Activity Of Carbapenems Research Articles

Antimicrobial-resistant Pseudomonas aeruginosa and Acinetobacter baumannii From Patients With Hospital-acquired or Ventilator-associated Pneumonia in Vietnam

PurposeMultidrug-resistant bacterial pathogens are becoming a significant problem worldwide. Acinetobacter baumannii and Pseudomonas aeruginosa are problematic multidrug-resistant pathogens. This multicenter study in Vietnam determined the level of resistance to antimicrobial agents used to treat A baumannii and P aeruginosa infections in this country. MethodsFive medical centers in Vietnam provided 529 P aeruginosa and 971 Acinetobacter species (904 A baumannii) isolates from patients with hospital-acquired or ventilator-associated pneumonia from 2012 to 2014. A central laboratory verified identification of the isolates and performed susceptibility testing using Clinical and Laboratory Standards Institute methods. FindingsResistance to cephalosporins, β-lactam/β-lactamase inhibitors, carbapenems, and fluoroquinolones was >90% against A baumannii. Aminoglycosides had only slightly better activity, with amikacin resistance >80%. Only colistin (MIC90, ≤0.25 mg/L) and tigecycline (MIC90, 4 mg/L) had appreciable activity against A baumannii. Similar activity was observed among the β-lactams tested against P aeruginosa. Cefepime demonstrated the highest activity (60.1% susceptible), which was similar to doripenem (58.6% susceptible), the most active carbapenem tested. Amikacin was the most active aminoglycoside tested against P aeruginosa, with susceptibility of 81.7% compared with tobramycin (58.0%) and gentamicin (56.5%). Fluoroquinolones had limited activity against P aeruginosa with susceptibility to ciprofloxacin (55.0%). All P aeruginosa isolates had colistin MIC values ≤2 mg/L. ImplicationsThe data from this 3-year longitudinal study in Vietnam demonstrate that 2 of the most common nonfermentative gram-negative pathogens associated with hospital-acquired and ventilator-associated pneumonia are significantly resistant to most of the available treatment options and require combination therapies unless new antimicrobial agents become available.

Comparative invitro activity of carbapenems against clinical isolates of Acinetobacter baumannii.

The aim of this multi-hospital study was to assess the invitro activity of doripenem and its comparators, imipenem and meropenem, using the new CLSI breakpoints against a large population of a frequently isolated nosocomial pathogen, Acinetobacter baumannii. During a 2-year period, four referral or tertiary hospitals submitted 400 isolates of Ac.baumannii for susceptibility testing using imipenem, meropenem and doripenem via disc diffusion and E-test methods. A subset of 390 isolates was resistant to all three tested carbapenems. Doripenem and meropenem (MIC50 , 32μgml(-1) ) had comparable activity, albeit doripenem's activity was greater than imipenem (MIC50 , >32μgml(-1) ). A significantly higher proportion of the isolates were inhibited by doripenem than by imipenem at MIC values of 12, 16, 24 and 32μgml(-1) (P<0·05). The cumulative percentage of imipenem MICs was lower compared to its comparators. The comparison of resistance rate to imipenem and meropenem based on old and new breakpoints showed <1% difference. The overall agreement between the two susceptibility testing methods was ≥95%. Doripenem has a slightly greater invitro activity than imipenem in terms of zone breakpoints and MIC values, but its activity is comparable to meropenem. Doripenem should be considered as a therapeutic option for monotherapy or combination therapy, particularly when the therapeutic options are limited.

Inactivation or inhibition of AcrAB-TolC increases resistance of carbapenemase-producing Enterobacteriaceae to carbapenems.

The objective of this study was to study the contribution of the multidrug resistance AcrAB-TolC efflux system to carbapenem resistance in carbapenemase-producing Enterobacteriaceae and the impact of the efflux inhibitor PABN on this resistance. Klebsiella pneumoniae, Escherichia coli, Salmonella enterica serovar Typhimurium and their corresponding AcrAB-TolC mutants, each carrying carbapenemase-carrying plasmids (pKpQIL-UK with blaKPC and pNDM-HK with blaNDM), were tested for their susceptibility to six β-lactam antibiotics according to the BSAC agar dilution method. MICs were also determined in the presence of efflux inhibitors. The susceptibility of ertapenem in the presence of 25 and 100 mg/L PABN was also determined for 86 non-replicate clinical isolates of carbapenemase-producing Enterobacteriaceae with OXA-48-like (n = 18), IMP (n = 12), VIM (n = 16), NDM (n = 20) or KPC (n = 20) enzymes. Outer membrane protein profiles were determined with SDS-PAGE. The carbapenemase-producing AcrAB mutants of K. pneumoniae and E. coli and the TolC mutant of Salmonella Typhimurium had elevated resistance to carbapenem antibiotics. In Salmonella Typhimurium, the increase in carbapenem MIC correlated with the loss of OmpF. Sixty-two (72%) of the clinical isolates tested were also more resistant to ertapenem in the presence of PABN. SDS-PAGE showed that the presence of PABN affected outer membrane porin production, which was associated with the increased MIC values of ertapenem. The decreased susceptibility to carbapenems of carbapenemase-producing Enterobacteriaceae in the absence of AcrAB or TolC and/or in the presence of an efflux inhibitor (e.g. PABN) is likely due to the changes in porin expression (e.g. OmpF). Efflux inhibitors may not potentiate carbapenem activity, but rather could increase levels of resistance in carbapenemase-producing organisms.

Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases.

The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine β-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.

Antibiotic susceptibility of Clostridium difficile is similar worldwide over two decades despite widespread use of broad-spectrum antibiotics: an analysis done at the University Hospital of Zurich.

BackgroundClostridium difficile infection (CDI) remains a major health problem worldwide. Antibiotic use, in general, and clindamycin and ciprofloxacin, in particular, have been implicated in the pathogenesis of CDI. Here, we hypothesized that antibiotics that are highly active in vitro against C. difficile are less frequently associated with CDI than others. The primary goals of our study were to determine if antibiotic susceptibility and CDI are associated and whether the antimicrobial susceptibility of C. difficile changed over the years.Methods and resultsWe examined a large panel of C. difficile strains collected in 2006-2008 at the University Hospital of Zurich. We found that the antimicrobial susceptibilities to amoxicillin/clavulanate, piperacillin/tazobactam, meropenem, clindamycin, ciprofloxacin, ceftriaxone, metronidazole and vancomycin were similar to those reported in the literature and that they are similar to those reported in other populations over the last two decades. Antibiotic activity did not prevent CDI. For example, thre use of meropenem, which is highly active against all strains tested, was a clear risk factor for CDI. Most of the antibiotics tested also showed a higher minimum inhibitory concentration distribution than that of EUCAST. All strains were susceptible to metronidazole. One strain was resistant to vancomycin.ConclusionsAntibiotic susceptibilities of the collection of C. difficile from the University Hospital of Zurich are similar to those reported by others since the 1980. Patients treated with carbapenems and cephalosporins had the highest risk of developing CDI irrespective of the antimicrobial activity of carbapenems.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0607-z) contains supplementary material, which is available to authorized users.

In Vitro Activity of Carbapenems Against Multi-Drug Resistant Gram-Negative Organisms at a Tertiary Care Center in Lebanon

In Vitro Activity of Carbapenems Against Multi-Drug Resistant Gram-Negative Organisms at a Tertiary Care Center in Lebanon

Effects of a combination of amlodipine and imipenem on 42 clinical isolates of Acinetobacter baumannii obtained from a teaching hospital in Guangzhou, China

BackgroundThe clonal spread of Acinetobacter baumannii is a global problem, and carbapenems, such as imipenem, remain the first-choice agent against A. baumannii. Using synergy to enhance the antibiotic activity of carbapenems could be useful. Here, amlodipine (AML) was tested alone and with imipenem against A. baumannii isolates.MethodsForty-two isolates of A. baumannii were collected. Multilocus sequence typing (MLST) assessed the genetic relationship of the isolates. The resistance phenotypes were determined using disc diffusion. The minimum inhibitory concentrations (MICs) of the drugs were determined by broth microdilution. The combined effects of the drugs were determined by a checkerboard procedure. Metallo-β-lactamase (MBL) was determined using the MBL Etest.ResultsForty-two A. baumannii isolates were collected from 42 patients who were mostly older than 65 years and had long inpatient stays (≥7 days). A. baumannii was mostly recovered from the respiratory system (N = 35, 83.3%). Most patients (N = 27, 64.3%) received care in intensive care units (ICUs). Disc diffusion testing demonstrated that A. baumannii susceptibility to polymyxin B was 100%, while susceptibility to other antimicrobial agents was less than 30%, classifying the isolates into 10 MDR and 32 XDR strains. MLST grouped the A. baumannii isolates into 4 existing STs and 6 new STs. STn4 carried allele G1, with a T → C mutation at nt3 on the gpi111 locus. STn5 carried allele A1, possessing A → C mutations at nt156 and nt159 on the gltA1 locus. ST195 and ST208 accounted for 68.05% (29/42) of the isolates. Clonal relation analysis showed that ST195 and ST208 belonged to clonal complex (CC) 92. The inhibitory concentration of imipenem ranged from 0.5 to 32 μg/ml, and that of AML ranged from 40 to 320 μg/ml. In combination, the susceptibility rate of A. baumannii isolates increased from 16.7% to 54.8% (P = 0.001). In the checkerboard procedure, half of the isolates (N = 21, 50.0%) demonstrated synergy or partial synergy with the drug combination. The MBL Etest revealed that 1 A. baumannii strain (N = 1, 2.4%) produced MBL.ConclusionsCC92 was the major clone spreading in our hospital. AML improved the activity of imipenem against A. baumannii isolates in vitro but did not inhibit MBL.

In vivo efficacy of biapenem with ME1071, a novel metallo-β-lactamase (MBL) inhibitor, in a murine model mimicking ventilator-associated pneumonia caused by MBL-producing Pseudomonas aeruginosa

ME1071, a maleic acid derivative, is a novel, specific inhibitor of metallo-β-lactamases (MBLs). In vitro, ME1071 can potentiate the activity of carbapenems against MBL-producing Pseudomonas aeruginosa. To confirm the clinical efficacy of ME1071 in ventilator-associated pneumonia (VAP) caused by MBL-producing P. aeruginosa, a mouse model that mimics VAP by placement of a plastic tube in the bronchus was used. Biapenem (100mg/kg) or ME1071 plus biapenem (each 100mg/kg) was administered intraperitoneally every 12h beginning at 12h after inoculation. Survival was evaluated over 7 days. At 30h post infection, mice were sacrificed and the numbers of viable bacteria in the lungs and bronchoalveolar lavage fluid (BALF) were compared. Histopathological analysis of lung specimens was also performed. The pharmacokinetics of ME1071 was analysed after initial treatment. The ME1071 plus biapenem combination group displayed significantly longer survival compared with the control and biapenem monotherapy groups (P<0.05). Furthermore, the number of viable bacteria in the lungs was significantly lower in the combination group (P<0.05). Histopathological examination of lung specimens indicated that progression of lung inflammation was prevented in the combination group. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in BALF were significantly decreased (P<0.05) in the combination group. The percentage time above the MIC (%T>MIC) for biapenem without ME1071 was 0% in plasma; however, this value was elevated to 10.8% with ME1071. These results suggest that ME1071 is potent and effective for treatment of VAP caused by MBL-producing P. aeruginosa.

Activities of carbapenem and comparator agents against contemporary US Pseudomonas aeruginosa isolates from the CAPITAL surveillance program

Antimicrobial susceptibilities of contemporary Pseudomonas aeruginosa clinical isolates were determined from the CAPITAL 2010 surveillance program. Isolates were collected from 100 sites throughout the USA and Puerto Rico, and included isolates representing a range of patient demographics and infection types. A total of 2722 isolates were tested for susceptibility to a broad spectrum of agents, with susceptibilities ranging from 98.8% for colistin to 74% for levofloxacin. Doripenem was the most active carbapenem agent, with 88.6% of isolates susceptible, in comparison with 78.1% and 84.6% for imipenem and meropenem, respectively. Lower respiratory tract isolates and isolates from the intensive care unit setting were the least susceptible overall. Resistance rates were typically highest in lower respiratory tract isolates, with the exception of urinary tract isolates, which displayed the highest resistance for levofloxacin. Overall, multidrug-resistant isolates comprised 14.8% of the total sample population.

Activity of carbapenems with ME1071 (disodium 2,3-diethylmaleate) against Enterobacteriaceae and Acinetobacter spp. with carbapenemases, including NDM enzymes

ME1071 is a maleic acid that inhibits metallo-β-lactamases (MBLs). We examined its ability to potentiate different carbapenems against MBL-producing Enterobacteriaceae in relation to its inhibition kinetics. Enterobacteriaceae and Acinetobacter isolates with IMP, VIM and NDM MBLs were tested; bacteria with other types of carbapenem resistance were used as controls. Chequerboard titrations were performed by CLSI agar dilution, carbapenemases were cloned into pET-28a(+) and purified by column chromatography, and kinetic parameters were determined by spectrophotometry. The key findings were: (i) the MICs of carbapenems varied widely among isolates with the same carbapenemase, but those with the NDM types were generally the most resistant; (ii) biapenem was the carbapenem least compromised by all MBL types, owing to weaker kinetic efficiency (k(cat)/K(m)) for hydrolysis, contingent on lower affinity (higher K(m)); (iii) MBLs were the only carbapenemases inhibited by ME1071, confirming its specificity of action; and (iv) irrespective of the partner carbapenem, synergy with ME1071 was least for organisms with NDM MBLs and most for those with IMP types, correlating with ME1071 having weakest affinity (highest K(i)) for NDM-1 and strongest affinity for IMP-1. ME1071 reduced the MICs of carbapenems for bacteria with NDM-1 enzyme though synergy was weaker than for bacteria with IMP and VIM metallo-enzymes; this correlated with ME1071 having weaker affinity for NDM-1 than IMP-1 and VIM-2. As the weakest MBL substrate carbapenem, biapenem was the easiest to protect.

Antimicrobial susceptibility of pathogens isolated from patients with complicated intra-abdominal infections at five medical centers in Taiwan that continuously participated in the Study for Monitoring Antimicrobial Resistance Trends (SMART) from 2006 to 2010

The Study for Monitoring Antimicrobial Resistance Trends (SMART) is a worldwide surveillance program designed to longitudinally monitor the in vitro activity of antimicrobial agents against pathogens that cause intra-abdominal infections (IAIs). In this study, trends in antimicrobial resistance during the period 2006 to 2010 were analyzed at five tertiary-care hospitals in Taiwan. Enterobacteriaceae accounted for the majority (80.9%) of the 2417 Gram-negative isolates, and the two most common species were Escherichia coli (38.8%) and Klebsiella pneumoniae (23.5%). The rates of susceptibility of Enterobacteriaceae isolates to cephalosporins decreased during the study period. Although carbapenems, fluoroquinolones, piperacillin-tazobactam, and amikacin were active in vitro against more than 80% of the Enterobacteriaceae isolates, the activity of carbapenems declined during the study period. Extended-spectrum β-lactamase (ESBL) production in E. coli was steady, but that in K. pneumoniae decreased during the study period. The rate of ESBL-producing species was three-fold higher among patients with nosocomial IAIs than among patients with community-acquired IAIs. The majority of isolates from liver were K. pneumoniae (69%) and very few of those isolates were ESBL producers (0.9%). Pseudomonas aeruginosa (9.3%) and Acinetobacter baumannii (3.8%) were the two most common non-Enterobacteriaceae. P. aeruginosa showed improved susceptibility, whereas A. baumannii showed a rapid development of resistance during the study period. There was marked geographic variation in resistance patterns of the isolates obtained during the study period. Northern Taiwan had the highest rate of ESBL producers and the highest rate of ceftazidime resistance among P. aeruginosa isolates. Central Taiwan had the lowest rate of ESBL producers but the highest rates of carbapenem resistance among P. aeruginosa and A. baumannii isolates. Continuous monitoring and regular updates of epidemiological data are needed to guide appropriate empiric antimicrobial therapy.

In vitro synergistic activity of carbapenems in combination with other antimicrobial agents against multidrug-resistant Acinetobacter baumannii

Multidrug-resistant Acinetobacter baumannii (MDR-AB) is emerging as a major nosocomial pathogen worldwide. In recent years, the inadequacy of antimicrobial agents available to treat infections particularly in Intensive Care Units (ICUs) due to MDR-AB, has constrained clinicians and forced them to use combination therapies. In this study, in vitrosynergistic activities of imipenem and meropenem in combination with cefoperazone-sulbactam, ampicillin-sulbactam, polymyxin B and rifampin were tested against 34 clinical isolates of (MDR-AB), all collected from the Intensive Care Units of Suleyman Demirel University Hospital. Minimum inhibitory concentration values of all antibiotics were determined by the broth microdilution method and antibiotic interactions were analyzed by checkerboard assay. The combination of meropenem with ampicillin-sulbactam showed synergy against 94.1% of MDR-AB while the synergy rates for combinations of imipenem and ampicillin-sulbactam, imipenem and rifampin, imipenem and cefoperazone-sulbactam, imipenem and polymyxin B, meropenem and rifampin, meropenem and cefoperazone-sulbactam and meropenem and polymyxin B were 88.2, 73.5, 70.6, 38.2, 17.6, 8.8 and 2.9%, respectively. Antagonism was not observed in any of the combinations. We must emphasize the fact that evaluating the efficacy of combinations against MDR-AB by synergy tests is essential to guide the treatment. Key words: Acinetobacter baumannii, antimicrobial combination, carbapenems, checkerboard assay, multidrug-resistant. .

Comparative in vitro activity of carbapenems against major Gram-negative pathogens: results of Asia-Pacific surveillance from the COMPACT II study

Resistance rates amongst Gram-negative pathogens are increasing in the Asia-Pacific region. The Comparative Activity of Carbapenem Testing (COMPACT) II study surveyed the carbapenem susceptibility and minimum inhibitory concentrations (MICs) of doripenem, imipenem and meropenem against 1260 major Gram-negative pathogens isolated from hospitalised patients at 20 centres in five Asia-Pacific countries (New Zealand, the Philippines, Singapore, Thailand and Vietnam) during 2010. Pseudomonas aeruginosa (n=625), Enterobacteriaceae (n=500), and other Gram-negative pathogens including Acinetobacter baumannii (n=135) were collected from patients with bloodstream infection (32.2%), nosocomial pneumonia including ventilator-associated pneumonia (58.1%), and complicated intra-abdominal infection (9.7%), with 36.7% being isolated from patients in an Intensive Care Unit. As high as 29.8% of P. aeruginosa and 73.0% of A. baumannii isolates were not susceptible to at least a carbapenem, whereas the majority of Enterobacteriaceae (97.2%) were susceptible to all carbapenems. Respective MIC50/MIC90 values (MICs for 50% and 90% of the organisms, respectively) of doripenem, imipenem and meropenem were: 0.38/8, 1.5/32 and 0.38/16mg/L for P. aeruginosa; 0.023/0.094, 0.25/0.5 and 0.032/0.094mg/L for Enterobacteriaceae; and 32/64, 32/128 and 32/64mg/L for A. baumannii. Doripenem and meropenem had comparable activity against P. aeruginosa, both being more active than imipenem. All carbapenems were highly potent against Enterobacteriaceae, although imipenem demonstrated higher MIC values than doripenem and meropenem. The three carbapenems showed less activity against A. baumannii. The high prevalence of carbapenem resistance amongst important nosocomial pathogens (P. aeruginosa and A. baumannii) warrants rigorous infection control measures and appropriate antimicrobial use in the Asia-Pacific region.

In Vitro Antimicrobial Activity of “Last-Resort” Antibiotics Against Unusual Nonfermenting Gram-Negative Bacilli Clinical Isolates

In this prospective multicentric study, we assessed the in vitro antimicrobial activity of carbapenems (imipenem, meropenem, and doripenem), tigecycline, and colistin against 166 unusual nonfermenting Gram-negative bacilli (NF-GNB) clinical isolates collected from nine French hospitals during a 6-month period (from December 1, 2008, to May 31, 2009). All NF-GNB isolates were included, except those phenotypically identified as Pseudomonas aeruginosa or Acinetobacter baumannii. Minimal inhibitory concentrations (MICs) of antimicrobial agents were determined by using the E-test technique. The following microorganisms were identified: Stenotrophomonas maltophilia (n=72), Pseudomonas spp. (n=30), Achromobacter xylosoxidans (n=25), Acinetobacter spp. (n=18), Burkholderia cepacia complex (n=9), Alcaligenes faecalis (n=7), and Delftia spp. (n=5). All isolates of Acinetobacter spp., A. faecalis, and Delftia spp. were susceptible to the three carbapenems. Imipenem exhibited the lowest MICs against Pseudomonas spp., and meropenem, as compared with imipenem and doripenem, displayed an interesting antimicrobial activity against A. xylosoxidans and B. cepacia complex isolates. Conversely, no carbapenem exhibited any activity against S. maltophilia. Except for S. maltophilia isolates, tigecycline and colistin exhibited higher MICs than carbapenems, but covered most of the microorganisms tested in this study. To our knowledge, no prior study has compared antimicrobial activity of these five antibiotics, often considered as "last-resort" treatment options for resistant Gram-negative infections, against unusual NF-GNB clinical isolates. Further studies should be carried out to assess the potential clinical use of these antibiotics for the treatment of infections due to these microorganisms.

&lt;b&gt;１．PK/PD理論からみたカルバペネム系抗菌薬の適正使用&lt;/b&gt;

Carbapenems have potent antibacterial effects and are widely used for the treatment of various infections.The activity of carbapenems is time dependent, and the antibacterial and therapeutic effects correlate with the duration of exposure to a drug concentration above the minimum inhibitory concentration for the bacterium (T>MIC), particularly the concentration in the target organ. Based on these pharmacokinetic/pharmacodynamic (PK/PD) properties, carbapenem regimens should be optimized to maximize the efficacy. However, measurement of drug concentrations of carbapenems in biological samples had been difficult, and there was no easy-to-use PK/PD software that supports carbapenem therapy. Thus, we developed simple methods for measuring blood concentrations of meropenem, biapenem, doripenem and imipenem, and reported their population PK parameters in Japanese patients. We also developed a new software with Monte Carlo simulation technique to calculate the probabilities of therapeutic target attainment for different regimens against various pathogens. Moreover, we examined in detail the drug disposition of carbapenems in target tissues such as peritoneal fluid, cerebrospinal fluid, bile and prostatic tissue. These results contribute to the proper use of carbapenems based on the PK/PD theory. ( Jpn J Clin Pharmacol Ther 2012; 43(4): 209-214)

Fighting resistant tuberculosis with old compounds: the carbapenem paradigm

Despite intensive efforts to improve tuberculosis (TB) care and control, the global burden of TB is falling only slowly, and the evolution of drug resistance remains uncertain. According to the WHO, the estimated incidence in 2009 was 9.4 million new cases [1]. In recent years, TB treatment has become more complicated because of the emergence of multidrugresistant (MDR) TB, i.e. TB caused by strains resistant to isoniazid and rifampin. In 2009, an estimated 250 000 patients had MDR TB, representing 3.3% of new TB cases and up to 28% in certain countries of the former Soviet Union [1]. In 2008, the number of deaths caused by MDR TB was estimated to be 150 000. The emergence of extensively drugresistant (XDR) TB, defined by resistance to isoniazid and rifampin combined with additional resistance to a fluoroquinolone and at least 1 s line injectable agent (amikacin, kanamycin, or capreomycin), has been associated with increasing mortality (65–100%), as efficient therapy is not available [2]. By July 2010, 58 countries had reported at least one case of XDR TB [1]. These alarming data highlight the urgent need for new anti-TB drugs. Except for fluroquinolones, no novel anti-TB antibiotic has been introduced in the last 45 years. b-Lactams have not been considered to be useful drugs for the treatment of TB, because Mycobacterium tuberculosis naturally produces BlaC, an extended-spectrum class A b-lactamase [3]. However, older reports have shown that the combination of amoxycillin and clavulanic acid is bactericidal in vitro [4], an efficacy that can be accounted for by the recent demonstration that BlaC is irreversibly inactivated by clavulanic acid [3]. Reduction of the burden of M. tuberculosis in the sputum of patients treated with amoxycillin and clavulanic acid has been reported [5], but clinical assessments for the treatment of MDR TB are limited to anecdotal cases in which amoxycillin–clavulanic acid was used in association with second-line drugs [6]. Among the different classes of b-lactams, very recent data concerning carbapenems have opened new avenues towards the potential use of this class in the treatment of TB, especially for MDR and XDR TB. Until recently, all b-lactams were thought to exclusively act on the active-site serine D,D-transpeptidases, the classic penicillin-binding proteins that catalyse the final cross-linking step of peptidoglycan synthesis. We have recently shown that these D,D-transpeptidases are bypassed by a novel family of polymerases, the active-site cysteine L,D-transpeptidases (Ldts), in b-lactam-resistant enterococci and in M. tuberculosis [7,8]. These enzymes are promising targets for the use of carbapenems, or for the development of anti-TB drugs belonging to this class, because the Ltds are responsible for the formation of 80% of the cross-links in M. tuberculosis, and these enzymes are irreversibly inactivated by carbapenems by the formation of covalent adducts [8,9]. Moreover, one of the five Ltds of M. tuberculosis (LdtMt2) is essential for virulence in a mouse model of acute infection [9]. Carbapenems are slowly hydrolysed by the b-lactamase BlaC [3], and one member of the carbapenem family, meropenem, has been reported to be uniformly active in vitro in association with clavulanic acid against a panel of XDR strains (meropenem MIC of <1 mg/L in the presence of 2.5 mg/L clavulanic acid [10]. Carbapenems may also have potential applications for the treatment of susceptible TB, because meropenem–clavulanic acid is active against non-replicative forms (‘dormant’ forms) of M. tuberculosis [10], which are difficult to eradicate even with isoniazid and rifampin. The adaptive response of M. tuberculosis during the transition from aerobic growth to stationary phase results in the activation of a ‘dormancy’ regulon, which includes genes that are likely to play an essential role in the long-term survival of the bacteria, and therefore encode potential targets for the development of sterilizing drugs. Among these genes, Rv0116c, which encodes LdtMt1, is upregulated 17-fold [11]. Thus, LdtMt1 could be an essential target accounting for the bactericidal activity of meropenem–clavulanic acid against dormant forms of M. tuberculosis in vitro [10]. In a mouse model, imipenem alone had antimycobacterial activity,

In vitro antibacterial activities of doripenem, imipenem, and meropenem against recent Streptococcus pneumoniae isolates

We investigated the in vitro activities of carbapenems against 347 Streptococcus pneumoniae isolates from Korea. While doripenem and imipenem resistance was displayed by only 1.2% and 3.2%, respectively, 21.3% of the isolates were resistant to meropenem. One isolate displaying very high carbapenem MICs and susceptibility only to vancomycin was also identified.

Longitudinal survey of carbapenem resistance and resistance mechanisms in Enterobacteriaceae and non-fermenters from the USA in 2007–09

Antibiotic resistance is problematic in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, and is often associated with serious infections. Carbapenems are often one of the few remaining therapeutic options, so it is important to monitor carbapenem activity against these pathogens and to identify resistance mechanisms. Carbapenem susceptibilities were determined for 14 359 Enterobacteriaceae, 3614 P. aeruginosa and 994 A. baumannii from the USA (2007-09). Klebsiella pneumoniae with doripenem MICs ≥2 mg/L (n = 88), and P. aeruginosa (n = 452), A. baumannii (n = 349) and other enterics (n = 13) with doripenem MICs ≥4 mg/L were screened for carbapenem resistance mechanisms. Doripenem/meropenem and imipenem susceptibilities for Enterobacteriaceae were >99% and 89%, respectively. Doripenem susceptibility (2007-09) for P. aeruginosa was 87.4%-84.1%; comparable to meropenem and higher than imipenem. For A. baumannii, doripenem susceptibility (2007-09) was 63%-58.2%; lower than imipenem and meropenem. Resistant K. pneumoniae had KPC and lacked porins OmpK35/OmpK36. In 2009, 3.4% of all K. pneumoniae possessed KPC. Five other enterics and one P. aeruginosa possessed KPC. Resistance mechanisms in P. aeruginosa were loss of porin OprD (90%), efflux (55%) and elevated AmpC activity (25%). Acquired carbapenemases OXA-23/-24 were present in 48% of resistant A. baumannii. VIM metallo-β-lactamases were present in three P. aeruginosa and one A. baumannii isolates. Doripenem and meropenem were more active than imipenem against Enterobacteriaceae and P. aeruginosa from the USA. Carbapenem resistance mechanisms included serine carbapenemases, elevated AmpC activity, efflux and porin deficiencies occurring mostly in P. aeruginosa. Metallo-β-lactamases were found in <0.1% of isolates.

Activity of Carbapenems Combined with Clavulanate against Murine Tuberculosis

Although beta-lactam antibiotics are not considered as antituberculous drugs, it has been recently shown that the combination of carbapenems and clavulanate is bactericidal in vitro. We evaluated in a murine model of tuberculosis the activity of carbapenems alone and combined with clavulanate against Mycobacterium tuberculosis. Swiss mice infected intravenously with 3 x 10⁵ M. tuberculosis H37Rv were treated for 4 weeks with clavulanate alone or imipenem, meropenem, and ertapenem alone or combined with clavulanate, whereas a positive control group was treated with isoniazid, and a negative control group was held without treatment. The combination of imipenem or meropenem plus clavulanate significantly improved survival. Among groups of mice with 100% survival, only isoniazid reduced lung CFU counts; the carbapenem-clavulanate combinations did not prevent bacterial growth. Although less active than isoniazid, the combinations of imipenem or meropenem plus clavulanate improved the survival of mice infected with M. tuberculosis and should be further evaluated.

In Vitro Activity of Carbapenems Alone and in Combination With Amikacin Against KPC-Producing Klebsiella Pneumoniae

BackgroundAlthough carbapenems are the primary treatment strategy for invasive infections caused by ESBL bacteria, case reports of these pathogens with reduced carbapenem susceptibility have emerged. One potential treatment modality is to optimize the use of anti-infectives with combination therapy. We evaluated the activity of carbapenems alone and in combination with amikacin against these clinical isolates.MethodsTime-kill studies evaluated ertapenem (ETP), imipenem (IPM), meropenem (MEM), and amikacin (AMK) against 4 non-duplicate clinical isolates of Klebsiella pneumoniae that were resistant to these antibiotics. Synergy was defined as ≥ 2 log10 decrease CFU/mL at 24 h for the combination when compared with the most active single agent of the combination, plus the number of surviving organisms for the antimicrobial combination was ≥ 2 log10 less than the initial inoculum.ResultsAll isolates carried blaKPC-3 and genes encoding TEM-1 and SHV-11/-36; and were resistant to carbapenems (MIC at ≥ 8 μg/mL for ETP, MEM and IPM) and AMK (MIC 32 μg/mL) using broth microdilution. As monotherapy, none of the carbapenems nor AMK achieved and maintained bactericidal activity defined as ≥ 99.9% or > 3 log10 killing. From time-kill studies, synergy was demonstrated for MEM and IPM in combination with AMK over the entire 24 h against all isolates. In addition, MEM and IPM with AMK achieved and maintained bactericidal activity (≥ 99.9% killing) at 24 h against 2 and 1 isolate(s), respectively. Bactericidal activity and synergy were not observed for ETP combinations.ConclusionsThe combination of MEM or IPM with AMK displayed synergistic activity against KPC-3-producing K. pneumoniae isolates.KeywordsESBL; Klebsiella pneumoniae; KPC; Carbapenemase; Time-kill; Meropenem; Amikacin; Imipenem; Ertapenem; Carbapenem; Synergy