance on Mortality in Pseudomonas aeruginosa Bloodstream Infections. A Prospective Multicenter Study.

Antimicrob Agents Chemother. 2011 Dec 12;

Authors: Peña C, Suarez C, Gozalo M, Murillas J, Almirante B, Pomar V, Aguilar M, Granados A, Calbo E, Rodríguez-Baño J, Rodríguez F, Tubau F, Martínez-Martínez L, Oliver A,

Abstract
The impact of antimicrobial resistance on clinical outcome is the subject of ongoing investigation, although uncertainty remains about its contribution to mortality. We investigated the impact of carbapenem resistance on mortality in Pseudomonas aeruginosa (PA) bacteremia in a prospective multicenter (ten teaching hospitals) observational study of patients with monomicrobial bacteremia followed up 30 days after bacteremia onset. The adjusted influence of carbapenem resistance on mortality was studied using Cox regression analysis. Of 632 episodes, 487 (77%) were caused by carbapenem-susceptible isolates (CSPA), and 145 (23%) by carbapenem-resistant (CRPA) isolates. The median incidence density of nosocomial CRPA bacteremia was 2.3 episodes per 100,000 patient-days (95%CI 1.9 to 2.8). The regression demonstrated a time-dependent effect of carbapenem resistance on mortality, as well as a significant interaction with the Charlson index: the deleterious effect of carbapenem resistance on mortality decreased with higher Charlson index scores. The impact of resistance on mortality was statistically significant only from the 5(th) day after the onset of the bacteremia, reaching its peak values at day 30 (adjusted hazard ratios [95% confidence intervals] Charlson 0 at day 30 = 9.9 [3.3 - 29.4]; Charlson 5 at day 30 = 2.6 [0.8 - 8]). This study clarifies the relationship between carbapenem resistance and mortality of patients with P. aeruginosa bacteremia. Although resistance was associated with a higher risk of mortality, the study suggested that this deleterious effect may be not as great during the first days of the bacteremia or in the presence of comorbidities.

PMID: 22155832 [PubMed - as supplied by publisher]

Changes in the use of broad-spectrum antibiotics after cefepime shortage: a time series analysis.

Antimicrob Agents Chemother. 2011 Nov 28;

Authors: Plüss-Suard C, Pannatier A, Ruffieux C, Kronenberg A, Mühlemann K, Zanetti G

Abstract
The original cefepime product was withdrawn from the Swiss market in January 2007, and replaced by a generic 10 months later. The goals of the study were to assess the impact of this cefepime shortage on the use and costs of alternative broad-spectrum antibiotics, on antibiotic policy, and on resistance of Pseudomonas aeruginosa towards carbapenems, ceftazidime and piperacillin-tazobactam. A generalized regression-based interrupted time series model assessed how much the shortage changed the monthly use and costs of cefepime and of selected alternative broad-spectrum antibiotics (ceftazidime, imipenem-cilastatin, meropenem, piperacillin-tazobactam) in 15 Swiss acute care hospitals from January 2005 to December 2008. Resistance of P. aeruginosa was compared before and after the cefepime shortage. There was a statistically significant increase in the consumption of piperacillin-tazobactam in hospitals with definitive interruption of cefepime supply, and of meropenem in hospitals with transient interruption of cefepime supply. Consumption of each alternative antibiotic tended to increase during the cefepime shortage and to decrease when the cefepime generic was released. These shifts were associated with significantly higher overall costs. There was no significant change in hospitals with uninterrupted cefepime supply. The alternative antibiotics for which an increase in consumption showed the strongest association with a progression of resistance were the carbapenems. The use of alternative antibiotics after cefepime withdrawal was associated with a significant increase in piperacillin-tazobactam and meropenem use and in overall costs, and with a decrease in susceptibility of P. aeruginosa in hospitals. This warrants caution with regard to shortages and withdrawals of antibiotics.

PMID: 22123703 [PubMed - as supplied by publisher]

Impact of inadequate empirical therapy on the mortality of patients with bloodstream infections: a propensity score-based analysis.

Antimicrob Agents Chemother. 2011 Oct 17;

Authors: Retamar P, Portillo MM, López-Prieto MD, Rodríguez-López F, de Cueto M, García MV, Gómez MJ, Del Arco A, Muñoz A, Sánchez-Porto A, Torres-Tortosa M, Martín-Aspas A, Arroyo A, García-Figueras C, Acosta F, Corzo JE, León-Ruiz L, Escobar-Lara T, Rodríguez-Baño J,

Abstract
The impact of the adequacy of empirical therapy on the outcome of patients with bloodstream infections (BSI) is key to determine whether adequate empirical coverage should be prioritized over other more conservative approaches. Recent systematic reviews outlined the need for new studies in the field with improve methodologies. We assessed the impact of inadequate empirical treatment on the mortality of patients with BSI in the present-day context, incorporating recent methodological recommendations. A prospective multicenter cohort including all BSI episodes in adult patients was performed in 15 hospitals in Andalucía, Spain, over a 2-month period in 2006-2007. The main outcome variables were 14 and 30-day mortality. Adjusted analyses were performed by multivariate analysis and propensity score-based matching. Eight hundred and one episodes were included. Inadequate empirical therapy was administered in 199 (24.8%) episodes; mortality at days 14 and 30 were 18.55% and 22.6%, respectively. After controlling for age, Charlson index, Pitt score, neutropenia, source, etiology and presentation with severe sepsis or shock, inadequate empirical treatment was associated with increased mortality at days 14 and 30 (ORs: 2.12 and 1.56; 95% CI: 1.34-3.34 and 1.01-2.40, respectively). The adjusted ORs after a propensity score-based matched analysis were: 3.03 and 1.70; 95% CI: 1.60-5.74 and 0.98-2.98, respectively. In conclusion, inadequate empirical therapy is independently associated with increased mortality in patients with BSI. Programs to improve the quality of empirical therapy in patients with suspicion of BSI and optimization of definitive therapy should be implemented.

PMID: 22005999 [PubMed - as supplied by publisher]

Identifying patients harboring extended-spectrum-beta-lactamase-producing Enterobacteriaceae on hospital admission: derivation and validation of a scoring system.

Antimicrob Agents Chemother. 2011 Jul;55(7):3485-90

Authors: Tumbarello M, Trecarichi EM, Bassetti M, De Rosa FG, Spanu T, Di Meco E, Losito AR, Parisini A, Pagani N, Cauda R

Abstract
Increases in community-acquired infections caused by extended-spectrum-?-lactamase (ESBL)-producing Enterobacteriaceae have important implications for hospital infection control and empirical antibiotic therapy protocols. We developed and validated a tool for identifying patients harboring these organisms at hospital admission. We retrospectively analyzed chart data for 849 adult inpatients. The derivation cohort included 339 patients admitted to a large hospital in Rome during 2008, with (n = 113) or without (n = 226) culture positivity for ESBL-producing Escherichia coli, Klebsiella spp., or Proteus mirabilis within 48 h after admission. Logistic-regression-based prediction scores were calculated based on variables independently associated with the outcome. The model was validated in a second cohort (n = 510) selected with identical criteria in hospitals in Genoa and Turin during 2009. Prediction scores were based on the following six variables (reported with odds ratio for study outcome and the 95% confidence intervals in brackets): recent (? 12 months before admission) hospitalization (5.69 [2.94 to 10.99]), transfer from another health care facility (5.61 [1.65 to 19.08]), Charlson comorbidity score ? 4 (3.80 [1.90 to 7.59]), recent (? 3 months before admission) ?-lactam and/or fluoroquinolone treatment (3.68 [1.96 to 6.91]), recent urinary catheterization (3.52 [1.96 to 6.91]), and age ? 70 years (3.20 [1.79 to 5.70]). The model displayed good calibration and good-to-excellent discrimination in the derivation and validation sets (Hosmer-Lemshow ?(2) = 15.28 and 14.07; P = 0.17 and 0.23; areas under the receiver-operating characteristic curve, 0.83 and 0.92). It reliably identified patients likely to be harboring ESBL-producing Enterobacteriaceae at hospital admission who may need special infection control measures. Further study is needed to confirm this model's potential as a guide for prescribing empirical antibiotic therapy.

PMID: 21537020 [PubMed - indexed for MEDLINE]

Procalcitonin-guided therapy in respiratory tract infections: a meta-analysis and systematic review.

Antimicrob Agents Chemother. 2011 Sep 26;

Authors: Li H, Luo YF, Blackwell TS, Xie CM

Abstract
Circulating procalcitonin (PCT) is a biomarker that can be used in diagnosing bacterial infections. We performed a quantitative meta-analysis of available randomized controlled trials to determine whether antibiotic therapy based on PCT measurements alters clinical outcomes and antibiotic use in patients with lower respiratory tract infections. We identified studies through MEDLINE (1996-2010), IS Web of knowledge (1996-2010), and OVID. Studies that met our criteria were prospective, randomized controlled trials involving patients with respiratory tract infections. Outcomes of mortality, ICU admission, length of hospital stay, number of antibiotic prescriptions, and duration of antibiotic treatment were evaluated. Eight studies randomizing 3431 patients met our criteria for inclusion. Pooled analysis showed a significant reduction in number of antibiotic prescriptions and duration of antibiotic use in patients with PCT-guided antibiotic treatment compared to standard therapy. In addition, the use of PCT-guided antibiotic therapy did not impact mortality, ICU admission, or hospital stay in these studies. A high degree of heterogeneity was identified in 3 of 5 outcomes that were evaluated and sensitivity analysis indicated that heterogeneity was decreased among studies using the same PCT based treatment algorithm. In conclusion, PCT-guided antibiotic therapy in patients with respiratory tract infections appears to reduce antibiotic use without affecting overall mortality or length of stay in the hospital.

PMID: 21947386 [PubMed - as supplied by publisher]

The Relationship Between Vancomycin Trough Concentrations and Nephrotoxicty: A Prospective, Multi-center Trial.

Antimicrob Agents Chemother. 2011 Sep 26;

Authors: Bosso JA, Nappi J, Rudisill C, Wellein M, Bookstaver PB, Swindler J, Mauldin PD

Abstract
Several single center studies have suggested that higher doses of vancomycin, aimed at producing trough concentrations > 15 mg/L, are associated with increased risk of nephrotoxicity. We prospectively assessed the relative incidence of nephrotoxicity in relation to trough concentration in patients with documented MRSA infections at 7 hospitals throughout South Carolina. Adult patients receiving vancomycin for at least 72 hr with at least one vancomycin trough concentration determined under steady-state conditions were prospectively studied. The relationship between vancomycin trough concentrations > 15 mg/mL and occurrence of nephrotoxicity was assessed using univariate and multivariate analyses, controlling for age, gender, race, dose, length of therapy, use of other nephrotoxins (including contrast media), ICU residence, episodes of hypotension, and comorbidities. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dL or ? 50% increase from baseline for two consecutive measurements. Minimum inhibitory concentrations of vancomycin for the MRSA isolates were also determined. 288 patients were studied between February 2008 and June 2010 with approximately one-half having initial trough concentrations ? 15 mg/mL. Nephrotoxicity was observed in 42 patients (29.6%) with trough concentrations > 15 mg/mL and in 13 (8.9%) with troughs ? 15 mg/mL. Multivariate analysis revealed vancomycin troughs > 15 mg/mL and race (Black) as risk factors for nephrotoxicity in this population. Vancomycin trough concentrations > 15 mg/mL appear to be associated with a 3-fold increased risk of nephrotoxicity.

PMID: 21947388 [PubMed - as supplied by publisher]

Dose of Trimethoprim-Sulfamethoxazole to Treat Skin and Skin Structure Infections Caused by Methicillin Resistant Staphylococcus aureus.

Antimicrob Agents Chemother. 2011 Sep 19;

Authors: Cadena J, Nair S, Henao-Martinez AF, Jorgensen JH, Patterson JE, Sreeramoju PV

Abstract
Objective: We undertook this study to investigate whether treatment with a higher dose of trimethoprim/sulfamethoxazole (TMP/SMX) led to greater clinical resolution in patients with skin and soft tissue infections (SSTI) caused by methicillin resistant Staphylococcus aureus (MRSA). Methods: A prospective, observational cohort with nested case control study was performed at a public tertiary health system. Among patients with MRSA SSTI during May-08 to Sep-08 who received oral monotherapy with TMP-SMX and known clinical outcome, the clinical characteristics and outcomes were compared between patients treated with high dose of TMP/SMX (320mg/1600mg twice daily) for 7-15 days and patients treated with standard dose of TMP/SMX (160mg/800mg twice daily) for 7-15 days. Results: In patients with MRSA SSTI, those treated with high dose of TMP/SMX (n=121) had similar clinical characteristics compared to patients treated with standard dose of TMP/SMX (n=170). The only exception was a higher proportion of patients with history of trauma upon admission in the patients treated with higher dose. The proportion of patients with clinical resolution of infection was not different in the two groups [88/121, 73% vs. 127/170, 75%; p-value=0.79). The lack of significance remained in patients with abscess upon stratified analysis by whether surgical drainage was performed. Conclusion: The study found that patients with MRSA SSTI treated with a higher dose of TMP/SMX 320/1600mg twice-daily for 7-15 days had a similar rate of clinical resolution compared to patients treated with a standard dose of TMP/SMX, 160/800mg twice-daily for 7-15 days.

PMID: 21930870 [PubMed - as supplied by publisher]

Carbapenems: past, present, and future.

Antimicrob Agents Chemother. 2011 Aug 22;

Authors: Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA

Abstract
In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ?-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ?-lactamases, in some cases act as "slow substrates" or inhibitors of ?-lactamases, and still target penicillin binding proteins (PBPs). This "value added feature" of inhibiting ?-lactamases serves as a major rationale for expansion of this class of ?-lactams. We describe the initial discovery and development of the carbapenem family of ?-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, greater than 80 compounds with mostly improved antimicrobial properties, as compared to thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we highlight some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.

PMID: 21859938 [PubMed - as supplied by publisher]