Multidrug-resistant Gram-positive Pathogens Research Articles

Design and synthesis of unprecedented cyclic γ-AApeptides for antimicrobial development

Antimicrobial drug resistance is one of the greatest threats facing mankind. Antimicrobial peptides (AMPs) can potentially circumvent drug resistance, probably through a bacterial membrane-disruption mechanism. However, they suffer from low in vivo stability, potential immunogenicity, and difficulty in optimization. The development of antimicrobial peptidomimetics is therefore an emerging research area as they avoid the potential disadvantages of AMPs. Cyclic peptidomimetics are of significant interest since constraints induced by cyclization are expected to further improve their antimicrobial activity. Nonetheless, the report of cyclic oligomeric peptidomimetics for antimicrobial development is rare. Herein, for the first time, we report the design and synthesis of cyclic γ-AApeptides via an on-resin cyclization. These cyclic γ-AApeptides are potent and broad-spectrum active against fungus and multi-drug resistant Gram-positive and Gram-negative bacterial pathogens. Our results demonstrate the potential of cyclic γ-AApeptides as a new class of antibiotics to circumvent drug resistance by mimicking the bactericidal mechanism of AMPs. Meanwhile, the facile synthesis of cyclic γ-AApeptides may further expand the applications of γ-AApeptides in biomedical sciences.

Studies for the Development of Novel Anti-MRSA/VRE Drugs

The widespread emergence of multidrug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) is a high threat for human health. In the course of screening for active compounds against the above drug-resistant bacteria from microbial metabolites, we discovered three kinds of novel compounds designated tripropeptins, pargamicin, and amycolamicin. Tripropeptin C (TPPC), major component of tripropeptins, is the most promising compound because it is efficacious against MRSA and VRE both in vitro and in a mouse septicemia model, and shows no cross-resistance to available drugs including vancomycin. Studies of incorporation of radioactive macromolecular precursors and accumulation of UDP-MurNAc-pentapeptide in the cytoplasm in S. aureus Smith revealed that TPPC is a cell wall synthesis inhibitor. Antimicrobial activity of TPPC was weakened by addition of prenylpyrophosphates but not with prenylphosphates, UDP-linked sugars, or the pentapeptide of peptidoglycan. Direct interaction between TPPC and undecaprenyl pyrophosphate (C(55)-PP) was observed by mass spectrometry and thin layer chromatography, and TPPC inhibits C(55)-PP phosphatase, which plays a crucial role in peptidoglycan synthesis at an IC(50) of 0.03-0.1 µM in vitro. From the analysis of accumulation of lipid carrier-related compounds, TPPC caused accumulation of C(55)-PP in situ, leading to the accumulation of a glycine-added lipid intermediate, suggesting a distinct mode of action from that of clinically important drugs such as vancomycin, daptomycin, and bacitracin. TPPC might represent a promising novel class of antibiotic against MRSA and VRE infections.

In vitro pharmacokinetic/pharmacodynamic activity of NXL103 versus clindamycin and linezolid against clinical Staphylococcus aureus and Streptococcus pyogenes isolates

NXL103 (linopristin/flopristin, 30/70) is a novel oral streptogramin combination with activity against a large variety of multidrug-resistant Gram-positive pathogens. The objective of this study was to evaluate the in vitro activity of NXL103 in comparison with oral comparators (clindamycin and linezolid). Six clinical isolates [four meticillin-resistant Staphylococcus aureus (MRSA) and two Streptococcus pyogenes] were exposed for 48h in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model at a starting inoculum of ca. 106 colony-forming units (CFU)/mL. Antimicrobial simulations included NXL103 500mg every 12h, linezolid 600mg every 12h and clindamycin 450mg every 6h. Bactericidal and static effects were defined as ≥3log10 and <3log10 CFU/mL kill from the starting inoculum, respectively. Experiments were performed in duplicate to ensure reproducibility, and differences between regimens were evaluated by analysis of variance (ANOVA) with Tukey's post-hoc test. NXL103 exhibited lower minimum inhibitory concentrations than comparators, with values ≤0.06mg/L for S. pyogenes and 0.125–0.25mg/L for MRSA isolates. In the PK/PD model, NXL103 demonstrated significantly better activity than linezolid and clindamycin (P<0.05), achieving sustained bactericidal activity within <2h against S. pyogenes strains and between 7.3–32h against MRSA isolates. In contrast, linezolid only exhibited a static effect, whereas clindamycin achieved 3log10 kill at 6h against the unique clindamycin-susceptible S. pyogenes strain evaluated. In conclusion, at therapeutic concentrations NXL103 exhibits promising activity against both MRSA and S. pyogenes strains, including clindamycin-resistant organisms. Further in vitro and in vivo experiments are warranted to explore the therapeutic benefit of NXL103 for the treatment of Gram-positive skin and soft-tissue infections.

Efficacy and safety of linezolid in liver transplant patients

Bacterial infections are the main cause of death within the first year after liver transplantation, and the increased incidence of multidrug-resistant gram-positive pathogens has created a major challenge in the treatment of these patients. Linezolid, the first US Food & Drug Administration-approved oxazolidinone, offers a valuable novel treatment option for serious gram-positive infections. Linezolid is relatively non-toxic but prolonged treatment with linezolid was associated with thrombocytopenia. Here we report on the experience of linezolid treatment in adult liver transplant patients, who are at an increased risk for thrombocytopenia because of hypersplenism. From November 2003 until December 2009, we evaluated the clinical course of 46 liver transplant patients (27 male/19 female) in our surgical intensive care unit. For proven or probable gram-positive infection, all patients received linezolid 600 mg intravenously every 12 h. On clinical improvement, treatment was changed to oral linezolid 600 mg twice daily. Treatment duration was 11 ± 7 days. Treatment indications were pneumonia (n = 8), blood stream infection (n = 30), and surgical site/abdominal infection (n = 3). Clinical cure was achieved in 43 out of 46 patients. During the course of treatment, no cases of severe thrombocytopenia occurred and a statistically significant platelet count increase was seen from day 1 (110 ± 73/nL) to day 7 (165 ± 116/nL) and day 14 (180 ± 140/nL). We did not observe any further adverse events, especially no severe neurological complications (e.g., serotonin syndrome) or signs of lactate acidosis. Two patients died from uncontrolled vancomycin-resistant Enterococcus faecium sepsis with septic shock and one due to uncontrolled methicillin-resistant Staphylococcus aureus pneumonia. These deaths were considered to be unrelated to linezolid treatment, and linezolid was regarded as the optimal treatment choice in these patients. A subgroup analysis of patients treated for >14 days revealed no statistically significant differences when compared with patients on shorter treatment. In particular, no cases of thrombocytopenia occurred during longer treatment. In conclusion, linezolid is a safe and effective treatment for adult liver transplant patients with gram-positive infections.

Efficacy of the new lantibiotic NAI-107 in experimental infections induced by multidrug-resistant Gram-positive pathogens.

NAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate the in vivo efficacy of NAI-107 in animal models of severe infection. In acute lethal infections induced with a penicillin-intermediate Streptococcus pneumoniae strain in immunocompetent mice, or with MRSA, GISA, and VRE strains in neutropenic mice, the 50% effective dose (ED(50)) values of NAI-107 were comparable or lower than those of reference compounds, irrespective of the strain and immune status (0.51 to 14.2 mg/kg of body weight for intravenous [i.v.] NAI-107, 5.1 to 22.4 for oral linezolid, and 22.4 for subcutaneous [s.c.] vancomycin). In the granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log(10)-CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observed in vitro was thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

CMI editorial report 2011

CMI 2009 theme section schedule January Greub G The medical importance of Chlamydia February Garau J Resistance: consensus on MRSA March Cornaglia G Fighting infections due to multidrug-resistant Gram-positive pathogens April Paul M Is there a treatment for sepsis other than antibiotics? May Cutler SJ Myths, legends and realities of relapsing fever borreliosis June Gould E Emerging viruses and the significance of climate change July Arendrup MC Invasive fungal infections: past achievements and challenges ahead August Brouqui P Ippoito G Facing highly infectious diseases

Stability of linezolid activity in an era of mobile oxazolidinone resistance determinants: results from the 2009 Zyvox® Annual Appraisal of Potency and Spectrum program

Linezolid is the only oxazolidinone agent approved for clinical use and has been administered to millions of patients over nearly a decade, becoming an important therapeutic alternative for infections caused by multidrug-resistant (MDR) Gram-positive pathogens. Resistance is due to mutations in 23S rRNA and the ribosomal proteins L3 and L4 and, more recently, the mobile cfr gene (causes resistance to several antimicrobial classes). Using reference broth microdilution methods in a central reference laboratory design, MIC values were obtained during the 2009 Zyvox® Annual Appraisal of Potency and Spectrum program (5754 sampled strains from 22 countries), and the following MIC 90 values were obtained for the leading pathogen or species groups: Staphylococcus aureus (2 μg/mL), coagulase-negative staphylococci (CoNS; 1 μg/mL), Enterococcus spp. (2 μg/mL), and 3 groups of streptococci (1 μg/mL) including Streptococcus pneumoniae. Linezolid-resistant strains (8 or 0.14% overall) that were not Staphylococcus aureus were observed in 5 nations and included CoNS (0.48%) having the mobile cfr gene. The results of this study demonstrate that linezolid continues to be effective in vitro against MDR pathogens, and the resistance rates appear stable.

Comparative in vitro activity of ceftobiprole against Gram-positive cocci

The activity of ceftobiprole and comparator agents was evaluated against a collection of 880 isolates, comprising 200 meticillin-susceptible Staphylococcus aureus, 200 meticillin-resistant S. aureus, 180 coagulase-negative staphylococci blood isolates, 100 Streptococcus pneumoniae and 200 macrolide-resistant β-haemolytic streptococci (100 Streptococcus pyogenes and 100 Streptococcus agalactiae). Ceftobiprole showed excellent activity against staphylococci (minimum inhibitory concentrations ≤4 μg/mL), irrespective of their susceptibility to other agents such as oxacillin, linezolid or glycopeptides. Ceftobiprole was also highly active against penicillin-resistant S. pneumoniae and macrolide-resistant β-haemolytic streptococci, inhibiting 99.6% of all streptococci tested at ≤0.5 μg/mL. Based on these results, ceftobiprole appears to be a promising agent for the treatment of infections caused by multidrug-resistant Gram-positive pathogens.

Linezolid treatment of shunt-related cerebrospinal fluid infections in children

The emergence of multidrug-resistant bacteria as a cause of ventriculoperitoneal (VP) shunt infection is a disconcerting phenomenon that often requires the use of alternative antimicrobial agents due to resistance against commonly used medications. Linezolid, a member of a new class of antimicrobial agents, has good activity against virtually all important gram-positive pathogens, including multidrug-resistant gram-positive pathogens. The object of this article is to report a single-center experience with linezolid treatment in 6 young patients with VP shunt infections caused by drug-resistant strains. The authors reviewed the records of 6 pediatric patients who developed VP shunt infection and in whom initial antimicrobial treatment regimens, including vancomycin, either failed or were associated with vancomycin-resistant enterococcus. All 6 patients were treated at their hospital between July 1, 2008, and June 29, 2009. The patients' demographic and clinical characteristics, underlying diseases, clinical manifestations, laboratory results, and various treatment modalities used before linezolid therapy were evaluated. The 6 patients included were 2 boys and 4 girls with a mean (+/- SD) age of 11.83 +/- 12 months (range 4-36 months). Five patients had acquired an infection within 4 months (mean 7.50 +/- 13.51 months, range 1-35 months) after shunt insertion. Four patients were treated with external ventricular drainage. Two patients' parents refused to allow shunt removal and placement of an external ventricular drain. The CSF was clear of bacterial growth within a mean of 3.67 +/- 1.36 days (range 2-6 days) after initiation of linezolid treatment. The mean duration of linezolid treatment was 18.17 +/- 3.31 days (range 14-21 days). Microbiological clearance of CSF and clinical cure were achieved in all patients. No laboratory or clinical side effects were observed during the treatment period. The mean length of hospital stay was 22.8 +/- 4.96 days (range 17-28 days). Linezolid could be an appropriate treatment alternative in children with ventriculostomy-related CSF infections caused by drug-resistant strains, including cases in which shunt removal is not an option. Well-designed prospective studies providing additional information on linezolid levels in plasma and CSF are necessary to confirm the authors' observations.

In vitro Characterization of Enzymes Involved in the Synthesis of Nonproteinogenic Residue (2S,3S)‐β‐Methylphenylalanine in Glycopeptide Antibiotic Mannopeptimycin

Mannopeptimycin, a potent drug lead, has superior activity against difficult-to-treat multidrug-resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA). (2S,3S)-beta-Methylphenylalanine is a residue in the cyclic hexapeptide core of mannopeptimycin, but the synthesis of this residue is far from clear. We report here on the reaction order and the stereochemical course of reaction in the formation of (2S,3S)-beta-methylphenylalanine. The reaction is executed by the enzymes MppJ and TyrB, an S-adenosyl methionine (SAM)-dependent methyltransferase and an (S)-aromatic-amino-acid aminotransferase, respectively. Phenylpyruvic acid is methylated by MppJ at its benzylic position at the expense of one equivalent of SAM. The resulting beta-methyl phenylpyruvic acid is then converted to (2S,3S)-beta-methylphenylalanine by TyrB. MppJ was further determined to be regioselective and stereoselective in its catalysis of the formation of (3S)-beta-methylphenylpyruvic acid. The binding constant (K(D)) of MppJ versus SAM is 26 microM. The kinetic constants with respect to k(cat Ppy) and K(M Ppy), and k(cat SAM) and K(M SAM) are 0.8 s(-1) and 2.5 mM, and 8.15 s(-1) and 0.014 mM, respectively. These results suggest SAM has higher binding affinity for MppJ than Ppy, and the C--C bond formation in betamPpy might be the rate-limiting step, as opposed to the C--S bond breakage in SAM.

Pharmacodynamics of SMP-601 (PTZ601) against Vancomycin-ResistantEnterococcus faeciumand Methicillin-ResistantStaphylococcus aureusin Neutropenic Murine Thigh Infection Models

SMP-601 (also known as PTZ601, PZ-601, or SM-216601) is a novel parenteral carbapenem with potent activity against multidrug-resistant gram-positive pathogens, including vancomycin-resistant Enterococcus faecium (VREF) and methicillin-resistant Staphylococcus aureus (MRSA). The pharmacodynamics of SMP-601 against VREF and MRSA were investigated in neutropenic murine thigh infection models. The percentage of the dosing interval that the unbound SMP-601 concentration exceeded the MIC (f%T>MIC) was the pharmacokinetic-pharmacodynamic parameter that correlated most closely with efficacy with R(2) values of 0.81 to 0.84 for two strains of VREF and 0.92 to 0.93 for two strains of MRSA, whereas the R(2) values for the area under the concentration-time curve from 0 to 24 h divided by the MIC were 0.12 to 0.89, and the R(2) values for the peak level divided by the MIC were 0 to 0.22. The f%T>MIC levels required for static or killing efficacy against two strains of VREF (9 to 19%) apparently were lower than those against two strains of MRSA (23 to 37%). These results suggested that SMP-601 showed time-dependent in vivo efficacy against VREF and MRSA, and SMP-601 had a sufficient therapeutic effect against VREF infections at lower exposure conditions compared to those for with MRSA infections.

Ceftobiprole: First Cephalosporin with Activity Against Methicillin‐Resistant Staphylococcus aureus

Ceftobiprole medocaril is the first member of a new series of advanced cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). The drug received an approvable letter from the United States Food and Drug Administration (FDA) in March 2008 and from Health Canada in June 2008 for the treatment of complicated skin and skin structure infections including diabetic foot infections. Ceftobiprole exerts its antibacterial activity by inhibiting the penicillin-binding proteins (PBPs) involved in cell wall synthesis. It has an established stability against hydrolysis by many gram-positive beta-lactamases and a higher affinity for various PBPs (such as PBP2a of MRSA or PBP2x of Streptococcus pneumoniae), which leads to a wider spectrum of activity compared with older beta-lactams. Ceftobiprole activity does not cover extended-spectrum beta-lactamase-producing Enterobacteriaceae and some other pathogens, including Enterococcus faecium or Acinetobacter baumanii. Generally well tolerated, with nausea and taste disturbance being the most common adverse events, ceftobiprole appeared noninferior to empiric therapy in several clinical trials. Ceftobiprole is available only for intravenous administration; recommended dosage regimens have not been approved by the FDA as of this writing. However, based on the Canadian package insert, expected dosage recommendations are 500 mg as a 1-hour intravenous infusion every 12 hours for the treatment of complicated skin and skin structure infections caused by certain gram-positive pathogens, and 500 mg as a 2-hour infusion every 8 hours when susceptible gram-negative or both gram-positive and susceptible gram-negative pathogens are involved. Dosage adjustments are indicated for patients with moderate or severe renal impairment, and dosage recommendations are expected to be 500 or 250 mg, respectively, as a 2-hour infusion every 12 hours. Several precautions regarding hypersensitivity and drug incompatibility are reported. Ceftobiprole represents a promising option for the treatment of mono- and polymicrobial infections caused by multidrug-resistant gram-positive and susceptible gram-negative pathogens, but further toxicity and safety studies are warranted.

Antibiotic therapeutic options for infections caused by drug-resistant Gram-positive cocci

Serious infections caused by Gram-positive bacteria are currently difficult to treat because many of these pathogens are now resistant to standard antimicrobial agents. As a result of the emergence and spread of multidrug-resistant Gram-positive pathogens, new antimicrobial agents are urgently needed for clinical use. In recent years, there has been an increase in the number of drugs that have activity against these Gram-positive pathogens. Daptomycin, tigecycline, linezolid, quinupristin/dalfopristin and dalbavancin are five antimicrobial agents that are useful for the treatment of infections due to drug-resistant Gram-positive cocci. This review focuses on their mechanism of action, pharmacokinetics, spectrum of activity, clinical effectiveness, drug interaction and safety. These antimicrobial agents provide the clinician with additional treatment options among the limited therapies for resistant Gram-positive bacterial infection.

Linezolid-Resistant CoNS

Linezolid is useful for treating multidrug-resistant gram-positive pathogens, including methicillin-resistant staphylococci and vancomycin-resistant

The role of vitamin B6 in the prevention of haematological toxic effects of linezolid in patients with cancer

Linezolid is the first approved synthetic oxazolidinone with activity against multidrug-resistant gram-positive pathogens. However, haematological toxic effects of linezolid frequently limit its prolonged use, especially in patients with poor marrow reserves such as those with cancer receiving chemotherapy. Previous authors have reported that administration of vitamin B6 with linezolid reversed pancytopenia in two patients. This is an open-label study of 31 patients with cancer who received linezolid at 600 mg twice daily and vitamin B6 at 50 mg/day for at least 2 weeks mean therapy duration and they were matched to 62 control patients who received linezolid without vitamin B6 to determine whether the concomitant use of vitamin B6 attenuates the haematological toxicity of linezolid in patients with cancer. Patients were matched according to age, underlying disease, duration of therapy, creatinine level and use of chemotherapy. We found no significant differences in the rate of haematological toxic effects between the two patient groups. The rate of thrombocytopenia was 13% in the vitamin B6 group and 15% in the control group (P = 0.82). Also, the rate of leucopenia was 7% versus 5%, respectively (P = 0.75). None of the patients in the vitamin B6 group had anaemia compared with 5% in the control group. Vitamin B6 given at 50 mg/day may have an impact on anaemia but did not prevent linezolid-induced thrombocytopenia or leucopenia in cancer patients.

Discovery of 1,4-Dihydroxy-2-naphthoate Prenyltransferase Inhibitors: New Drug Leads for Multidrug-Resistant Gram-Positive Pathogens.

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionDiscovery of 1,4-Dihydroxy-2-naphthoate Prenyltransferase Inhibitors: New Drug Leads for Multidrug-Resistant Gram-Positive Pathogens.Michio Kurosu, Prabagaran Narayanasamy, Kallolmay Biswas, Rakesh Dhiman, and Dean C. CrickCite this: J. Med. Chem. 2007, 50, 20, 5048Publication Date (Web):September 12, 2007Publication History Published online12 September 2007Published inissue 1 October 2007https://doi.org/10.1021/jm701036zCopyright © 2007 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views411Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (3 KB) Get e-Alerts Get e-Alerts

Phase 2 Study of Ceftaroline versus Standard Therapy in Treatment of Complicated Skin and Skin Structure Infections

Ceftaroline, the bioactive metabolite of ceftaroline fosamil (previously PPI-0903, TAK-599), is a broad-spectrum cephalosporin with potent in vitro activity against multidrug-resistant gram-positive aerobic pathogens, including methicillin-resistant Staphylococcus aureus. A randomized, observer-blinded study to evaluate the safety and efficacy of ceftaroline versus standard therapy in treating complicated skin and skin structure infections (cSSSI) was performed. Adults with cSSSI, including at least one systemic marker of inflammation, were randomized (2:1) to receive intravenous (i.v.) ceftaroline (600 mg every 12 h) or i.v. vancomycin (1 g every 12 h) with or without adjunctive i.v. aztreonam (1 g every 8 h) for 7 to 14 days. The primary outcome measure was the clinical cure rate at a test-of-cure (TOC) visit 8 to 14 days after treatment. Secondary outcomes included the microbiological success rate (eradication or presumed eradication) at TOC and the clinical relapse rate 21 to 28 days following treatment. Of 100 subjects enrolled, 88 were clinically evaluable; the clinical cure rate was 96.7% (59/61) for ceftaroline versus 88.9% (24/27) for standard therapy. Among the microbiologically evaluable subjects (i.e., clinically evaluable and having had at least one susceptible pathogen isolated at baseline), the microbiological success rate was 95.2% (40/42) for ceftaroline versus 85.7% (18/21) for standard therapy. Relapse occurred in one subject in each group (ceftaroline, 1.8%; standard therapy, 4.3%). Ceftaroline exhibited a very favorable safety and tolerability profile, consistent with that of marketed cephalosporins. Most adverse events from ceftaroline were mild and not related to treatment. Ceftaroline holds promise as a new therapy for treatment of cSSSI and other serious polymicrobial infections.

Discovery of 1,4-Didydroxy-2-naphthoate Prenyltransferase Inhibitors: New Drug Leads for Multidrug-Resistant Gram-Positive Pathogens

Since utilization of menaquinone in the electron transport system is a characteristic of Gram-positive organisms, the 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) inhibitors 1a and 2a act as selective antibacterial agents against organisms such as methicillin-resistant Stapylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE), and Mycobacterium spp. Growth of drug-resistant Gram-positive organisms was sensitive to the MenA inhibitors, indicating that menaquinone synthesis is a valid new drug target in Gram-positive organisms.

P1121 Patterns of susceptibility of Gram-negatives/positives isolated in the United Kingdom and Ireland

Tigecycline is a novel antimicrobial with expanded broad-spectrum activity from a new class of compounds, the glycylcyclines. Tigecycline inhibits protein synthesis by binding to the 30S ribosomal subunit. Although it is perceived to be bacteriostatic, its anti-bacterial activity is significant and has shown some bactericidal activity against key targeted pathogens [1,2]. Tigecycline was developed to provide activity against tetracycline and multidrug-resistant gram-positive pathogens and has demonstrated significant broad-spectrum activity against aerobic and anaerobic gram-positive and gram-negative microorganisms [2-4].

Multidrug-Resistant Gram-Negative Pathogens Multiple Approaches and Measures for Prevention

From the Department of Medicine, University of Texas Health Science Center at San Antonio, and the Medical Service, South Texas Veterans Health Care System, San Antonio, Texas. Received July 4, 2006; accepted July 4, 2006; electronically published August 24, 2006. Infect Control Hosp Epidemiol 2006; 27:889-892 2006 by The Society for Healthcare Epidemiology of America. All rights reserved. 0899-823X/2006/2709-0001$15.00. Antimicrobial resistance continues to emerge in our hospitals. Despite the predominance of gram-positive healthcare-associated infections in the past 2 decades, gram-negative pathogens continue to be a concern because of the high mortality from these infections among seriously ill patients. Although several alternative antimicrobials active against multidrugresistant gram-positive pathogens are now available, multidrug resistant gram-negative pathogens continue to emerge and new alternative therapies are not available. Preventive measures, then, become all the more important. Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter species are among the most problematic gram-negative pathogens with emerging resistance. Four articles in this month’s journal address important issues in the prevention of the emergence of resistance in these pathogens. Lautenbach et al. and Fortaleza et al. study risk factors associated with imipenem resistance and ceftazidime resistance 3 in P. aeruginosa. The setting of the study by Fortaleza et al. was a 400-bed general teaching hospital in Campinas, Brazil. Cases in which imipenem-resistant P. aeruginosa strains were recovered (108 patients) and in which ceftazidime-resistant strains were recovered (56 patients) were selected during the years 1999-2002. Case-control studies showed that independent risk factors associated with imipenem resistance in their hospital were transfer from another hospital (perhaps a marker for longer time at risk), receipt of hemodialysis, and use of imipenem, amikacin, or vancomycin. Only transfer from another hospital and amikacin use were independent risk factors for recovery of ceftazidimeresistant P. aeruginosa; ceftazidime use was not. The setting of the study by Lautenbach et al. was a 625bed tertiary care hospital in Philadelphia, Pennsylvania. Cases in which imipenem-resistant P. aeruginosa strains were recovered (142 patients) were identified during the years 19992000. Results of a case-control study showed that fluoroquinolone use, and not imipenem use, was an independent risk factor for recovery of an imipenem-resistant strain. Why was imipenem use a risk factor in one study and not in the other? Both were case-control studies that evaluated imipenem resistance in P. aeruginosa at large teaching hospitals. There was a similar distribution of anatomical sites from which the clinical specimens were isolated and a similar amount of intensive care unit exposure in both studies. Recent studies have discussed the importance of the method used to select control subjects in case-control studies of antibiotic resistance. In the study by Lautenbach et al., the question being asked was “Among clinical isolates of P. aeruginosa, what are the risk factors associated with imipenem resistance in a given isolate?” Thus, patients colonized or infected with imipenem-resistant P. aeruginosa were classified as case patients and patients colonized or infected with imipenem-susceptible P. aeruginosa were classified as control subjects. The study by Fortaleza et al. was designed to evaluate risk factors associated with the recovery of imipenemresistant and ceftazidime-resistant P. aeruginosa isolates from patients admitted to the authors’ hospital. Case patients were those from whom imipenem-resistant or ceftazidime-resistant strains of P. aeruginosa were recovered, and control subjects matched to case patients were selected from the patients admitted to the same ward. The questions asked were different, and thus the procedures for selection of control subjects were different. Harris et al. have reviewed the methodologies for casecontrol studies of antibiotic resistance that may lead to varying results with respect to risk factors. Both Lautenbach et al. and Fortaleza et al. acknowledged the impact of methodology and chose control subjects on the basis of their intended question. The novel case-case-control study design described by Kaye et al. addresses some limitations in study design and has been used to study risk factors for colonization or infection with imipenem-resistant P. aeruginosa among hospitalized patients. Findings of the study by Kaye et al. showed that receipt of imipenem, piperacillin-tazobactam, vancomycin, and/or aminoglycosides were risk factors for isolation of imipenem-resistant P. aeruginosa. The odds ratio for the risk of isolation of imipenem-resistant P. aeruginosa, how-