Multiresistant Gram-positive Pathogens Research Articles

Decreased Linezolid Serum Concentrations in Three Critically Ill Patients: Clinical Case Studies of a Potential Drug Interaction between Linezolid and Rifampicin

Linezolid is a valuable treatment option for treating infections caused by multi-resistant gram-positive pathogens. Lack of effective linezolid levels due to the co-administration of rifampicin has been described in healthy subjects. However, the clinical significance of this potential drug interaction (DI) for critically ill patients is still unclear. This was a retrospective analysis of 3 critically ill patients with the combination therapy of linezolid and rifampicin or rifampicin pre-treatment. Despite increasing the dose of linezolid, the majority of observed linezolid trough concentrations in all 3 patients were below 2 mg/l. Furthermore, linezolid trough concentrations remained below 2 mg/l after discontinuation of rifampicin. This potential DI between linezolid and rifampicin could lead to treatment failure. Therefore, we strongly recommend that linezolid serum concentrations be monitored in patients with rifampicin co-administration or rifampicin pretreatment.

Auranofin efficacy against MDR Streptococcus pneumoniae and Staphylococcus aureus infections.

Auranofin is an FDA-approved, gold-containing compound in clinical use for the oral treatment of rheumatoid arthritis and has been recently granted by the regulatory authorities due to its antiprotozoal properties. A reprofiling strategy was performed with a Streptococcus pneumoniae phenotypic screen and a proprietary library of compounds, consisting of both FDA-approved and unapproved bioactive compounds. Two different multiresistant S. pneumoniae strains were employed in a sepsis mouse model of infection. In addition, an MRSA strain was tested using both the thigh model and a mesh-associated biofilm infection in mice. The repurposing approach showed the high potency of auranofin against multiresistant clinical isolates of S. pneumoniae and Staphylococcus aureus in vitro and in vivo. Efficacy in the S. pneumoniae sepsis model was obtained using auranofin by the oral route in the dose ranges used for the treatment of rheumatoid arthritis. Thioglucose replacement by alkyl chains showed that this moiety was not essential for the antibacterial activity and led to the discovery of a new gold derivative (MH05) with remarkable activity in vitro and in vivo. Auranofin and the new gold derivative MH05 showed encouraging in vivo activity against multiresistant clinical isolates of S. pneumoniae and S. aureus. The clinical management of auranofin, alone or in combination with other antibiotics, deserves further exploration before use in patients presenting therapeutic failure caused by infections with multiresistant Gram-positive pathogens. Decades of clinical use mean that this compound is safe to use and may accelerate its evaluation in humans.

Re-evaluation of in vitro activity of primycin against prevalent multiresistant bacteria

With the increasing emergence of antibiotic resistances old antibiotics became a valuable source to find agents suitable to address this problem. More than 20 years after the last report, our purpose was to re-evaluate the in vitro antibacterial activity of the topical agent primycin against current important bacterial pathogens. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of primycin were tested in comparison with agents widely applied topically, and with those of mupirocin and vancomycin, the topical and the non-topical gold-standard anti-MRSA agents. Primycin was ineffective (MIC>64μg/ml) against all the Gram-negative isolates tested. On the other hand, all the tested Gram-positive isolates were susceptible with MIC90 values of 0.06μg/ml for staphylococci and 0.5–1μg/ml for enterococci, streptococci, and P. acnes isolates, including all the multiresistant strains. Against MRSA isolates primycin showed slightly higher activity than mupirocin, and inhibited the mupirocin-resistant strains also. MBC90 values ranged from 0.25 to 2μg/ml for the investigated Gram-positive species. The bactericidal effect proved to be concentration-dependent in time-kill experiments. Spontaneous resistant mutants did not emerge in single-step mutation experiments and the resistance development was very slow by serial passaging. Passaged S. aureus strains showing increased primycin MIC values exhibited elevated vancomycin and daptomycin MIC values also. Though elucidation of the mechanisms behind warrants further investigations, these correlations can be related to development of vancomycin-intermediate phenotype. From the point of view of medical practice it is noteworthy that the increased primycin MIC values remained far below the concentration accessible by local application of the agent. These data make primycin a remarkable object of further investigations as well as a promising candidate for topical application against multiresistant Gram-positive pathogens.

Clinical update on linezolid in the treatment of Gram-positive bacterial infections

Gram-positive pathogens are a significant cause of morbidity and mortality in both community and health care settings. Glycopeptides have traditionally been the antibiotics of choice for multiresistant Gram-positive pathogens but there are problems with their use, including the emergence of glycopeptide-resistant strains, tissue penetration, and achieving and monitoring adequate serum levels. Newer antibiotics such as linezolid, a synthetic oxazolidinone, are available for the treatment of resistant Gram-positive bacteria. Linezolid is active against a wide range of Gram-positive bacteria and has been generally available for the treatment of Gram-positive infections since 2000. There are potential problems with linezolid use, including its bacteriostatic action and the relatively high incidence of reported adverse effects, particularly with long-term use. Long-term use may also be complicated by the development of resistance. However, linezolid has been shown to be clinically useful in the treatment of several serious infections where traditionally bacteriocidal agents have been required and many of its adverse effects are reversible on cessation. It has also been shown to be a cost-effective treatment option in several studies, with its high oral bioavailability allowing an early change from intravenous to oral formulations with consequent earlier patient discharge and lower inpatient costs.

Solution structure by nuclear magnetic resonance of the two lantibiotics 97518 and NAI‐107

Lantibiotics 97518 and NAI-107, produced by the related genera Planomonospora and Microbispora respectively, are members of a family of nisin-related compounds. They represent promising compounds to treat infections caused by multiresistant Gram-positive pathogens. Despite their similar structure and a similar antibacterial spectrum, the two lantibiotics exhibit significant differences in their potency. To gain an insight into the structure-activity relationships, their conformational properties in solution are determined by NMR. After carrying out an NOE analysis of 2D (1)H NMR spectra, high-resolution 3D structures are determined using molecular dynamics simulations.

Vancomycin tolerance in Gram-positive cocci

Vancomycin, a glycopeptide antimicrobial agent, represents the last line of defence against a wide range of multi-resistant Gram-positive pathogens such as enterococci, staphylococci and streptococci. However, vancomycin-resistant enterococci and staphylococci, along with vancomycin-tolerant clinical isolates, are compromising the therapeutic efficacy of vancomycin. It is conceivable that tolerance may emerge during prolonged vancomycin use. It has not been until recently, however, that the molecular basis of this tolerance began to be understood. Superoxide anions might be involved in the bactericidal activity of vancomycin in enterococci, and recent evidence suggests that the stringent response is partly responsible for vancomycin tolerance in Enterococcus faecalis. The mechanism of vancomycin tolerance in Staphylococcus aureus and Streptococcus pneumoniae is sometimes associated with a reduction of autolysin activity. Vancomycin tolerance in S. aureus and S. pneumoniae also appears to be somehow related with the two-component regulatory systems linked to cell envelope stress, although the precise molecular regulatory pathways remain poorly defined.

Linezolid treatment of nosocomial bacterial infection with multiresistant Gram-positive pathogens in preterm infants: a systematic review

Linezolid is an antibiotic of the oxazolidinone class that has bacteriostatic and bactericidal activity against a broad range of Gram-positive bacteria, including multiresistant pathogens. Owing to increasing resistance of Gram-positive pathogens to traditional antibiotics such as vancomycin, the oxazolidinones were introduced into therapy. The aim of this review was to summarise actual data on the pharmacokinetics, safety and clinical use of linezolid in preterm infants. The Medline and EMBASE databases were searched using the term ‘linezolid’ combined with ‘newborn’, ‘neonate’, ‘preterm’ and ‘premature’ for papers published between January 1987 and June 2009. Studies reporting on a population including preterm infants and other age groups as well as case reports on preterm infants only were acceptable for analysis. Five studies and eight case reports were identified evaluating linezolid in preterm infants. A dosage regimen of 10 mg/kg body weight given either orally or intravenously every 8 h in infants aged ≥1 week and the same dose given every 12 h in infants <1 week was shown to be safe and effective with a mean treatment duration of 10–28 days. In summary, linezolid was shown to be a safe and effective alternative to vancomycin in the treatment of infections with multiresistant Gram-positive pathogens in preterm infants.

Oxazolidinonas, glucopéptidos y lipopéptidos cíclicos

A review of the chemical structure, pharmacokinetics, spectrum of activity, clinical use, and adverse effects of oxazolidinones (linezolid), glycopeptides, and cyclic lipopeptides (daptomycin) is presented. Oxazolidinones inhibit protein synthesis, and glycopeptides and cyclic lipopeptides act against the bacterial cell wall. The antibacterial spectrum of these agents covers gram-positive pathogens, including multiresistant microorganisms. Absorption of linezolid is approximately 100% and it can be administered orally or intravenously. Linezolid is cleared by both the kidney and liver; thus, dose adjustments are not needed in patients with renal or hepatic failure. Oral absorption of glycopeptides is minimal, and excretion occurs through the kidneys. Daptomycin has fast, potent bactericidal activity, and can only be administered intravenously. The main clinical indication for these antimicrobial agents is the treatment of infections caused by multiresistant gram-positive pathogens, particularly staphylococci. Linezolid can cause anemia, thrombocytopenia, and gastrointestinal side effects, especially in prolonged therapy. The main side effect of vancomycin is nephrotoxicity, and teicoplanin can cause fever. Daptomycin is a safe antibiotic, with myotoxicity being the most relevant side effect.

Microbiological patterns in sepsis: what happened in the last 20 years?

Changes in the microbiological characteristics of sepsis have been observed over the past few decades. Infections caused by Gram-positive bacteria and fungi have become more common in some areas, possibly as a consequence of the increased use of intravascular and other medical devices, an increase in invasive procedures and the use of immunosuppressant agents. As observed with other infections there has been an emergence of multiresistant Gram-positive and Gram-negative pathogens. Most of the published data come from wealthy countries in temperate climates, and although many of the same changes have been observed in developing countries, there are important regional differences in the microbiology of sepsis. For example, typhoidal salmonellae remain the most important cause of bloodstream infection in parts of South Asia, nontyphoidal salmonella infections are predominant in parts of sub-Saharan Africa and melioidosis is important in endemic areas. The microbiological pattern of sepsis has also been influenced by the rise in prevalence of HIV infection in many regions.

In vitro activities of tigecycline combined with other antimicrobials against multiresistant Gram-positive and Gram-negative pathogens

To test the activity of tigecycline combined with 16 antimicrobials in vitro against 22 gram-positive and 55 gram-negative clinical isolates. Antibiotic interactions were determined by chequerboard and time-kill methods. By chequerboard, of 891 organism-drug interactions tested, 97 (11%) were synergistic, 793 (89%) were indifferent and 1 (0.1%) was antagonistic. Among gram-positive pathogens, most synergisms occurred against Enterococcus spp. (7/11 isolates) with the tigecycline/rifampicin combination. No antagonism was detected. Among gram-negative organisms, synergism was observed mainly with trimethoprim/sulfamethoxazole against Serratia marcescens (5/5 isolates), Proteus spp. (2/5) and Stenotrophomonas maltophilia (2/5), with aztreonam against S. maltophilia (3/5), with cefepime and imipenem against Enterobacter cloacae (3/5), with ceftazidime against Morganella morganii (3/5), and with ceftriaxone against Klebsiella pneumoniae (3/5). The only case of antagonism occurred against one S. marcescens with the tigecycline/imipenem combination. Selected time-kill assays confirmed the bacteriostatic interactions observed by the chequerboard method. Moreover, they revealed a bactericidal synergism of tigecycline with piperacillin/tazobactam against one penicillin-resistant Streptococcus pneumoniae and with amikacin against Proteus vulgaris. Combinations of tigecycline with other antimicrobials produce primarily an indifferent response. Specific synergisms, especially against enterococci and problematic gram-negative isolates, might be worth investigating in in vitro models and/or in animal models simulating the human environment.

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.

Antimicrobial activity of tigecycline against clinical isolates from Spanish medical centers. Second multicenter study

The antimicrobial activity of tigecycline, a novel glycylcycline, was evaluated against 1102 bacterial isolates from 20 centers in Spain. The MIC of tigecycline at which 90% (MIC 90) of the pneumococci tested were inhibited was the lowest (0.06 μg/mL) of all the antibiotics tested. The MICs of tigecycline against enterococci ranged from 0.03 to 0.125 μg/mL. All staphylococci were inhibited by ≤0.25 μg/mL of tigecycline, and 99.6% of Enterobacteriaceae isolates were inhibited by ≤2 μg/mL of tigecycline. Tigecycline demonstrated good activity against Bacteroides fragilis group organisms with an MIC 90 of 4 μg/mL. The results of this study confirm the excellent activity of tigecycline against multiresistant Gram-positive and Gram-negative pathogens.

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.

Daptomycin: The First Approved Lipopeptide Antimicrobial

To review the literature concerning the first Food and Drug Administration-approved lipopeptide antimicrobial, daptomycin. A PUBMED search was conducted to identify pertinent English-language journal articles between 1985 and November 2003, and additional references were obtained from the bibliographies of these articles. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy meetings from 1985 through 2003 also were reviewed. All studies evaluating any aspect of daptomycin. Daptomycin is a semisynthetic lipopeptide, the first such antimicrobial agent to reach the marketplace. Its mechanism of action differs from that of the related agent vancomycin in that much of its effect is not because of inhibition of peptidoglycan biosynthesis, but instead is a result of alterations in cell-membrane electrical charge and transport. It exhibits a broad spectrum of activity against gram-positive aerobes and anaerobes, including methicillin-, penicillin-, aminoglycoside-, and vancomycin-resistant strains. In subjects with normal renal function, the terminal disposition half-life is about 7 to 10 hours. It is principally eliminated as unchanged drug in the urine. Available clinical trial data demonstrate efficacy in complicated skin and skin-structure infections resulting from susceptible gram-positive pathogens, but not in pneumonia. The principal adverse event of concern, although rare, is myotoxicity, manifested by muscle pain and/or weakness and elevated serum creatine phosphokinase (CPK) concentrations. The approved dosage regimen is 4 mg/kg intravenously over 30 minutes once daily for 7 days to 14 days. Studies are underway evaluating doses of up to 8 mg/kg once daily. Daptomycin, the first lipopeptide antimicrobial to be marketed, exhibits activity against multiresistant gram-positive pathogens, including linezolid- and quinupristindalfopristin-resistant strains. As such, it is a potentially valuable agent to treat infections resulting from such pathogens. To preserve its utility, it should not be used indiscriminately for infections resulting from pathogens sensitive to other antimicrobials. It is probably best used with restricted access and used only for multiresistant gram-positive pathogens where alternative agents cannot be employed. If used, careful monitoring for the signs and symptoms of myotoxicity, including obtaining weekly serum CPK levels, is mandatory. In addition, bacterial sensitivities to this agent should be prospectively monitored by national antimicrobial surveillance programs like SENTRY, TRUST, and LIBRA.

Benzo[ f]naphtyridones: a new family of topical antibacterial agents active on multi-resistant Gram-positive pathogens

The synthesis and antibacterial activity of benzo[ f][1,7]naphtyridone derivatives are reported. These compounds are potent antibacterial agents with a Gram-positive spectrum of activity. They are active against multi-resistant cocci, especially Staphylococcus aureus strains. Their physico-chemical and biological properties make them particularly suitable for topical antibacterial use.

Nosocomial pneumonia in pediatric patients: practical problems and rational solutions.

Nosocomial pneumonia is a common hospital-acquired infection in children, and is often fatal. Risk factors for nosocomial pneumonia include admission to an intensive care unit, intubation, burns, surgery, and underlying chronic illness. Viruses, predominantly respiratory syncytial virus (RSV), are the most common cause of pediatric nosocomial respiratory tract infections. Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) are the predominant bacterial pathogens, and are associated with a high mortality rate. Staphylococcus aureus and Staphylococcus epidermidis are the most common Gram-positive bacteria causing nosocomial pneumonia; infections with these organisms have a better outcome than those with Gram-negative organisms. An increasing problem is the emergence of multiresistant Gram-positive and Gram-negative nosocomial pathogens. Distinguishing nosocomial pneumonia from other pulmonary processes may be difficult; diagnosis is based on clinical signs, radiological findings, and microbiological results. Recommended empiric therapy should consider factors such as the time of onset of illness, severity of disease, and specific risk factors for nosocomial pneumonia, including use of mechanical ventilation, underlying disease, or recent use of antibacterials. The resident local hospital flora should be considered when selecting therapy for nosocomial pneumonia. Early initiation of appropriate empiric therapy reduces morbidity and mortality. For empiric treatment of bacterial nosocomial pneumonia, an intravenous antibacterial regimen that includes coverage of Gram-negative bacilli and Gram-positive organisms should be used. A carbapenem or ureidopenicillin derivative (piperacillin) plus a beta-lactamase inhibitor should be used where extended spectrum beta-lactamase-producing Enterobacteriaceae are endemic. Therapy should be modified when a specific pathogen and its antimicrobial susceptibility are identified. Effective prevention of nosocomial pneumonia requires infection control measures that affect the environment, personnel, and patients. Of these, hand hygiene, appropriate infection control policies, and judicious use of antibacterials are essential.

Quinupristin‐Dalfopristin: An Overview

Synercid (RP 59500), the first injectable streptogramin antibiotic, is composed of two semisynthetic pristinamycin derivatives, quinupristin and dalfopristin. Individually, each component has bacteriostatic activity against staphylococci and streptococci, but together, the agents exhibit synergy, leading to bactericidal activity. The combination drug, however, is bacteriostatic against Enterococcus faecium and has poor activity against Enterococcus faecalis. Despite a short half-life, an extended postantibiotic effect allows the agent to be dosed every 8-12 hours. Both drugs are largely hepatically metabolized and excreted in bile. Although not metabolized by cytochrome P450 3A4, quinupristin-dalfopristin can inhibit agents that are metabolized through this pathway. Dosage adjustments may be necessary in patients with hepatic dysfunction. Alterations in renal function have minimal effects on the agent's pharmacokinetics. Adverse events include arthralgia, myalgias, and infusion-related pain. Based on available data, quinupristin-dalfopristin appears to have a role in treating severely ill patients with infections due to multiresistant gram-positive pathogens.

Quinupristin/dalfopristin: A novel selective-spectrum antibiotic for the treatment of multi-resistant and other gram-positive pathogens

Quinupristin/dalfopristin: A novel selective-spectrum antibiotic for the treatment of multi-resistant and other gram-positive pathogens

Interventional antimicrobial therapy in febrile neutropenic patients

In febrile neutropenic patients, prompt empiric antimicrobial intervention is mandatory. Numerous studies have demonstrated the benefit of broad-spectrum β-lactams active against Gram-negative aerobes as well as against streptococci and Staphylococcus aureus in this setting. With this interventional strategy, a reduction of infection-related mortality to ≤10% of patients undergoing intensive remission induction or consolidation chemotherapy could be obtained. Thereby, subgroups of patients have been identified who require an empiric modification of antimicrobial treatment, e.g., patients with catheter-related infections, with pulmonary infiltrates, or with unexplained fever (FUO) not responding to first-line antibacterials. In two consecutive, prospectively randomized trials conducted by the German Paul Ehrlich Society it could be shown that empiric antifungal therapy is beneficial for second-line treatment in patients with persistent FUO and improves first-line treatment results in patients with lung infiltrates. The addition of glycopeptides, however, should be restricted to patients with catheter-related infections due to coagulase-negative staphylococci or with infections due to multiresistant Gram-positive pathogens.

Section Review Anti-infectives: New approaches to the treatment of vancomycin-resistant bacterial infections

Commercially available glycopeptides Vancomycin (V) and Teicoplanin (T) are drugs of choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (CNS), which are resistant to beta-lactams and almost all other first-line antibiotics. They are extensively used in the treatment of severe infections caused by multi-resistant Gram-positive pathogens including enterococci. Enterococcal infections have become a dramatic clinical problem since few antibacterial agents are efficacious against these refractory organisms and increasing resistance is rapidly eliminating the current options. The recent emergence and spread of resistance also to glycopeptides in VanA enterococci poses a serious threat for the future. Some strains of methicillin-resistant CNS have reduced susceptibility to T and occasionally to V. Currently, a major concern is the possibility already demonstrated at laboratory level, that high glycopeptide resistance could be transferred from enterococci to staphylococci. It follows that there is an urgent need for new more potent glycopeptides which combine improved activity against methicillin-resistant staphylococci with excellent activity against highly glycopeptide-resistant enterococci (GRE), or alternative drugs effective against these multi-resistant bacteria. This article describes the most recent findings and results achieved in this field with new glycopeptide derivatives and novel approaches based on modifications of the natural glycopeptide-core structure. Other promising investigational drugs potentially useful for overcoming the serious therapeutic problem of glycopeptide-resistant bacterial infections are also reviewed.