anti-MRSA Antibiotics Research Articles

SP1-3 Individualized dosing of anti-MRSA antibiotics based on PK/PD

Bacterial resistance is undoubtedly recognised as a major medical challenge in most healthcare systems. Resistance-determining genes, mostly in combination, and multidrug-resistant (MDR) pathogens are spreading with unprecedented speed. Well known resistance carriers with high clinical impact include the Gram-positive organisms Staphylococcus aureus and Enterococcus spp. In contrast to these organisms that are usually still treatable with newer alternative antibacterial drugs, some Gram-negative bacteria, especially Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., have developed resistance to most or all available antibiotics. Such strains are already a reality in some Mediterranean and Asian countries. According to their resistance epidemiology (based on major drivers favouring resistance), three regions are pinpointed as high-impact resistance hot spots. Despite the clear medical need for novel antibiotics without cross-resistance issues, antibacterial research and development pipelines are nearly dry, thus failing to provide the flow of novel antibiotics required to match the fast emergence and spread of MDR bacteria. In a globalised world, only concerted global actions can mitigate a future with untreatable infectious diseases.

Effects of Japanese Herbal Medicine on MRSA Otitis

Objective: Establish new treatment for patients with MRSA infected ears without using anti-MRSA antibiotics, in order to not produce new resistant bacteria to the anti-MRSA antibio-tics. Japanese herbal medicines have never produced any new resistant bacteria, and some agents have anti-MRSA function. Method: Three concurrent therapies using 2 local treatments, ear irrigation with normal saline and nasal povidone iodine gel treatment, and Japanese herbal medicine administration were applied 3 times a week to 14 patients with MRSA-infected ears. In this study, we first selected Hocchuekikitou as Japanese herbal medicine. Results: In 11 patients, MRSA successfully disappeared after several weeks and the infection was also controlled. However, 3 patients were cured after changing Japanese herbal medicine from Hocchuekikitou to Jyuzentaihotou. The mucous membrane of the tympanic cavity which can be observed through tympanic perforation was normal. Therefore, tympanoplasty was easily performed under the normal noninfectious condition after the present combined treatments and postoperative course were fairly good. Conclusion: The present new combined therapy, concurrent 2 local treatments and Japanese herbal administration, is useful for the MRSA infected ears.

Efficacy of combination oral antimicrobial agents against biofilm-embedded methicillin-resistant Staphylococcus aureus

The combination of fusidic acid and rifampicin has a demonstrated synergistic effect against methicillin-resistant Staphylococcus aureus (MRSA), including planktonic and biofilm-related organisms. However, the in vitro efficacy of other combinations of oral anti-MRSA antibiotics in biofilm models has not been established. The antibacterial activity of fusidic acid, linezolid, rifampicin, and minocycline against 33 biofilm-embedded MRSA isolates in low susceptibility and high resistance breakpoint concentrations was investigated using the 3-[4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium-bromide staining method. The compounds were further examined to determine their antibacterial efficacies in combination. The optical density ratio (ODr) was used to evaluate the antibacterial effects of these antibiotics, and the results indicate higher survival rates of MRSA on biofilm. A biofilm-positive phenotype (determined using the crystal violet stain) was defined as an optical density ≥ 0.17 at 492 nm, and strong biofilm formation was defined as an optical density ≥ 1.0. One-third of the MRSA isolates demonstrated weak biofilm formation, and two-thirds demonstrated strong biofilm formation. At low concentrations, linezolid alone lowered the ODr to 0.55 and was effective against biofilm-embedded MRSA (p < 0.001). The activity of minocycline was concentration-dependent and more effective against MRSA isolates that demonstrated weak biofilm formation. The effect of minocycline seems to be further enhanced when used in combination with either fusidic acid or linezolid at low concentrations, with the obtained results equal to those obtained with rifampicin-based regimens (p < 0.001). Rifampicin plus minocycline was also effective against MRSA in biofilm. In comparison with monotherapy, minocycline-based combinations exhibit highly effective bactericidal effects against biofilm-embedded MRSA.

MRSA new treatments on the horizon: Current status

There is a choice of anti-MRSA antibiotic available with proven efficacy in the treatment of complicated skin and skin structure infection (cSSSI). Additional anti-MRSA antibiotics are in development, which have the potential to influence how such infections are managed. The emergence of resistance to current anti-MRSA agents, toxicity, and general lack of oral agents with proven efficacy for deep seated infection justify the development of new agents. However, there is a relative dearth of information specific to patients with orthopaedic-related infection. Combination therapy is often used in these patients, although there is a paucity of controlled trial data to support particular antibiotic combinations. As the choice of anti-MRSA agents increases, so does the need to identify which are best for the large variety of infections included in the group of cSSSIs. This is particular true for infections occurring in orthopaedic patients where poorly vascularised tissue, trauma or implanted prosthetic material, pose specific challenges.

Prospective Investigation of Nasal Mupirocin, Hexachlorophene Body Wash, and Systemic Antibiotics for Prevention of Recurrent Community-Associated Methicillin-Resistant Staphylococcus aureus Infections

Recurrent community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) skin infections are an increasingly common problem. However, there are no data on the efficacy of decolonization regimens. We prospectively evaluated 31 patients with recurrent CA-MRSA skin infections who received nasal mupirocin, topical hexachlorophene body wash, and an oral anti-MRSA antibiotic. The mean number of MRSA infections after the intervention decreased significantly from baseline (0.03 versus 0.84 infections/month, P = <0.0001). This regimen appears promising at preventing recurrent CA-MRSA infections.

Identification and Characterization of the Anti-Methicillin-Resistant Staphylococcus aureus WAP-8294A2 Biosynthetic Gene Cluster from Lysobacter enzymogenes OH11

Lysobactor enzymogenes strain OH11 is an emerging biological control agent of fungal and bacterial diseases. We recently completed its genome sequence and found it contains a large number of gene clusters putatively responsible for the biosynthesis of nonribosomal peptides and polyketides, including the previously identified antifungal dihydromaltophilin (HSAF). One of the gene clusters contains two huge open reading frames, together encoding 12 modules of nonribosomal peptide synthetases (NRPS). Gene disruption of one of the NRPS led to the disappearance of a metabolite produced in the wild type and the elimination of its antibacterial activity. The metabolite and antibacterial activity were also affected by the disruption of some of the flanking genes. We subsequently isolated this metabolite and subjected it to spectroscopic analysis. The mass spectrometry and nuclear magnetic resonance data showed that its chemical structure is identical to WAP-8294A2, a cyclic lipodepsipeptide with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and currently in phase I/II clinical trials. The WAP-8294A2 biosynthetic genes had not been described previously. So far, the Gram-positive Streptomyces have been the primary source of anti-infectives. Lysobacter are Gram-negative soil/water bacteria that are genetically amendable and have not been well exploited. The WAP-8294A2 synthetase represents one of the largest NRPS complexes, consisting of 45 functional domains. The identification of these genes sets the foundation for the study of the WAP-8294A2 biosynthetic mechanism and opens the door for producing new anti-MRSA antibiotics through biosynthetic engineering in this new source of Lysobacter.

Bacterial Toxin-Triggered Drug Release from Gold Nanoparticle-Stabilized Liposomes for the Treatment of Bacterial Infection

We report a new approach to selectively deliver antimicrobials to the sites of bacterial infections by utilizing bacterial toxins to activate drug release from gold nanoparticle-stabilized phospholipid liposomes. The binding of chitosan-modified gold nanoparticles to the surface of liposomes can effectively prevent them from fusing with one another and from undesirable payload release in regular storage or physiological environments. However, once these protected liposomes "see" bacteria that secrete toxins, the toxins will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. Using methicillin-resistant Staphylococcus aureus (MRSA) as a model bacterium and vancomycin as a model anti-MRSA antibiotic, we demonstrate that the synthesized gold nanoparticle-stabilized liposomes can completely release the encapsulated vancomycin within 24 h in the presence of MRSA bacteria and lead to inhibition of MRSA growth as effective as an equal amount of vancomycin-loaded liposomes (without nanoparticle stabilizers) and free vancomycin. This bacterial toxin enabled drug release from nanoparticle-stabilized liposomes provides a new, safe, and effective approach for the treatment of bacterial infections. This technique can be broadly applied to treat a variety of infections caused by bacteria that secrete pore-forming toxins.

A new anti-MRSA antibiotic complex, WAP-8294A II. Structure characterization of minor components by ESI LCMS and MS/MS

The anti-MRSA antibiotic, WAP-8294A, was isolated from the fermentation broth of Lysobacter sp. The major component, WAP-8294A2, is composed of 1 mol of Gly, L-Leu, L-Glu, D-Asn, D-Trp, D-threo-β-hydroxyasparagine, N-Me-D-Phe and N-Me-L-Val, and 2 mol of L-Ser, D-Orn and D-3-hydroxy-7-Me-octanoic acid. The structure of the WAP-8294A2 was mainly determined as a cyclic depsipeptide by 2D NMR experiments. However, it was difficult to use the NMR experiment to determine the minor components, A1, A4 and Ax13, isolated in small amounts. In the present study, ESI MS/MS was applied to the structure elucidation of these minor components. The structures of these minor components were determined on the basis of the fragmentation pattern of the product ions of WAP-8294A2 in the ESI MS/MS. As a result, it was confirmed that A1 and A4 had the same amino acid sequence as A2, while A1 and A4 had the 3-OH-octanoic acid and 3-OH-8-Me-nonanoic acid, respectively, in the place of the 3-OH-7-Me-octanoic acid in A2. In the structure of Ax13, it was found that Gly of A2 was changed to β-Ala of Ax13.

Risk factors for carbapenem-resistant Acinetobacter baumannii infections at a tertiary care hospital in New Caledonia, South Pacific

In New Caledonia, South Pacific, Acinetobacter baumannii is a nosocomial pathogen. OXA-23 carbapenem-resistant A. baumannii (CRAB) has been ranked third among all multidrug-resistant (MDR) bacteria at the main hospital of Nouméa in New Caledonia (24.8%, 50/202 isolates). In the present study, risk factors and outcomes for 50 patients with CRAB infection were compared with those of 152 patients infected with other MDR bacteria. Independent risk factors for infection with CRAB were respiratory ward admission (odds ratio 2.8, 95% confidence interval 1.1-7.1) and previous treatment with quinolones, β-lactams and anti-MRSA antibiotics. The 30-day mortality was higher for CRAB infections compared with other MDR infections (14% vs 3.3%, p = 0.006). These findings highlight the importance of knowing specific local characteristics relating to the ecology and patterns of resistance of MDR bacteria so as to avoid the emergence of unexpected pan-resistant bacteria.

ChemInform Abstract: A Practical and Efficient Preparation of the Releasable Naphthosultam Side Chain of a Novel anti-MRSA Carbapenem.

A practical large-scale synthesis of the naphthosultam-based side chain of the anti-MRSA antibiotic 1 has been achieved in 29% overall yield over seven steps from 1-methylnaphthalene. The synthesis was completed without the use of protecting groups, featuring a novel naphthosultam annelation, a chemoselective acid-catalyzed triflation, and the use of a novel naphthosultam dianion to effect functionalization through benzylic metalation.

Determining treatment effectiveness and period of treatment

Judging the effect of treatment for hospital-acquired pneumonia is difficult using only inflammatory parameters or findings from chest radiography. Preferably, treatment effects should be judged comprehensively from body temperature, findings of chest radiography, inflammatory parameters, status of purulent discharge, bacteriological findings and oxygenation. In VAP, the parameter most closely correlated with prognosis is trend in PaO(2)/FiO(2). Clinical improvements are normally seen within 72 h. Antimicrobials thus should not be changed until the third day unless a dramatic deterioration in symptoms is seen. With the exception of pneumonia from microbes that tend to possess strong resistance, such as Pseudomonas aeruginosa, a treatment period of 7-10 days is adequate if the early-stage drugs are effective. If no improvements in the course are achieved by 3 days after starting treatment, an investigation should be made into whether treatment should be continued or changed to a different antimicrobial agent.

Correlation between Vancomycin MIC Values and Those of Other Agents against Gram-Positive Bacteria among Patients with Bloodstream Infections Caused by Methicillin-Resistant Staphylococcus aureus

An increase in the distribution of vancomycin MIC values among methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates has been noted. It is postulated that the shift in vancomycin MIC values may be associated with a concurrent rise in the MIC values of other anti-MRSA agents. Scant data are available on the correlation between vancomycin MIC values and the MIC values of other anti-MRSA agents. This study examined the correlation between vancomycin MIC values and the MIC values of daptomycin, linezolid, tigecycline, and teicoplanin among 120 patients with bloodstream infections caused by MRSA at a tertiary care hospital between January 2005 and May 2007. For each included patient, the MIC values of the antibiotics under study were determined by the Etest method and were separated into the following two categories: day 1 (index) and post-day 1 (subsequent). For subsequent isolates, the MIC values for each antibiotic from the post-day 1 terminal isolate were used. Among the index isolates, there was a significant correlation (P value, <0.01) between the MIC values for vancomycin and daptomycin and between the MIC values for vancomycin and teicoplanin. The MIC values for daptomycin were significantly correlated with linezolid, tigecycline, and teicoplanin MIC values. Among the 48 patients with subsequent isolates, vancomycin MIC values were significantly correlated with MIC values for daptomycin, linezolid, and teicoplanin (rho value of >or=0.38 for all comparisons). This study documented an association between vancomycin MIC values and the MIC values of other anti-MRSA antibiotics among patients with bloodstream infections caused by MRSA primarily treated with vancomycin.

Successful treatment of post-MRSA infection glomerulonephritis with steroid therapy

A 48-year-old man without underlying disease developed mediastinitis and was treated by mediastinal drainage. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in a culture of the abscess material. He was treated with anti-MRSA antibiotics and the MRSA infection improved. Four weeks after the onset of MRSA infection, he developed rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome (NS). A renal biopsy showed endocapillary proliferative glomerulonephritis with IgA-predominant glomerular deposition. These clinicopathological findings were consistent with those in glomerulonephritis following MRSA infection (post-MRSA infection glomerulonephritis). The level of serum creatinine increased to 6.3 mg/dl, 7 weeks after the onset of RPGN. At that time, the eradication of MRSA infection was considered. He was given middle-dose steroid therapy. Thereafter, his RPGN with NS improved. MRSA infection did not recur. If the disease activity of post-MRSA infection glomerulonephritis persists after the disappearance of MRSA infection, the application of immunosuppressive therapy with steroids may be useful.

Co-opting the Cell Wall in Fighting Methicillin-Resistant Staphylococcus aureus: Potent Inhibition of PBP 2a by Two Anti-MRSA β-Lactam Antibiotics

Methicillin-resistant Staphylococcus aureus (MRSA) is a global bacterial scourge that has become resistant to many classes of antibiotics, and treatment options for MRSA infections are limited. The cause of MRSA resistance to all commercially available beta-lactam antibiotics is the acquisition of the gene mecA, which encodes penicillin-binding protein 2a (PBP 2a). PBP 2a is a transpeptidase, which in contrast to the other transpeptidases of S. aureus does not experience inhibition by beta-lactam antibiotics. The lack of inhibition is due to a closed conformation for the active site for PBP 2a, which opens up only in the course of the catalytic function of the protein. Here we show that two new anti-MRSA antibiotics now undergoing clinical trials, ceftaroline and ME1036, are able to inhibit PBP 2a effectively, a process that is enhanced in the presence of a cell wall structural surrogate. It is likely that in the course of bacterial growth the occupancy of the allosteric site for the cell wall is co-opted by these antibiotics, and under these conditions the second-order rate constant for the encounter of the antibiotic and PBP 2a approaches the clinically useful value of 10(4)-10(5) M-1 s-1. These compounds are potent inhibitors of PBP 2a as well as PBPs from other species, and have potential as therapeutic agents for treatment of serious infections by MRSA and other resistant bacterial pathogens.

テイコプラニンの初期投与設計における薬剤師介入の効果―血漿中濃度と臨床効果の比較―

In Chugoku-Rosai General Hospital,doctors have notified the department of pharmacy of the use of anti-MRSA antibiotics beforehand since June 2005,and pharmacists have actively intervened in the determination of initial dosages of teicoplanin (TEIC).In the present study,we evaluated the effectiveness of pharmacist intervention by comparing the initial dosage,days of administration,plasma concentrations,and the clinical effect of TEIC treatment between before and after intervention by pharmacists began.The relationships between the initial dosage and plasma TEIC concentrations and between plasma TEIC concentrations and clinical efficacy were also evaluated.The following findings were obtained : 1)higher unbound plasma concentrations of TEIC did not always result in greater clinical efficacy ; 2)higher trough concentrations of TEIC resulted in greater clinical efficacy ; 3)trough TEIC concentrations of more than 20μg/mL caused hepatic damage,as evaluated by plasma AST and ALT activities and 4)higher initial TEIC dosages resulted in higher TEIC plasma concentrations in the early stage,shortening treatment periods as compared with before pharmacist intervention started,and severe renal dysfunction was avoided.In conclusion,active intervention by pharmacists in determining optimal dosages was considered effective in improving pharmacotherapy with TEIC.

透析患者におけるＭＲＳＡ感染の生命予後に影響する因子の検討

This study involved 180 hemodialysis (HD) patients using anti-MRSA antibiotics. The subjects were divided into a survival group (n=100) and a dead group (n=80), and the factors affecting the prognosis were investigated and compared between the two groups. Factors examined were age, sex, dry weight (DW), duration of HD, presence of DM, and laboratory data {Alb, BUN, Cr, IP one month before starting administration of anti-MRSA antibiotics, and the maximum CRP, WBC and neutrophil fractions (maxCRP, maxWBC and maxNeut, respectively) from one month before to after starting the administration of anti-MRSA antibiotics}. A decrease in DW, increase in age, presence of DM, decrease in Alb, BUN, Cr and IP (taken as markers of the nutritional status of the HD patients) and increase in maxCRP, maxWBC and maxNeut (taken as inflammatory markers) were significant factors in exacerbating the prognosis of MRSA infections. Further, a decrease in DW and IP, presence of DM and increase in maxCRP were found to be significant factors in death due to MRSA infections, as determined by multiple logistic regression analysis. Also, when the factors of total fat mass (TFM), body mass index (BMI) and estimated-lean body mass (E-LBM) were compared between the two groups, while TMF was not significantly different between them, a decrease in BMI and E-LBM were significantly associated with death due to MRSA infections. Thus, muscle content appears to be a more important factor than TFM. These results suggest that nutritional supervision can play an important role in the prevention of MRSA infections in HD patients.

緑膿菌の抗MRSA活性および抗MRSA薬不活化作用について

Bacterial interactions such as methicillin-resistant Staphylococcus aureus (MRSA) growth inhibition or inactivation of anti-MRSA antibiotics by Pseudomonas aeruginosa as an indirect pathogen were tested by in vitro assay. Paired strains, P. aeruginosa and MRSA, used in this experiment were isolated from 63 respiratory samples at Juntendo University Hospital from 2002 to 2003. Growth inhibitory activities against MRSA by P. aeruginosa were tested with reversed agar plate method. Inactivation of anti-MRSA antibiotics by P. aeruginosa were assayed with disk diffusion method using agar over lay technique. Fifty-six (88.9%) out of 63 samples showed the significant MRSA growth inhibitory activity by co-existed P. aeruginosa. Anti-MRSA antibiotics such as trimetoprim-sulfamethoxazole combination (ST), arbekacin (ABK) and minocycline (MINO) except Vancomycin (VCM) and Teicoplanin (TEIC) were inactivated by the co-existed P. aeruginosa. Our data suggests that P. aeruginosa may play not only as a chronic respiratory pathogen but also as an indirect pathogen. Further, the most P. aeruginosa with anti-MRSA activity isolated respiratory sample may play as a modulator of MRSA infection.

TPU‐0037‐A, B, C and D, Novel Lydicamycin Congeners with anti‐MRSA Activity from Streptomyces platensis TP‐A0598.

AbstractFor Abstract see ChemInform Abstract in Full Text.

徳島大学医学部附属病院における抗菌薬適正使用の取り組みと使用状況

The working committee for the proper use of antibiotics was organized at Tokushima University Hospital in March 2002, and the institutional guidelines for the selection and use of antibiotics were established. The infection control team (ICT) also started monitoring the use of particular antibiotics, including third-and fourthgeneration cephalosporins, calbapenems and anti-MRSA antibiotics, and reported on their use in August 2002. To assess these activities, we examined the status of antibiotic use for injections and compared our findings with the previous data.The results were as follows : 1) the reports required were presented in 47% of the total antibiotics used; 2) after starting the surveillance, the use of the third-and fourth-generation cephalosporins and calbapenems shifted to the first-and second-generation drugs, while the use of anti-MRSA drugs clearly decreased; 3) these changes resulted in a savings of more than two million yen in medical expenditures in a month. These results suggest that closely monitoring the use of antibiotics may thus be beneficial not only for promoting the proper use of antibiotics but also for reducing overall medical costs.

TPU-0037-A, B, C and D, novel lydicamycin congeners with anti-MRSA activity from Streptomyces platensis TP-A0598.

In screening for anti-MRSA antibiotics, novel lydicamycin congeners, TPU-0037-A, B, C and D, were isolated from a culture broth of an actinomycete strain. The producing strain, TP-A0598, was isolated from a seawater sample collected in Toyama Bay, Japan, and identified as Streptomyces platensis based on taxonomic characteristics. TPU-0037-A, B, C and D were purified by HP-20 resin, ODS column chromatographies and preparative HPLC, consecutively, and their structures were determined to be 30-demethyllydicamycin, 14,15-dehydro-8-deoxylydicamycin, 30-demethyl-8-deoxylydicamycin and 8-deoxylydicamycin, respectively, by NMR and MS analyses. The new congeners showed antibiotic activity against gram-positive bacteria including MRSA with the MIC of 1.56 to approximately 12.5 microg/ml.