Multiresistant Gram-positive Cocci Research Articles

Synergy of Linezolid with Several Antimicrobial Agents against Linezolid-Methicillin-Resistant Staphylococcal Strains.

Linezolid is a synthetic oxazolydinone active against multi-resistant Gram-positive cocci that inhibits proteins synthesis by interacting with the 50S ribosomal subunit. Although linezolid-resistant strains are infrequent, several outbreaks have been recently described, associated with prolonged treatment with the antibiotic. As an alternative to monotherapy, the combination of different antibiotics is a commonly used option to prevent the selection of resistant strains. In this work, we evaluated combinations of linezolid with classic and new aminoglycosides (amikacin, gentamicin and plazomicin), carbapenems (doripenem, imipenem and meropenem) and fosfomycin on several linezolid- and methicillin-resistant strains of Staphylococcus aureus and S. epidermidis, isolated in a hospital intensive care unit in Madrid, Spain. Using checkerboard and time-kill assays, interesting synergistic effects were encountered for the combination of linezolid with imipenem in all the staphylococcal strains, and for linezolid–doripenem in S.epidermidis isolates. The combination of plazomicin seemed to also have a good synergistic or partially synergistic activity against most of the isolates. None of the combinations assayed showed an antagonistic effect.

Actividad de cobre sobre cocáceas grampositivas multi-resistentes a los antibióticos aisladas en hospitales chilenos

Nosocomial infections caused by multiresistant Gram-positive cocci are a serious problem for public health systems worldwide. The use of copper surfaces in hospital environments has proven to be an effective alternative for the control of various microorganisms, including multiresistant nosocomial pathogens. To determine the association between antibiotic multiresistance and higher levels of copper tolerance in Gram-positive cocci isolated from Chilean hospitals, which might confer a selective advantage in environments with copper. The ionic copper tolerance levels were evaluated using the Mueller Hinton agar dilution method, in S. aureus and Enterococcus spp. strains with different levels of susceptibility to clinically relevant antibiotics. A statistically significant association between higher levels of tolerance to copper ion and multi-resistance to antibiotics in Enterococcus spp. was observed.

Single-dose linezolid pharmacokinetics in critically ill patients with impaired renal function especially chronic hemodialysis patients.

Renal failure patients were treated with linezolid (LZD) for proven or suspected infections by multi-resistant Gram-positive cocci. The aim of this study was to determine if dose adjustment of LZD is needed as a function of renal impairment or not, especially that a significant component of LZD is eliminated unchanged in urine. The single dose pharmacokinetics of LZD was investigated. Eighteen non-infected male subjects with various degrees of renal impairment ranged from normal to severe chronic impairment were enrolled, including end-stage renal disease (ESRD) patients maintained on hemodialysis (HD). LZD was administered as a single oral 600 mg dose, and blood samples were drawn at different times and analysed by a validated HPLC assay method. Plasma profiles were evaluated by non-compartmental and compartmental approaches. A similar rate and extent of LZD absorption and elimination and comparable body exposure was observed in both healthy subjects and acute renal failure patients. The extent of LZD exposure was significantly increased by 3-fold in ESRD patients in their off-dialysis day. Furthermore, the t1/2 and MRT values were significantly increased by ~5- and 3-fold, respectively. The Vd /F values of LZD did not change with renal function. A significant decrease in CL/F by ~3-fold was observed in ESRD patients in their off-dialysis day however, CL/F was significantly increased by ~4-fold during HD. Approximately half of the administered LZD dose was removed during the HD session in these selected cohorts of ESRD patients. LZD was generally well tolerated. The dose of LZD did not need to be adjusted for patients with acute renal dysfunction or ESRD on HD. One of the twice-daily doses should be administered after the dialysis session because almost half of the LZD dose was substantially removed by HD. During the first three dialysis sessions of the treatment course, to avoid potentially ineffective therapy, a supplemental dose of LZD might be given if necessary or the dose of LZD should be administered 4 h before the beginning of the HD session. This was to keep LZD levels above the MIC for the organism causing the infection being treated.

Impact of administration of vancomycin or linezolid to critically ill patients with impaired renal function

The aim of this study was to assess the impact of vancomycin (VAN) versus linezolid (LZD) on renal function in patients with renal failure (RF) admitted to intensive care units. This was a multicenter, retrospective, comparative cohort study. Renal failure patients were treated with VAN or LZD for proven or suspected infections by multiresistant Gram-positive cocci. Changes in plasma creatinine levels and creatinine clearance at the start and end of treatment were used as endpoints. A total of 147 patients were treated with VAN (group A, n = 68) or LZD (group B, n = 79). Group B included more patients with diabetes mellitus [9 (13.2%) vs. 25 (31.6%); p = 0.007], septic shock [39 (57.4%) vs. 60 (75.9%); p = 0.013] and greater RF (mean ClCr 42.24 ml/min vs. 37.57 ml/min; p = 0.04). Renal function improved in patients from both groups who did not require renal replacement therapy. A greater improvement was seen in group B [percent decrease in Cr (27.94 vs. 9.48; p = 0.02) and percent increase in ClCr (95.96 vs. 55.06; p = 0.05)]. In group A, nine patients (13.2%) experienced an antibiotic-related increase in RF, and antibiotic was discontinued in five patients due to adverse effects. It is reasonable to avoid use of VAN in critically ill patients with acute renal failure.

Daptomicina para el tratamiento de las infecciones por microorganismos grampositivos en el paciente crítico

Introduction Infections caused by multiresistant Gram-positive cocci have increased among critically ill patients admitted to the intensive care unit (ICU). In the last few years, treatment of these infections has changed due to better knowledge of the limitations of glycopeptides and the introduction of novel antimicrobials, such as daptomycin. Objectives To describe the characteristics of daptomycin that justify its administration in critically ill patients and to present data on the use of this antibiotic in patients admitted to Spanish ICUs. Material and method We reviewed the literature on daptomycin to identify the characteristics that may favor clinical response in critically ill patients. To describe the indications and modalities of use in critically patients, information from the European Cubicin ® Outcome Registry and Experience (EUCORE) database of Spanish patients admitted to the ICU was employed. Results The following favorable conditions were identified: a) scarce systemic response, maintaining high bactericidal activity, b) scarce impact on renal function, c) no requirement for monitoring of plasma levels, d) scarce selection of resistance, and d) excellent tolerability. To assess indications and the use of this agent in the ICU, 122 patients from the EUCORE database were analyzed. The indications were bacteremias (36.2%), complicated infections of the skin and soft tissues (27.6%), and endocarditis (19%). Prominent pathogens were Staphylococcus aureus (26%), S. epidermidis (25%), and other coagulase-negative staphylococci (12%). In 85.7% of patients, treatment was administered as second-line (rescue treatment). In 65 patients (52%), a dose of 6 mg/kg/day was used, with a mean treatment duration of 10.2 days. Overall clinical efficacy was 73.7%. No adverse effects leading to treatment withdrawal were recorded and no increases in creatine phosphokinase (CPK) levels greater than 10-fold the initial values were observed. Conclusions Daptomycin is a novel therapeutic option to be considered in the treatment of severe infections caused by Gram-positive cocci in critically-ill patients.

Epidemiología de las bacteriemias primarias y relacionadas con catéteres vasculares en pacientes críticos ingresados en servicios de medicina intensiva

In recent years, changes have occurred in the setting of bacteriemia related with the use of vascular catheters (BVC) and with the appearance of multiresistant gram positive cocci (MR-GPC), knowledge of the limitations regarding the antibiotics used most for their treatment (glycopeptides) and the appearance of new antibiotics active against these pathogens. This article analyzes the evolution of the rates, etiologies and markers of multiresistance of the most common pathogens in the BVC (including the primary bacteriemias) in the Spanish Intensive Medicine Departments (ICU). A multicenter, prospective, observational study of incidence, with voluntary participation, was conducted. A total of 74, 105, 112 and 121 ICUs belonging to 71, 97, 103 and 112 hospitals, respectively, collaborated including the years 2005-2008. The information included in the ENVIN-HELICS registry was used. The rates of this complication have decreased and are now at about 5 episodes per 1,000 days of central venous catheter (CVC). One third of the episodes occur with significant systemic response (severe sepsis or septic shock). The MR-GPC were the most frequent, however Gram-negative bacilli (GNB) were identified in 30% of the cases and fungi (different species of Candida) in 6%. Staphylococcus epidermidis and coagulase-negative, methicillin-resistant staphylococci (CNS) persist in a proportion greater than 80%, while methicillin-resistance S. aureus have decreased to less than 40%. The empirical treatment in situations of extreme seriousness should consider coverage of the most frequent pathogens such as the MR-GPC and GNB and in special conditions, the fungi.

Novel Therapeutic Agents for Resistant Gram-Positive Infections

Multiresistant Gram-positive cocci, including Staphylococcus aureus, the group of coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium, as well as Streptococcus pneumoniae and other streptococci, represent emerging pathogens in the community, but especially in the setting of immunocompromised, hospitalized patients. In these last subjects, it happens in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are of concern, and broad-spectrum antibiotics are widely used in the environment. The spectrum of antimicrobial compounds now available for an effective management and treatment of these relevant infections is significantly threatened by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant microbial strains. The streptogramine association represented by quinupristin/dalfopristin, the oxazolidinone derivative linezolid, and the recently licensed daptomycin and tigecycline, together with a number of glycopeptides, quinolones, and other experimental compounds on the pipeline, represent an effective response to the majority of these problems, due to their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic/pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also to compromised patients. The main problems related to the epidemiology of multiresistant gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of all these compounds, are updated and outlined based on an extensive review of all available, recent evidences from the international literature. Keywords: Enterococci, glycopeptides, gram-positive organisms, novel antimicrobial agents, oxazolidinones, Pneumococci, resistance, Staphylococci, streptogramins

Evaluation of the in vitro activity of tigecycline against multiresistant Gram-positive cocci containing tetracycline resistance determinants

This study was undertaken to test the in vitro activity of tigecycline against 117 clinically relevant Gram-positive pathogens and to correlate this activity with their resistance gene content. Overall, tigecycline showed a minimal inhibitory concentration (MIC) range of 0.015–0.5 mg/L, able to inhibit potently all multiresistant streptococci, enterococci and MR staphylococci . Tigecycline was active against methicillin-resistant Staphylococcus aureus (MRSA) and enterococci, with MICs for 90% of the organisms (MIC 90) of 0.25 mg/L and 0.12 mg/L, respectively, being more active than linezolid (MIC 90 = 2 mg/L) and quinupristin/dalfopristin (MIC 90 = 0.5 and 2–4 mg/L, respectively). Molecular characterisation of resistance determinants demonstrated the concomitant presence of different classes of genes: in particular, tet(M), erm(B) and erm(C) in Streptococcus agalactiae; tet(O), variably associated with different erm genes, in Streptococcus pyogenes; vanA, tet(M) and erm(B) in Enterococcus faecalis, and vanA and erm(B) in Enterococcus faecium. All the MRSA strains harboured SCC mec and erm genes and 50% possessed tet(K) with tet(M) genes. Staphylococcus epidermidis strains were only resistant to erythromycin. These results clearly demonstrate that tigecycline has a MIC 90 range of 0.015–0.5 mg/L both against tetracycline-susceptible and -resistant isolates carrying other resistance determinants, suggesting that this drug could play an important role in the treatment of infections caused by these multiresistant Gram-positive pathogens.

The First Years of Linezolid Experience in Clinical Practice: A Balance and Future Implications

Multi-antibiotic resistant Gram-positive cocci, which include Staphylococcus aureus, the coagulase-negative staphylococcal group, Enterococcus faecalis and Enterococcus faecium, and other streptococci, represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are to be considered, and broad-spectrum antibiotics or immunosuppressive drugs are needed for prolonged administration. During the recent years, the phenomenon of multi-resistant Gram-positive cocci is spreading from the Hospital into the community, where the retrieval of such microorganism is progressively increasing. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial strains. The first oxazolidinone derivative linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds on the pipeline or approaching the market in the year 2006, represent an effective response to the great majority of these concerns. Because of their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic-pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also when compromised patients are of concern. The main problems related to the epidemiological and clinical features of multiresistant Gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of linezolid as the golden standard compound for vancomycinresistant Gram-positive cocci in multiple clinical situations, are outlined and updated on the ground of an extensive review of all the available. Recent evidences are commented from the international literature. Keywords: Linezolid, oxazolidinones, resistant gram-positive organisms, staphylococci, enterococci

Update on the appropriate use of linezolid in clinical practice

Multi-antibiotic resistant Gram-positive cocci, which include Staphylococcus aureus, the coagulase-negative staphylococcal group, Enterococcus faecalis and Enterococcus faecium, and other streptococci, represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are of concern, and broad-spectrum antibiotics or immunosuppressive drugs are widely administered. During the recent years, the phenomenon of multiresistant Gram-positive cocci is spreading to the community, where the retrieval of such microorganism is progressively increasing. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial strains. The first oxazolidinone derivative linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin, and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds on the pipeline, represent an effective response to the great majority of these concerns, due to their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic/pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also when compromised patients are of concern. The main problems related to the epidemiological and clinical features of multiresistant Gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of linezolid as the golden standard compound for vancomycin-resistant Gram-positive cocci in multiple clinical situations, are outlined and updated on the ground of an extensive review of all the available, recent evidences coming from the international literature.

In vitro activities of the lipopeptides palmitoyl (Pal)-Lys-Lys-NH(2) and Pal-Lys-Lys alone and in combination with antimicrobial agents against multiresistant gram-positive cocci.

The in vitro activities of the lipopeptides palmitoyl (Pal)-Lys-Lys-NH(2) and Pal-Lys-Lys against gram-positive cocci were investigated. Enterococci and streptococci demonstrated higher susceptibilities than staphylococci and Rhodococcus equi. A positive interaction was shown when the lipopeptides were combined with beta-lactams and vancomycin. These results suggest that lipopeptides are promising candidates for antimicrobial therapy for infections caused by gram-positive organisms.

Update on management of infections in cancer and stem cell transplant patients

Infections are the most important causes of morbidity and mortality in patients with aggressive malignancies and those undergoing allogeneic stem cell transplantation. The introduction of new therapeutic approaches including the use of nucleoside analogs and of monoclonal antibodies to CD20 and CD52 and the increased use of matched unrelated stem cell donors has resulted in new challenges with regard to systemic viral and fungal infections. In patients with bacterial infections, emergence of resistance to formerly widely used antibiotics as well as a shift of causative pathogens towards a predominance of multi-resistant gram-positive cocci has to be taken into consideration. In high-risk neutropenic patients with fever of unknown origin, prompt empiric monotherapy with piperacillin-tazobactam, cefepime, ceftazidime, or a carbapenem is mandatory. In patients with lung infiltrates, early preemptive intervention with an antifungal active against aspergilli is recommended, whereas in patients with catheter-related, skin or soft tissue infections, preemptive addition of a glycopeptide shows a high response rate. The prompt preemptive use of ganciclovir or foscarnet in allogeneic stem cell transplant recipients can reliably be guided by serial monitoring of cytomegalovirus antigen and polymerase chain reaction monitoring.

A Re-Emerging Class of Antimicrobial Agents: Streptogramins (Quinupristin/Dalfopristin) in the Management of Multiresistant Gram- Positive Nosocomial Cocci in Hospital Setting

Multiresistant gram-positive cocci, including Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium, are emerging pathogens in the setting of immunocompromised, hospitalized patients, especially when surgery or invasive procedures are of concern, and patients are admitted in intensive care units. The spectrum of antimicrobial compounds available for an effective treatment of these infection is significantly threatened by the emerging and spread of glycopeptide-resistant strains. Quinupristin/dalfopristin is a novel streptogramine association, which represents an effective response to most of these problems, due to its innovative mechanim of action, its maintained activity against multiresistant pathogens, and its possibility of synergistic activity with other compounds. Problems related to the epidemiology of multiresistant gram-positive infection, potential clinical indications of quinupristin/dalfopristin, and updated data on efficacy and tolerability of this compound and its derivatives, are outlined on the ground of a review of available literature evidences.

A 2-Year Survey of Bacteriologic Profile and Antimicrobial Susceptibility Levels of Enterococci in a Large Italian Teaching Hospital

Background: Antimicrobial susceptibility levels of enterococci (including those to glycopeptides) are borne by a broad range of variations, due to the numerous involved variables. Methods: To assess the epidemiology and antimicrobial resistance profile of enterococci identified in all clinical specimens cultured at the bacteriology laboratory of a large Italian teaching hospital in a 2-year period, with special attention deserved to differences between Enterococcus faecalis and Enterococcus faecium and the role of novel compounds effective on multiresistant gram-positive cocci (dalfopristin-quinupristin, linezolid, and levofloxacin), 4628 E. faecalis strains and 648 E. faecium isolates were examined. Results: Compared with the year 2000, during the year 2001, a proportional increase of E. faecium isolates was found opposed to E. faecalis (P < 0.0001), associated with a greater involvement of cardiovascular (P < 0.0001), intra-abdominal (P < 0.0001), and genital tract (P < 0.003). When considering the in vitro susceptibility pattern, E. faecalis proved more sensitive to penicillin, ampicillin, and amoxicillin, and also to nitrofurantoin, levofloxacin, and streptomycin (P < 0.0001). On the other hand, E. faecium had a significantly more elevated susceptibility to gentamicin and dalfopristin-quinupristin (P < 0.0001). Tetracyclines showed a comparable activity against E. faecalis and E. faecium (around 30% of tested strains), as well as linezolid (nearly 99%) and glycopeptides-these last drugs, together with linezolid, showed the greatest activity against enterococci as a whole, as only 2 E. faecalis strains recovered from urine were resistant (0.04% of the 4628 tested strains), and all the 648 E. faecium isolates were susceptible to both teicoplanin and vancomycin. When comparing antimicrobial susceptibility levels, no significant difference was found between years 2000 and 2001, when excluding a slight increase of sensitivity to penicillin, ureidopenicillins, gentamicin, streptomycin, nitrofurantoin, and linezolid for E. faecalis, and penicillin, tetracyclines, and linezolid for E. faecium. Discussion: Our experience of microbiologic monitoring conducted on over 5000 Enterococcus spp. strains evaluated during 24 months pointed out an increased amount of isolates in the year 2001, especially involving E. faecium. The in vitro susceptibility studies confirmed a significantly different profile of E. faecalis opposed to E. faecium. When E. faecalis is of concern, penicillin and ureidopenicillins are still highly effective, but are not in the case of E. faecium, an emerging pathogen in our experience. The maintained in vitro efficacy of nitrofurantoin, gentamicin, and streptomycin is of particular interest. Among recently introduced molecules, linezolid proves effective against around 99% of examined strains, including multiresistant E. faecium isolates. On the other hand, dalfopristin-quinupristin and levofloxacin are characterized by a significantly greater activity against E. faecium and E. faecalis, respectively. Glycopeptides showed lower resistance levels compared with most of literature series and therefore remain the reference compounds for the entire Enterococcus spp., especially when multiresistant baterial strains are of concern. A permanent surveillance of the epidemiology of these organisms in both hospital-acquired and community-acquired infections, the assessment of specific risk factors, the evolution of antibiotic sensitivity levels, and eventual consequences on morbidity and mortality rates are the mainstay of adequate programs of control and prevention. The initial spread of resistance against recently available molecules (last-generation quinolones, streptogramines, and linezolid) recommends a prudent exploitation of older therapeutic resources, which remain effective against most enterococci.

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.

The clinical impact of multiresistant gram-positive microorganisms in long-term care facilities.

Nursing homes and other long-term care facilities (LTCFs) have traditionally been viewed as reservoirs for antibacterial agent-resistant bacteria. Because urinary tract infection is one of the leading causes of infections in this population, Gramnegative microorganisms rapidly developed high levels of resistance to antimicrobial agents. However, the incidence of infections with resistant Gram-positive cocci increased significantly during the 1990s. The emergence of methicillin-resistant Staphylococcus aureus (MRSA) was followed by the appearance of Streptococcus pneumoniae resistant to penicillin and other antibiotics and vancomycin-resistant enterococci (VRE). In addition, the frequency of infections produced by these organisms is increasing, particularly among patients with serious medical conditions. Thus, new and effective antimicrobial agents are needed to treat patients with multidrug-resistant Gram-positive cocci. I would like to consider the factors that induce the appearance and spread of microorganism in general, and Grampositive cocci in particular, in LTCFs. The development of new antibiotics against multiresistant Gram-positive cocci infections and their specific indications will also be discussed. THE PROBLEM

Atividade antimicrobiana in vitro de quinupristina/dalfopristina para cocos gram-positivos isolados de cinco centros brasileiros: resultado do estudo de vigilância L-SMART

Há alguns anos tem-se verificado um aumento progressivo da resistência de alguns cocos gram-positivos a determinados antimicrobianos. Este aumento da resistência tem sido observado principalmente no ambiente hospitalar, e as bactérias mais comumente envolvidas são os Staphylococcus spp. e os Enterococcus spp. Devido a este fato, novos antimicrobianos são avaliados para o tratamento de infecções causadas por estas cepas multirresistentes. A associação quinupristina/dalfopristina (Q/D), também conhecida como Synercid®, é um antibacteriano da classe das estreptograminas, de uso endovenoso, composto por dois derivados semi-sintéticos da pristinamicina. A combinação das estreptograminas B e A na razão de 30:70 tem atividade antimicrobiana voltada para cocos gram--positivos, como Staphylococcus spp., Streptococcus spp., incluindo S. pneumoniae e Enterococcus faecium, sendo o E. faecalis habitualmente resistente. Neste estudo foi avaliada a atividade in vitro de Q/D e outros oito antimicrobianos frente a 631 amostras de cocos gram-positivos isoladas de cinco centros brasileiros, complementadas com outras 20 cepas de E. faecium resistentes à vancomicina, provenientes dos Estados Unidos. Para a avaliação da sensibilidade aos antimicrobianos foi determinada a concentração inibitória mínima (MIC) pelo método do Etest (AB Biodisk, Solna, Suécia) e as cepas testadas foram: Staphylococcus aureus (n = 267), Staphylococcus coagulase negativo (n = 131), Streptococcus pneumoniae (n = 130), Streptococcus beta-hemolíticos (n = 28), Enterococcus faecalis (n = 44) e E. faecium (n = 51). A Q/D demonstrou excelente atividade contra Staphylococcus spp., independente de serem sensíveis ou resistentes à oxacilina. Para S. pneumoniae, a Q/D apresentou igualmente uma ótima atividade, inclusive para as cepas com resistência intermediária ou total para penicilina. Entre as cepas de E. faecium sensíveis à vancomicina, o MIC90 de Q/D obtido foi de 3µg/ml, sendo que 45% das cepas testadas foram sensíveis e 55% apresentaram sensibilidade intermediária à associação. Desta forma, pode-se afirmar que a associação Q/D representa uma nova opção para o tratamento endovenoso de infecções causadas por cocos gram-positivos, principalmente para as cepas multirresistentes, sendo também uma alternativa ao uso de glicopeptídeos.

Multicenter assessment of the linezolid spectrum and activity using the disk diffusion and Etest methods: report of the Zyvox® Antimicrobial Potency Study in Latin America (LA-ZAPS)

Linezolid was the first clinically applied member of the new antimicrobial class called the oxazolidinones. These agents have a powerful spectrum of activity focussed against Gram-positive organisms including strains with documented resistances to other antimicrobial classes. We conducted a multicenter surveillance (Zyvox Antimicrobial Potency Study; ZAPS) trial of qualifying Gram-positive isolates from 24 medical centers in eight countries in Latin America. The activity and spectrum of linezolid was compared to numerous agents including glycopeptides, quinupristin/dalfopristin, beta-lactams and fluoroquinolones when testing 2,640 strains by the standardized disk diffusion method or Etest (AB BIODISK, Solna, Sweden). The linezolid spectrum was complete against staphylococci (median zone diameter, 29 - 32 mm), as was the spectrum of vancomycin and quinupristin/dalfopristin. Among the enterococci, no linezolid resistance was detected, and the susceptibility rate was 93.1 - 96.4%. Only the vancomycin-susceptible Enterococcus faecium strains remained susceptible (92.8%) to quinupristin/dalfopristin. Marked differences in the glycopeptide resistance patterns (van A versus van B) were noted for the 22 isolates of VRE, thus requiring local susceptibility testing to direct therapy. Streptococcus pneumoniae and other species were very susceptible (100.0%) to linezolid, MIC(90) at 0.75 microg/ml. Penicillin non-susceptible rate was 27.7% and erythromycin resistance was at 17.4%. Other streptococci were also completely susceptible to linezolid (MIC(90), 1 microg/ml). These results provide the initial benchmark of potency and spectrum for linezolid in Latin American medical centers. Future comparisons should recognize that the oxazolidinones possess essentially a complete spectrum coverage of the monitored staphylococci, enterococci and streptococcal isolates in 2000-2001. This positions linezolid as the widest spectrum empiric choice against multi-resistant Gram-positive cocci, a spectrum of activity greater than available glycopeptides and the streptogramin combination.

In vitro antimicrobial activity of linezolid tested against vancomycin-resistant enterococci isolated in Brazilian hospitals.

The emergence of vancomycin-resistant enterococci (VRE) has been described recently in Brazil. This is in contrast to the USA and Europe, where the VRE appeared in the late 1980s. The progressive increase in VRE isolation poses important problems in the antimicrobial therapy of nosocomial infections. Treatment options and effective antimicrobial agents for VRE are often limited and the possibility of transfer of vancomycin genes to other Gram-positive microorganisms continues. In the search for antimicrobial agents for multiresistant Gram-positive cocci, compounds such as linezolid and quinupristin/dalfopristin have been evaluated. The present study was conducted to evaluate the in vitro activity of the oxazolidinone linezolid and 10 other antimicrobial agents, including quinupristin-dalfopristin, against multiresistant enterococci isolated in Brazilian hospitals. Thirty-three vancomycin resistant isolates (17 Enterococcus faecium and 16 E. faecalis), were analyzed. Strains were isolated from patients at São Paulo Hospital, Oswaldo Cruz Hospital, Hospital do Servidor Público Estadual, Santa Marcelina Hospital, Santa Casa de Misericórdia de São Paulo, and Hospital de Clínicas do Paraná. The samples were tested by a broth microdilution method following the National Committee for Clinical Laboratory Standards (NCCLS) recommendations. All isolates were molecular typed using pulsed-field gel electrophoresis (PFGE). Linezolid was the most active compound against these multiresistant enterococci, showing 100% inhibition at the susceptible breakpoints. Quinupristin/dalfopristin and teicoplanin showed poor activity against both species. The molecular typing results suggest that there has been interhospital spread of vancomycin resistant E. faecium and E. faecalis among Brazilian hospitals. The results of this study indicate that linezolid is an appropriate therapeutic option for the treatment of vancomycin-resistant enterococci infections in Brazil.

Oxazolidinones: new players in the battle against multi-resistant Gram-positive bacteria

For many years the pharmaceutical industry did not pursue the development of antimicrobial agents that specifically targeted Gram-positive bacteria. Semi-synthetic penicillins and vancomycin were the mainstays of therapy for methicillin-susceptible and -resistant strains of staphylococci, respectively, as was penicillin for Streptococcus pneumoniae and beta-lactam-aminoglycoside combinations for serious enterococcal infections. In the 1980s enterococci resistant to glycopeptides emerged, followed shortly thereafter by a dissemination of penicillin-insensitive S. pneumoniae and, more recently, the occurrence of vancomycin-intermediately susceptible Staphylococcus aureus. The emergence of fully glycopeptide-resistant S. aureus is clearly on the horizon. Multi-resistant Gram-positive bacteria now pose an important therapeutic challenge for clinicians. New drugs with activity against some of these dangerous pathogens have recently been pursued, and linezolid, the first member of the oxazolidinone class, has now been licensed for clinical use in many countries. This drug has excellent in vitro and in vivo activity against all clinically relevant multi-resistant Gram-positive cocci and fills an important void in infectious disease chemotherapy.