Multi-resistant Gram-positive Bacteria Research Articles

Identification of SagA as a novel vaccine target for the prevention of Enterococcus faecium infections

Infections caused by multiresistant Gram-positive bacteria represent a major health burden in the community as well as in hospitalized patients. Enterococci, especially Enterococcus faecium, are well-known pathogens of hospitalized patients and are frequently linked with resistance against multiple antibiotics, which compromises effective therapy. Rabbit immune serum raised against heat-killed E. faecium E155, a HiRECC clone, was used in an opsonophagocytic assay, an inhibition assay and a mouse bacteraemia model to identify targets of opsonic and protective antibodies. Serum against whole heat-killed bacteria was opsonic and recognized a protein of about 72 kDa that was abundantly secreted. This protein, identified as SagA by LC-ES-MS/MS, was expressed in Escherichia coli and purified. Rabbit serum raised against the purified protein showed opsonic killing activity that was inhibited by almost 100% using 100 µg purified protein ml(-1). In a mouse bacteraemia model, a statistically significant reduction of the colony counts in blood was shown with immune rabbit serum compared with preimmune serum using the homologous and a heterologous vancomycin-resistant enterococci (VRE) strain. These results indicate that SagA could be used as a promising vaccine target to treat and/or prevent VRE bacteraemia.

Population biology of Gram-positive pathogens: high-risk clones for dissemination of antibiotic resistance.

Infections caused by multiresistant Gram-positive bacteria represent a major health burden in the community as well as in hospitalized patients. Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium are well-known pathogens of hospitalized patients, frequently linked with resistance against multiple antibiotics, compromising effective therapy. Streptococcus pneumoniae and Streptococcus pyogenes are important pathogens in the community and S. aureus has recently emerged as an important community-acquired pathogen. Population genetic studies reveal that recombination prevails as a driving force of genetic diversity in E. faecium, E. faecalis, S. pneumoniae and S. pyogenes, and thus, these species are weakly clonal. Although recombination has a relatively modest role driving the genetic variation of the core genome of S. aureus, the horizontal acquisition of resistance and virulence genes plays a key role in the emergence of new clinically relevant clones in this species. In this review, we discuss the population genetics of E. faecium, E. faecalis, S. pneumoniae, S. pyogenes and S. aureus. Knowledge of the population structure of these pathogens is not only highly relevant for (molecular) epidemiological research but also for identifying the genetic variation that underlies changes in clinical behaviour, to improve our understanding of the pathogenic behaviour of particular clones and to identify novel targets for vaccines or immunotherapy.

Biotransformation of ent-8(14),15-pimaradiene and antimicrobial activity of the obtained derivatives against multi-resistant Gram-positive bacteria

Biotransformation of ent-8(14),15-pimaradiene and antimicrobial activity of the obtained derivatives against multi-resistant Gram-positive bacteria

Carlina Oxide – A Natural Polyacetylene fromCarlina acaulis(Asteraceae) with Potent Antitrypanosomal and Antimicrobial Properties

Carlina acaulis (Asteraceae) has a long history of medicinal use in Europe due to its antimicrobial properties. The strong activity of Carlina oxide, themain compound of the essential oil of C. acaulis against two MRSA strains, Streptococcus pyogenes, Pseudomonas aeruginosa, Candida albicans, and C. glabrata was confirmed. A strong and selective activity against Trypanosoma brucei brucei with an IC₅₀ of 1.0 μg/mL and a SI of 446 compared to human HeLa cells was recorded. The selective toxicity of Carlina oxide makes it a promising lead compound for the development of drugs to treat African trypanosomiasis and multiresistant gram-positive bacteria.

Pharmacokinetics of linezolid in septic patients with and without extended dialysis

Linezolid is an option for the treatment of infections caused by multiresistant Gram-positive bacteria. The survival of critically ill patients with acute renal failure (ARF) can be improved by increasing the dose of renal replacement therapy. Extended (daily) dialysis (ED) is a new and important approach to renal replacement therapy in intensive care units. The aim of the study was to evaluate the pharmacokinetics of linezolid in septic patients without ED and on ED, respectively. We studied the pharmacokinetics of linezolid in adult intensive care patients with sepsis (n = 5) and anuric septic patients with ARF being treated with ED (n = 10). Linezolid 600 mg was administered intravenously twice daily. The pharmacokinetic parameters, their variability, and possible covariates were analyzed using NONMEM. The pharmacokinetics of linezolid followed a two-compartment model with clearance (Cl) = 0.159 L h(-1) kg(-1) +/- 51% (population mean +/- interindividual variability), central volume of distribution (V(1)) = 0.273 L/kg +/- 21%, intercompartmental clearance (Q) = 0.369 L h(-1) kg(-1), and peripheral volume of distribution (V(2)) = 0.271 L/kg. The clearance in ED patients while on dialysis was increased by 3.5 L/h, and patients with liver transplantation/resection had their clearance reduced by 60%. Intra-individual variability was much smaller than inter-individual variability. Our results suggest that linezolid pharmacokinetics in critically ill patients with ARF undergoing ED is not comparable to that in healthy subjects and patients without ARF. The best method of managing linezolid dosage in such a complex group of patients, whose physiology can vary daily, would be to use therapeutic drug monitoring.

Advances in Antibacterial Therapy Against Emerging Bacterial Pathogens

During the last decade, both gram-positive and gram-negative bacteria that are resistant to most or all available antibacterial classes have become increasingly prevalent nosocomial pathogens, particularly among immunocompromised patients and those hospitalized in intensive care units. Among gram-positive bacteria, increasing concerns are posed for health care- and community-associated methicillin-resistant Staphylococcus aureus (MRSA), S aureus with reduced susceptibility to vancomycin, and vancomycin-resistant enterococci (VRE). A spectrum of newer antibacterial agents has been developed for the treatment of multi-resistant gram-positive bacteria, such as linezolid, tigecycline, daptomycin, and novel glycopeptides. Gram-negative bacteria have also developed multidrug resistance (MDR), which in the Enterobacteriacae is commonly due to the production of extended-spectrum beta-lactamases and carbapenemases of VIM, IMP, or KPC types. Currently, non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii are commonly resistant to all available antibiotics, including the newer agents. Colistin retains activity against most P aeruginosa and A baumannii, but its clinical use remains questionable, while newer carbapenems and tigecycline have limited additional advantages. Rational use of newer antibacterial agents coupled with enhanced infection control measures may be able to sufficiently control MDR organisms as to allow hematological patients to recover from serious infectious complications.

Antimicrobial activity of selected plant species from “the Argentine Puna” against sensitive and multi-resistant bacteria

Aim The plant species reported here are traditionally used in the “Puna” or “Altiplano” of Argentina for ailments related to bacterial infections. The aim of this study was to evaluate their antimicrobial properties against a panel of sensitive and multi-resistant Gram-positive and Gram-negative bacteria. Materials and methods The antimicrobial activity of tinctures and aqueous extracts ( Baccharis boliviensis, Chiliotrichiopsis keidelii, Chuquiraga atacamensis, Fabiana bryoides, Fabiana densa, Fabiana punensis, Frankenia triandra, Parastrephia lucida, Parastrephia lepidophylla, Parastrephia phyliciformis, Tetraglochin cristatum) was determined using the agar macrodilution and broth microdilution methods recommended by the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS). The antibiotic resistant clinical strains were isolated from nosocomial infection in human lesions of skin and soft parts. Results The ethanolic extracts of 11 plant species inhibited the growth of one or more of the following strains: Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Morganella morganii, Pseudomonas aeruginosa. Ethanol extracts (tinctures) of aerial parts of Baccharis, Fabiana and Parastrephia showed the highest levels of antibacterial activity on methicillin, oxacillin and gentamicin resistant Staphylococcus with MIC values from 20 to 150 μg/ml. Baccharis boliviensis and Fabiana bryoides were more active than the other plant species on Enterococcus faecalis with different phenotype. The most interesting activity on multi-resistant Gram-negative strains was obtained from Chuquiraga atacamensis. Parastrephia species showed activity against Enterobacter cloacae, Pseudomonas aeruginosa and Proteus mirabilis. The ethanolic extracts exhibited stronger activity and broader spectrum of action than aqueous extracts. The extracts were bactericidal in most cases. Conclusions The presence of antibacterial activity in Puna plant extracts against multi-resistant bacteria give support to their traditional use for treating conditions associated with microorganisms in humans and animals and consequently seems promising for the treatment of multi-resistant bacteria.

Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens

Antimicrobial drugs targeting the reportedly essential type II fatty acid synthesis (FASII) pathway have been recently acclaimed for their efficacy against infections caused by multiresistant Gram-positive bacteria. Our findings show that the strategy for antibiotic development based on FASII pathway targets is fundamentally flawed by the fact that exogenous fatty acids fully bypass inhibition of this pathway in both in vitro and in vivo conditions. We demonstrate that major Gram-positive pathogens-such as streptococci, pneumococci, enterococci and staphylococci-overcome drug-induced FASII pathway inhibition when supplied with exogenous fatty acids, and human serum proves to be a highly effective source of fatty acids. For opportunist pathogen Streptococcus agalactiae, growth in serum leads to an overall decrease of FASII gene expression. No antibiotic inhibitor could have a stronger effect than the inactivation of the target gene, so we challenged the role of FASII using deletion mutants. Our results unequivocally show that the FASII target enzymes are dispensable in vivo during S. agalactiae infection. The results of this study largely compromise the use of FASII-based antimicrobials for treating sepsis caused by Gram-positive pathogens.

Tigecycline in combination with other antimicrobials: a review of in vitro, animal and case report studies

Tigecycline has been investigated in combination with other antibacterials against a wide range of susceptible and multiresistant Gram-positive and Gram-negative bacteria. Combinations have been analysed in vitro, in animal models and in human case reports. In vitro, tigecycline combined with other antimicrobials produces primarily an indifferent response (neither synergy nor antagonism). Nevertheless, synergy occurred when tigecycline was combined with rifampicin against 64–100% of Enterococcus spp., Streptococcus pneumoniae, Enterobacter spp. and Brucella melitensis isolates. Combinations of tigecycline with amikacin also showed synergy for 40–100% of Enterobacter spp., Klebsiella pneumoniae, Proteus spp. and Stenotrophomonas maltophilia isolates. Moreover, bactericidal synergisms occurred with tigecycline plus amikacin against problematic Acinetobacter baumannii and Proteus vulgaris, and with colistin against K. pneumoniae. Data from animal experiments and case reports, although limited, displayed consistent beneficial activity of tigecycline in combination with other antibacterials against multiresistant organisms, including vancomycin against penicillin-resistant S. pneumoniae in experimental meningitis, gentamicin against Pseudomonas aeruginosa in experimental pneumonia, daptomycin against Enterococcus faecium endocarditis, and colistin against K. pneumoniae bacteraemia and P. aeruginosa osteomyelitis. Antagonism was extremely rare in vitro and was not reported in vivo. Thus, tigecycline may be combined with a second antimicrobial as part of a combination regimen.

A Global Evaluation of Vancomycin Resistant Enterococci (VRE) Against Tigecycline: The T.E.S.T. Program

Background: Tigecycline (TIG), a member of a new class of antimicrobials (glycylcyclines), has been shown to have potent expanded broad spectrum activity against most commonly encountered species responsible for community and hospital acquired infections. The T.E.S.T. program determined the in vitro activity of tigecycline compared to amoxicillin-clavulanic acid, piperacillin-tazobactam, levofloxacin, ceftriaxone, linezolid (LZD), minocycline, vancomycin (VAN), ampicillin (AM), penicillin, and imipenem against VRE collected from hospitals globally throughout 2004–2007. Methods: 742 VRE (110 Enterococcus faecalis, 632 E. faecium) clinical isolates were identified to the species level at each participating site and confirmed by the central laboratory. Minimum Inhibitory Concentrations (MICs) were determined by the local laboratory using supplied broth microdilution panels and interpreted according to CLSI guidelines with tigecycline susceptible defined as ≤0.25 mcg/mL. Results: %S of all VRE to TIG, LZD, and MIN were 100, 96.4, and 72.2, respectively. For E. faecalis strains, the three most active drugs were TIG (100%), LZD (100%), and AM (100%). For E. faecium, the three most active drugs were TIG (100%), LZD (95.7%), and MIN (74.4%). There were significant differences in VRE rates between North America (E. faecalis 4.7%, E. faecium 65.8%), Europe (E. faecalis 1.3%, E. faecium 16.4%), and Asia (E.faecalis 0%, E.faecium 30%). Conclusions: TIG exhibited outstanding activity against VRE, inhibiting 100% of strains with MICs ≤0.25 mcg/ml (MIC90 = 0.06), surpassing LZD as the most active drug in this study. The exceptionally broad spectrum of TIG, which includes many other multi-resistant gram-positive and gram-negative bacteria in addition to VRE, will make it a very attractive addition to hospital formularies.

Therapeutic options for the treatment of infections with multiresistant grampositive bacteria in oncological patients

Infections with highly resistant grampositive bacteria are a major threat to the patients with underlying malignant diseases and due to more aggressive treatment strategies the incidence of these infections increased over the past years. For many years, glycopeptides such as vancomycin, have been the standard treatment for methicillin-resistant S. aureus (MRSA) and ampicillin-resistant enterococci. However, the clinical use of vancomycin may be limited by the adverse effects like poor tissue penetration and the emergence of vancomycin-resistant strains such as vancomycin-resistant enterococci and staphylococci. Thus, in recent years, new antimicrobial agents have been introduced into clinical praxis or are under investigation. This review summarizes current clinical data on novel therapeutics such as linezolid, tigecycline and daptomycin as well as investigational new drugs. Linezolid, an oxazolidinone derivative, has proven clinical activity only against infections with grampositive bacteria including vancomycin-resistant rods. Tigecycline is a tetracycline derivative with a very broad antimicrobial spectrum including multiresistant grampositive strains. Daptomycin, belonging to a new class of cyclic lipopeptide antibiotics, is approved for the treatment of skin and skin-structure infections, bactermia and endocarditis with grampositive bacteria. However, only limited data exist on the clinical use of tigecycline and daptomycin in oncological patients. In the near future, novel cephalosporins and carbapenems with activity against MRSA as well as new semisynthetic glycopeptides will extend our therapeutic possibilities in the treatment of infections by multiresistant grampositive bacteria.

Tigecycline for the treatment of patients with severe sepsis or septic shock: a drug use evaluation in a surgical intensive care unit

Adequate antimicrobial therapy is crucial for the survival of critically ill patients with severe nosocomial infections. Tigecycline, the first available agent in the new class of glycylcyclines, is active against multiresistant gram-positive and gram-negative bacteria. The aim of this observational, retrospective evaluation was to assess tigecycline use patterns in a surgical intensive care unit (SICU) of a tertiary care centre. Data from 70 patients receiving tigecycline in the SICU were analysed. We reviewed tigecycline use in terms of demographic data and co-morbidities, disease severity, clinical indication, microbiology, therapy regimens and mortality. A logistic regression analysis was performed to identify prognostic factors for mortality. The majority of patients had co-morbidities such as cancer (51%) or renal replacement therapy (57%). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of patients at admission was 27. Intra-abdominal infection was most frequently diagnosed (50% of patients); intra-abdominal infection and pneumonia were diagnosed in 14%. Methicillin-resistant Staphylococcus aureus was found in 16% of patients (colonization; infection: 6%) and vancomycin-resistant enterococci in 27% (colonization; infection: 21%). The mean duration of tigecycline therapy was 9 +/- 4 days; 76% of patients received tigecycline in combination, with 64% being treated second line. APACHE score and renal replacement were identified as predictive factors for mortality. SICU mortality was 30%. Tigecycline treatment of critically ill SICU patients with severe sepsis or septic shock appeared to result in remarkably low mortality. Tigecycline may be an important treatment option for septic patients with infections resistant to other available agents.

A simple isocratic HPLC assay to determine linezolid concentrations in different biomatrices for in vivo and in vitro studies

Linezolid is an important therapeutic option for the treatment of infections caused by multiresistant Gram-positive bacteria such as vancomycin-resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). However, the clinical benefit of linezolid is threatened by the emergence of resistant strains of MRSA and VRE reported in North America and Europe. For effective antimicrobial treatment, it is extremely important to have exact knowledge of drug concentrations at the site of action. A simple HPLC method for the rapid and precise determination of linezolid in different biomatrices (e.g., plasma, soft tissue, bone, dialysis fluid and used microbiological broth) was developed and validated. Proteins were precipitated with acetonitrile and separation was performed on a reversed-phase C8 column with a mobile phase consisting of water/acetonitrile (80:20, v/v). UV detection was performed at 251 nm. This method has a lower limit of quantification of 0.3 microg/mL and a linear calibration range of 0.5-40 microg/mL. The method showed excellent reproducibility, with an inter- and intra-day assay precision of <5% (% relative standard deviation), as well as excellent accuracy, with inter- and intra-day assay accuracy ranging from 100.6% to 103.2%. Stability up to 6 months in water and plasma was proven. Quantitative recovery was possible after up to three freeze thaw cycles. The method is useful in the acquisition of in vivo and in vitro data. It is simple, flexible, specific, precise and reproducible, as well as of adequate sensitivity for clinical use.

Treatment of prosthetic valve infective endocarditis due to multi-resistant Gram-positive bacteria with linezolid

Clinical experience with linezolid in the treatment of infective endocarditis either alone or in combination with other agents is limited. We describe our experience in the treatment of two patients with IE due to multi-resistant Gram-positive bacteria. One patient with MRSE and one with VRE endocarditis were treated with regimens containing linezolid. The killing kinetics of linezolid in combination with gentamicin or vancomycin against isolates of Staphylococcus epidermidis and Enterococcus faecalis were analysed in vitro. Clinical response and eradication of bacteraemia was achieved with linezolid therapy in both patients. Time-kill curve studies showed that linezolid was bacteriostatic against the MRSE and VRE isolates used. Combination with gentamicin or vancomycin did not produce synergy or antagonism but at best only marginal additive effect. Although bacteriostatic, linezolid provides an important therapeutic option in IE due to multi-resistant Gram-positive pathogens. It challenges the conventional wisdom that bactericidal synergy is required for the effective treatment of most cases of IE due to Gram-positive organisms.

The in vitro Activity of Pentane-1,5-diol against Aerobic Bacteria. A New Antimicrobial Agent for Topical Usage?

Multi-resistance to antibiotic therapy and to biocides is becoming increasingly common, which has led to mounting concern worldwide regarding the future use of traditional antimicrobials. Diols or glycols also have antimicrobial effects. Pentane-1,5-diol has low oral toxicity, is essentially non-irritating to the skin and has high antimicrobial activities against bacteria, fungi and viruses. The effect of pentane-1,5-diol against both sensitive and multi-resistant Gram-positive and Gram-negative bacteria was tested in vitro against 85 bacterial strains showing minimal inhibitory concentrations in the range of 2.5 to 15.0% (vol/vol) against both antibiotic-susceptible and multi-resistant aerobic bacteria. The exact mechanism of action is unknown but probably pentane-1,5-diol sucks water out of the bacterial cells which then collapse, a mechanism to which it is probably very difficult to develop resistance. The high activity against multi-resistant bacteria makes pentane-1,5-diol an interesting new compound for topical antimicrobial therapy in humans.

Activity of daptomycin against multi-resistant Gram-positive bacteria including enterococci and Staphylococcus aureus resistant to linezolid

The activity of daptomycin was assessed against 545 isolates of Gram-positive bacteria including enterococci, coagulase-positive and -negative staphylococci, β-haemolytic streptococci, viridans streptococci and coryneforms. The panel of isolates was biased towards those with resistance to first-line antimicrobial agents and included linezolid-resistant enterococci and Staphylococcus aureus. MICs of daptomycin were ≤1 mg/l for all the staphylococci, streptococci, and coryneforms, except for two isolates of Corynebacterium aquaticum, for which MICs were 8 mg/l. Daptomycin MICs were ≤2 and ≤4 mg/l for Enterococcus faecalis and Enterococcus faecium, respectively.

Distribution of multi-resistant Gram-negative versus Gram-positive bacteria in the hospital inanimate environment

We prospectively studied the difference in detection rates of multi-resistant Gram-positive and multi-resistant Gram-negative bacteria in the inanimate environment of patients harbouring these organisms. Up to 20 different locations around 190 patients were surveyed. Fifty-four patients were infected or colonized with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) and 136 with multi-resistant Gram-negative bacteria. The environmental detection rate for MRSA or VRE was 24.7% (174/705 samples) compared with 4.9% (89/1827 samples) for multi-resistant Gram-negative bacteria ( P<0.0001). Gram-positive bacteria were isolated more frequently than Gram-negatives from the hands of patients ( P<0.0001) and hospital personnel ( P=0.1145). Environmental contamination did not differ between the intensive care units (ICUs) and the general wards (GWs), which is noteworthy because our ICUs are routinely disinfected twice a day, whereas GWs are cleaned just once a day with detergent. Current guidelines for the prevention of spread of multi-resistant bacteria in the hospital setting do not distinguish between Gram-positive and Gram-negative isolates. Our results suggest that the inanimate environment serves as a secondary source for MRSA and VRE, but less so for Gram-negative bacteria. Thus, strict contact isolation in a single room with complete barrier precautions is recommended for MRSA or VRE; however, for multi-resistant Gram-negative bacteria, contact isolation with barrier precautions for close contact but without a single room seems sufficient. This benefits not only the patients, but also the hospital by removing some of the strain placed on already over-stretched resources.

In vitro and in vivo activities of novel 2-(thiazol-2-ylthio)-1beta-methylcarbapenems with potent activities against multiresistant gram-positive bacteria.

SM-197436, SM-232721, and SM-232724 are new 1beta-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC(90) of </=4 micro g/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae strains, ranged from </=0.063 to 0.5 micro g/ml. These drugs were the most active beta-lactams tested against Enterococcus faecium, and the MIC(90) s for ampicillin-resistant E. faecium ranged between 8 and 16 micro g/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the E. faecium strain: its efficacy was superior to that of linezolid, although the MICs (2 micro g/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.

Neue Therapieoption für Intensivpatienten mit Infektionen durch Gram-positive Bakterien - Überblick über Linezolid

During the last decade, there has been an emergence of multiresistant Gram-positive bacteria in intensive care units. Oxazolidinones are a new class of antibiotics without cross-resistance to other antimicrobial agents, and linezolid was recently introduced as first oxazolidinone on the German market. In this overview, we summarize important data and discuss possible indications for linezolid in the treatment of infections in critically ill patients. ANTIMICROBIAL ACTIVITY AND PHARMACOLOGY: The antimicrobial spectrum comprises mainly Gram-positive bacteria, especially Staphylococcus aureus (including MRSA), coagulase-negative staphylococci, enterococci, and streptococci. Linezolid is mostly bacteriostatic and inhibits the bacterial protein synthesis at an early stage. Adults may receive 600 mg b.i.d. intravenously or p. o. About 30 % of the dose are excreted by the kidneys as mother compound and 50 % as metabolites. Dosage reductions are not necessary, even in severe renal impairment, but about one third of the dose is eliminated during dialysis. Overall, linezolid is well tolerated, but approximately 5 % of the patients may suffer from diarrhea or nausea and there have been a few reports about reversible myelosuppressive side effects. Linezolid has been compared to vancomycin for treatment of Gram-positive nosocomial pneumonia, and the clinical cure rates were 66.4 % and 68.1 %, respectively. Linezolid is highly active and bactericidal against pneumococci. The clinical cure rates for treatment of skin and soft tissue infections were 88.1 % with linezolid and 86.1 % with penicillinase-stable penicillins. MRSA were excluded in this study, but it may be assumed from data in vitro that linezolid is equally effective against these bacteria. Data for the treatment of catheter-associated and other forms of bacteremias are mainly derived from the compassionate-use-program, where linezolid has been used in complicated cases, mainly after failure of standard therapy. The majority of infections was caused by multiresistant Enterococcus faecium and the clinical cure rates were approximately 80 %. The currently available data suggest that linezolid will serve as useful agent in the treatment of severe infections caused by multiresistant staphylococci and enterococci. Further studies are necessary to define the role of linezolid as first-line agent, e. g. in the treatment of central venous catheter infections. In light of the severe prognosis of pneumonias caused by MRSA, studies on the combination of linezolid and vancomycin are warranted. Despite the low level of resistance, it seems prudent not to use linezolid as first line agent in the treatment of uncomplicated infections, as long as effective standard antibiotics are available.

Minimal inhibitory concentrations and time-kill determination of moxifloxacin against aerobic and anaerobic isolates

Moxifloxacin is a new oral 8-methoxy-quinolone with a wide spectrum of activity against Gram-negative and anaerobic bacteria, atypical micro-organisms and multi-resistant Gram-positive bacteria. This study was designed to assess the in vitro activity of moxifloxacin against Gram-positive bacteria with different resistance patterns, anaerobes and atypical micro-organisms such as Chlamydia and Mycoplasma. Moxifloxacin had good activity against Streptococcus pneumoniae with all strains inhibited by ⩽0.12 mg/l. The minimal inhibitory concentrations (MICs) of moxifloxacin for Streptococcus pyogenes and Streptococcus agalactiae ranged from 0.03 to 0.5 mg/l while those of ciprofloxacin were about two- to four-fold higher (MICs=0.12–1 mg/l). Moxifloxacin was poorly active against enterococci but its activity against Clostridium and Bacteroides spp. was in the same range as that of metronidazole and superior to that of clindamycin. Moxifloxacin was substantially more active than both ciprofloxacin and sparfloxacin against Chlamydia.