Antibiotic-resistant Gram-positive Bacteria Research Articles

Purification and characterization of nisin P produced by a strain of Streptococcus gallolyticus

Introduction. Against the backdrop of increasing resistance to conventional antibiotics, bacteriocins represent an attractive alternative, given their potent activity, novel modes of action and perceived lack of issues with resistance.Aim. In this study, the nature of the antibacterial activity of a clinical isolate of Streptococcus gallolyticus was investigated.Methods. Optimization of the production of an inhibitor from strain AB39 was performed using different broth media and supplements. Purification was carried out using size exclusion, ion exchange and HPLC. Gel diffusion agar overlay, MS/MS, de novo peptide sequencing and genome mining were used in a proteogenomics approach to facilitate identification of the genetic basis for production of the inhibitor.Results. Strain AB39 was identified as representing Streptococcus gallolyticus subsp. pasteurianus and the successful production and purification of the AB39 peptide, named nisin P, with a mass of 3133.78 Da, was achieved using BHI broth with 10 % serum. Nisin P showed antibacterial activity towards clinical isolates of drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and penicillin-resistant Streptococcus pneumoniae. In addition, the peptide exhibited significant stability towards high temperature, wide pH and certain proteolytic enzymes and displayed very low toxicity towards sheep red blood cells and Vero cells.Conclusion. To the best of our knowledge, this study represents the first production, purification and characterization of nisin P. Further study of nisin P may reveal its potential for treating or preventing infections caused by antibiotic-resistant Gram-positive bacteria, or those evading vaccination regimens.

Molecular epidemiology and mechanisms of antibiotic resistance in Enterococcus spp., Staphylococcus spp., and Streptococcus spp. in Africa: a systematic review from a One Health perspective.

A systematic review of antibiotic-resistant Gram-positive bacteria in Africa from a One Health perspective is lacking. Here, we report result from a search for English-language articles on the resistance mechanisms and clonality of Gram-positive bacteria in Africa between 2007 and 2019 reported in PubMed, Web of Science, ScienceDirect, and African Journals OnLine; 172 studies from 22 different African countries were identified. Resistance genes, such as mecA, erm(B), erm(C), tet(M), tet(K), tet(L), vanB, vanA, vanC, and tet(O), were found to be common. Staphylococcus spp., Enterococcus spp., and Streptococcus spp. were the main species reported by the studies, with clones such as Staphylococcus aureus ST5 (n=218 isolates), ST8 (n=127 isolates), ST80 (n=133 isolates), and ST88 (n=117 isolates), and mobile genetic elements such as IS16 (n=28 isolates), IS256 (n=96), Tn916 (n=107 isolates), and SCCmec (n=4437 isolates) identified. SCCmec IV (n=747 isolates) was predominant, followed by SCCmec III (n=305 isolates), SCCmec II (n=163 isolates), SCCmec V (n=135 isolates), and SCCmec I (n=79 isolates). Resistance to penicillin (n=5926 isolates), tetracycline (n=5300 isolates), erythromycin (n=5151 isolates), rifampicin (n=3823 isolates), gentamycin (n=3494 isolates), sulfamethoxazole/trimethoprim (n=3089 isolates), and ciprofloxacin (n=2746 isolates) was common in most reports from 22 countries. Clonal dissemination of resistance across countries and between humans, animals, and the environment was observed. Resistance rates ranged from 1.4% to 100% for 15 of the studies; 10 were One Health-related studies. Strict infection control measures, antimicrobial stewardship, and periodic One Health epidemiological surveillance studies are needed to monitor and contain the threat of increasing antibiotic resistance in Africa.

Optimization of biaryloxazolidinone as promising antibacterial agents against antibiotic-susceptible and antibiotic-resistant gram-positive bacteria

We previously discovered a series of novel biaryloxazolidinone analogues bearing a hydrazone moiety with potent antibacterial activity. However, the most potent compound OB-104 exhibited undesirable chemical and metabolic instability. Herein, novel biaryloxazolidinone analogues were designed and synthesized to improve the chemical and metabolic stability. Compounds 6a-1, 6a-3, 14a-1, 14a-3 and 14a-7 showed significant antibacterial activity against the tested Gram-positive bacteria as compared to radezolid and linezolid. Further studies indicated that most of them exhibited improved water solubility and chemical stability. Compound 14a-7 had MIC values of 0.125–0.25 μg/mL against all tested Gram-positive bacteria, and showed excellent antibacterial activity against clinical isolates of antibiotic-susceptible and antibiotic-resistant bacteria. Moreover, it was stable in human liver microsome. From a safety viewpoint, it showed non-cytotoxic activity against hepatic cell and exhibited lower inhibitory activity against human MAO-A compared to linezolid. The potent antibacterial activity and all these improved drug-likeness properties and safety profile suggested that compound 14a-7 might be a promising drug candidate for further investigation.

Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin

Antibiotics that interfere with the bacterial cytoplasmic membrane have long-term potential for the treatment of infectious diseases as this mode of action is anticipated to result in low resistance frequency. Vancoresmycin is an understudied natural product antibiotic consisting of a terminal tetramic acid moiety fused to a linear, highly oxygenated, stereochemically complex polyketide chain. Vancoresmycin shows minimum inhibitory concentrations (MICs) from 0.125 to 2 μg/mL against a range of clinically relevant, antibiotic-resistant Gram-positive bacteria. Through a comprehensive mode-of-action study, utilizing Bacillus subtilis reporter strains, DiSC3(5) depolarization assays, and fluorescence microscopy, we have shown that vancoresmycin selectively targets the cytoplasmic membrane of Gram-positive bacteria via a non-pore-forming, concentration-dependent depolarization mechanism. Whole genome sequencing of the producing strain allowed identification of the 141 kbp gene cluster encoding for vancoresmycin biosynthesis and a preliminary model for its biosynthesis. The size and complex structure of vancoresmycin could confound attempts to generate synthetic analogues. To overcome this problem and facilitate future studies, we identified, cloned, and expressed the 141 kbp biosynthetic gene cluster in Streptomyces coelicolor M1152. Elucidation of the mode-of-action of vancoresmycin, together with the heterologous expression system, will greatly facilitate further studies of this and related molecules.

Effect of meteorological factors and geographic location on methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci colonization in the US.

BackgroundLittle is known about the effect of meteorological conditions and geographical location on bacterial colonization rates particularly of antibiotic-resistant Gram-positive bacteria. We aimed to evaluate the effect of season, meteorological factors, and geographic location on methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) colonization.MethodsThe prospective cohort included all adults admitted to 20 geographically-dispersed ICUs across the US from September 1, 2011 to October 4, 2012. Nasal and perianal swabs were collected at admission and tested for MRSA and VRE colonization respectively. Poisson regression models using monthly aggregated colonization counts as the outcome and mean temperature, relative humidity, total precipitation, season, and/or latitude as predictors were constructed for each pathogen.ResultsA total of 24,704 ICU-admitted patients were tested for MRSA and 24,468 for VRE. On admission, 10% of patients were colonized with MRSA and 12% with VRE. For MRSA and VRE, a 10% increase in relative humidity was associated with approximately a 9% increase in prevalence rate. Southerly latitudes in the US were associated with higher MRSA colonization, while northerly latitudes were associated with higher VRE colonization. In contrast to MRSA, the association between VRE colonization and latitude was observed only after adjusting for relative humidity, which demonstrates how this effect is highly driven by this meteorological factor.ConclusionsTo our knowledge, we are the first to study the effect of meteorological factors and geographical location/latitude on MRSA and VRE colonization in adults. Increasing humidity was associated with greater MRSA and VRE colonization. Southerly latitudes in the US were associated with greater MRSA and less VRE. The effect of these factors on MRSA and VRE rates has the potential not only to inform patient management and treatment, but also infection prevention interventions.

Pharmacokinetics and cerebrospinal fluid penetration of norvancomycin in Chinese adult patients.

Norvancomycin is an antibiotic that has been approved for the treatment of infections caused by antibiotic-resistant Gram-positive bacteria and has been used in China for more than a decade. However, the cerebrospinal fluid (CSF) penetration of norvancomycin has not been evaluated. The aims of the study were (i) to investigate the pharmacokinetics and CSF penetration of norvancomycin in meningitis and non-meningitis patients and (ii) to recommend favourable dosing regimens in meningitis patients. Twenty adult patients (ten with meningitis and ten without meningitis) requiring norvancomycin treatment were enrolled. All patients received a norvancomycin regimen of 800 mg every 12 h. Blood and CSF samples were consecutively collected up to 12 h after the end of the fourth 60-min infusion. Norvancomycin concentrations both in serum and CSF were measured using a high-performance liquid chromatography (HPLC) assay. CSF penetration of norvancomycin was evaluated by calculating the CSF/serum ratio. Mean norvancomycin serum trough levels were 9.9 ± 1.44 µg/mL in patients with meningitis and 10.08 ± 1.12 µg/mL in patients without meningitis (P > 0.05). In addition, norvancomycin penetrated into the inflamed meninges, with mean CSF concentrations of 3.93-10.52 µg/mL and mean CSF/serum ratios of 0.18-0.43, both of which were significantly higher than in patients without meningitis (P <0.05). These results suggest that norvancomycin has higher CSF penetration in patients with meningitis compared with other groups and that norvancomycin is effective in treating patients with purulent meningitis at a comparably low dose.

Increase in Antibiotic-Resistant Gram-Negative Bacterial Infections in Febrile Neutropenic Children.

BackgroundThe incidence of bacteremia caused by Gram-negative bacteria has increased recently in febrile neutropenic patients with the increase of antibiotic-resistant Gram-negative bacterial infections. This study aimed to identify the distribution of causative bacteria and the proportion of antibiotic-resistant bacteria in bacteremia diagnosed in febrile neutropenic children.Materials and MethodsThe medical records of febrile neutropenic children diagnosed with bacteremia between 2010 and 2014 were retrospectively reviewed. The causative bacteria and proportion of antibiotic-resistant bacteria were investigated and compared yearly during the study period. The clinical impact of antibiotic-resistant bacterial infections was also determined.ResultsA total of 336 bacteremia episodes were identified. During the entire study period, 181 (53.9%) and 155 (46.1%) episodes were caused by Gram-negative and Gram-positive bacteria, respectively. Viridans streptococci (25.9%), Klebsiella spp. (16.7%), and Escherichia coli (16.4%) were the most frequent causative bacteria. The overall distribution of causative bacteria was not significantly different annually. Antibiotic-resistant bacteria were identified in 85 (25.3%) episodes, and the proportion of antibiotic-resistant bacteria was not significantly different annually. Extended-spectrum β-lactamase-producing E. coli and Klebsiella spp. were most common among antibiotic-resistant Gram-negative bacteria, and they accounted for 30.6% (n = 34) of the identified E. coli and K. pneumoniae. Methicillin-resistant coagulase-negative staphylococci were most common among antibiotic-resistant Gram-positive bacteria, and it accounted for 88.5% (n = 23) of the identified coagulase-negative staphylococci. Antibiotic-resistant bacterial infections, especially antibiotic-resistant Gram-negative bacterial infections, caused significantly higher mortality due to bacteremia compared with non-antibiotic-resistant bacterial infections (P <0.001).ConclusionRecently, Gram-negative bacteria caused more bacteremia cases than Gram-positive bacteria in febrile neutropenic children, and antibiotic-resistant Gram-negative bacterial infections increased. Antibiotic-resistant bacterial infections caused poorer prognosis compared with non-antibiotic-resistant bacterial infections, and therefore, continuous surveillance for changing epidemiology of antibiotic-resistant bacterial infections and their clinical impact is necessary.

Linezolid, vancomycin and daptomycin modulate cytokine production, Toll-like receptors and phagocytosis in a human in vitro model of sepsis.

Conventional antibiotics exhibit immunomodulatory properties beneficial in the treatment of sepsis. Antibiotic-resistant Gram-positive bacteria have become a problem in sepsis therapy, giving rise to increased use of last-resort antibiotics; for example, linezolid (LIN), vancomycin (VAN) and daptomycin (DAP). As the immunomodulatory properties of these antibiotics in treating sepsis are unknown, this study examined the effect of VAN, LIN and DAP on the immune response under sepsis-like conditions in vitro. Lipopolysaccharide (LPS)-activated THP-1 monocytes were incubated with LIN, VAN or DAP. Gene expression of cytokines (TNFα, IL-1β, IL-6, IL-10) and Toll-like receptors (TLR1, 2, 4, 6, 7 and 9) was monitored and phagocytosis was determined following coincubation with E. coli. The antibiotics differentially modulated the gene expression of the investigated cytokines. While LIN and VAN upregulated the expression of all TLRs, DAP downregulated mRNA levels of TLR1, TLR2 and TLR6, which recognize pathogen-associated molecular patterns from Gram-positive bacteria. In addition, LIN inhibited, whereas VAN promoted the phagocytic activity of monocytes. Our results suggest that LIN and VAN possess pro-inflammatory properties, whereas DAP might reduce the immune response to Gram-positive bacteria in sepsis. Furthermore, VAN might be beneficial in the prevention of Gram-negative infections by increasing the phagocytosis of E. coli.

Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria

The current epidemic of infections caused by antibiotic-resistant gram-positive bacteria requires the discovery of new drug targets and the development of new therapeutics. Lipoteichoic acid (LTA), a cell wall polymer of gram-positive bacteria, consists of 1,3-polyglycerol-phosphate linked to glycolipid. LTA synthase (LtaS) polymerizes polyglycerol-phosphate from phosphatidylglycerol, a reaction that is essential for the growth of gram-positive bacteria. We screened small molecule libraries for compounds inhibiting growth of Staphylococcus aureus but not of gram-negative bacteria. Compound 1771 [2-oxo-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)ethyl 2-naphtho[2,1-b]furan-1-ylacetate] blocked phosphatidylglycerol binding to LtaS and inhibited LTA synthesis in S. aureus and in Escherichia coli expressing ltaS. Compound 1771 inhibited the growth of antibiotic-resistant gram-positive bacteria and prolonged the survival of mice with lethal S. aureus challenge, validating LtaS as a target for the development of antibiotics.

Characterization and Optimization of an Anti-Aeromonas Bacteriocin Produced by Lactococcus lactis Isolated from Hukuti Maas, an Indigenous Fermented Fish Product

Lactococcus lactis ssp. lactis HKBT-9 strain isolated from hukuti maas, produced a bacteriocin active against foodborne pathogens with specificity toward Aeromonas spp. The bacteriocin produced was sensitive to proteolytic enzymes, stable between pH 2.0 and 10.0, and was thermoresistant (15 min at 121C). Proteinase K, pepsin, ethylenediaminetetraacetic acid and urea strongly inhibited bacteriocin production indicating that the active component of bacteriocin was proteinaceous. Among detergents, sodium dodecyl sulphate, Tween 80 and Tween 20 enhanced bacteriocin activity, which may be due to nondenaturation or its association with other molecules, with a stabilizing effect on bacteriocin activity. Enzymes like α-amylase; DNase and RNase showed slightly increased bacteriocin activity. Maximum activity (2,844 arbitrary units [AU]/mL) against Aeromonas hydrophila was observed and remained for at least 24 h. Optimization using response surface methodology resulted in increased bacteriocin production of 3,591.09 AU/mL at 37.36C, pH 6.63 and inoculum size of 1.53 optical density. Practical Applications Bacteriocins of lactic acid bacteria have been found to kill or inhibit the growth of foodborne pathogens and spoilage microflora, and hence, can be used as natural preservatives in the production of foods with enhanced shelf life and/or safety. With the emergence of antibiotic-resistant gram-positive pathogenic bacteria, the possibility of bacteriocins as supplements or replacements for antibiotics for therapeutic use is also being considered. Of all the antimicrobial peptides, very few have been used as preservatives in the food industry and/or as antibiotic substances in medicine. In the present study, characterization and optimization of an anti-Aeromonas bacteriocin produced by Lactococcus lactis isolated from hukuti maas was attempted, which could be used a potential food biopreservative.

Ultraviolet Disinfection of Antibiotic Resistant Bacteria and Their Antibiotic Resistance Genes in Water and Wastewater

Disinfection of wastewater treatment plant effluent may be an important barrier for limiting the spread of antibiotic-resistant bacteria (ARBs) and antibiotic resistance genes (ARGs). While ideally disinfection should destroy ARGs, to prevent horizontal gene transfer to downstream bacteria, little is known about the effect of conventional water disinfection technologies on ARGs. This study examined the potential of UV disinfection to damage four ARGs, mec(A), van(A), tet(A), and amp(C), both in extracellular form and present within a host ARBs: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), Escherichia coli SMS-3-5, and Pseudomonas aeruginosa 01, respectively. An extended amplicon-length quantitative polymerase chain reaction assay was developed to enhance capture of ARG damage events and also to normalize to an equivalent length of target DNA (∼1000 bp) for comparison. It was found that the two Gram-positive ARBs (MRSA and VRE) were more resistant to UV disinfection than the two Gram-negative ARBs (E. coli and P. aeruginosa). The two Gram-positive organisms also possessed smaller total genome sizes, which could also have reduced their susceptibility to UV because of fewer potential pyrimidine dimer targets. An effect of cell type on damage to ARGs was only observed in VRE and P. aeruginosa, the latter potentially because of extracellular polymeric substances. In general, damage of ARGs required much greater UV doses (200-400 mJ/cm² for 3- to 4-log reduction) than ARB inactivation (10-20 mJ/cm² for 4- to 5-log reduction). The proportion of amplifiable ARGs following UV treatment exhibited a strong negative correlation with the number of adjacent thymines (Pearson r < -0.9; p < 0.0001). ARBs surviving UV treatment were negatively correlated with total genome size (Pearson r < -0.9; p < 0.0001) and adjacent cytosines (Pearson r < -0.88; p < 0.0001) but positively correlated with adjacent thymines (Pearson r > 0.85; p < 0.0001). This suggests that formation of thymine dimers is not the sole mechanism of ARB inactivation. Overall, the results indicate that UV is limited in its potential to damage ARGs and other disinfection technologies should be explored.

Tn916-like genetic elements: a diverse group of modular mobile elements conferring antibiotic resistance

Antibiotic-resistant Gram-positive bacteria are responsible for morbidity and mortality in healthcare environments. Enterococcus faecium, Enterococcus faecalis, Staphylococcus aureus and Streptococcus pneumoniae can all exhibit clinically relevant multidrug resistance phenotypes due to acquired resistance genes on mobile genetic elements. It is possible that clinically relevant multidrug-resistant Clostridium difficile strains will appear in the future, as the organism is adept at acquiring mobile genetic elements (plasmids and transposons). Conjugative transposons of the Tn916/Tn1545 family, which carry major antibiotic resistance determinants, are transmissible between these different bacteria by a conjugative mechanism during which the elements are excised by a staggered cut from donor cells, converted to a circular form, transferred by cell-cell contact and inserted into recipient cells by a site-specific recombinase. The ability of these conjugative transposons to acquire additional, clinically relevant antibiotic resistance genes importantly contributes to the emergence of multidrug resistance.

Critical shortage of new antibiotics in development against multidrug-resistant bacteria—Time to react is now

Two commercial databases (Pharmaprojects and Adis Insight R&D) were queried for antibacterial agents in clinical development. Particular attention was given to antibacterial agents for systemic administration. For each agent, reviewers were requested to indicate whether its spectrum of activity covered a set of selected multidrug-resistant bacteria, and whether it had a new mechanism of action or a new target. In addition, PubMed was searched for antibacterial agents in development that appeared in review articles. Out of 90 agents that were considered to fulfil the inclusion criteria for the analysis, 66 were new active substances. Fifteen of these could be systemically administered and were assessed as acting via a new or possibly new mechanism of action or on a new or possibly new target. Out of these, 12 agents were assessed as having documented in vitro activity against antibiotic-resistant Gram-positive bacteria and only four had documented in vitro activity against antibiotic-resistant Gram-negative bacteria. Of these four, two acted on new or possibly new targets and, crucially, none acted via new mechanisms of action. There is an urgent need to address the lack of effective treatments to meet the increasing public health burden caused by multidrug-resistant bacteria, in particular against Gram-negative bacteria.

ISOLATION, BIOCHEMICAL PROPERTIES AND APPLICATION OF BACTERIOCINS FROM PEDIOCOCCUS PENTOSACEOUS ISOLATES

Bacteriocins are ribosomally synthesized peptides having considerable potential as a food preservative because of their strong antagonistic activity against many food spoilage and pathogenic organisms. Bacteriocins from Pediococcus pentosaceous isolates, DFR-JJ1 and DFR-JJ6, were purified using cold-acetone precipitation, cell adsorption-desorption and gel permeation chromatography techniques. Cold-acetone fractionation resulted in higher yields of bacteriocins, but the specific activity and fold purification were higher for cell adsorption-desorption and gel permeation chromatography. Both bacteriocins JJ1 and JJ6 exhibited broad inhibitory spectrum against foodborne pathogens and spoilage microorganisms, including some Gram-negative bacteria. Amylase, lipase and catalase did not alter the antimicrobial activity but proteolytic enzymes inactivated these bacteriocins. They were heat stable and exhibited activity in a pH range of 2–8 with maximum activity between pH 4.0 and 5.0. Molecular weights of bacteriocin JJ1 and JJ6 were found to be ∼4.95 and 4.3 kDa, respectively. PRACTICAL APPLICATIONS Bacteriocins of lactic acid bacteria have been found to kill or inhibit the growth of foodborne pathogens and spoilage microflora, and hence, can be used as natural preservatives in the production of foods with enhanced shelf life and/or safety. With the emergence of antibiotic-resistant Gram-positive pathogenic bacteria, the possibility of bacteriocins as supplements or replacements for antibiotics for therapeutic use is also being considered. Of all the antimicrobial peptides, very few have been used as preservatives in the food industry and/or as antibiotic substances in medicine. However, an increasing number of bacteriocins are being tested in model systems, some of them show promising results and may reach commercial acceptance in the near future. In the present study, two bacteriocins from Pediococcus pentosaceous strains were purified, which inhibited the growth of Staphylococcus aureus in liquid medium and Salmonella typhimurium in orange juice, justifying their potential as food biopreservatives.

Laundering of Theatre Scrubs at Home

Infections, particularly those caused by antibiotic-resistant gram-positive bacteria, such as methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), are a growing concern, particularly in units in which patients are immunosuppressed either intentionally (as for transplantation) or as a result of trauma (severe burns) or disease (such as acquired immunodeficiency disease) (Steinstraesser et al 2009). As more bacteria become resistant to antibiotics, our ability to control the spread of these bacteria with antibiotic treatments decreases (Steinstraesser et al 2009).

Experience of European intensive care physicians with infections due to antibiotic-resistant bacteria, 2009

A survey was performed among European intensive care physicians to obtain information about their perception and experience with selected antibiotic-resistant bacteria. Seventy-eight out of 95 (82%) participants considered having to deal with infections due to antibiotic-resistant bacteria in the intensive care unit where they work was a major or significant problem. Methicillin-resistant Staphylococcus aureus (MRSA) and third-generation cephalosporin-resistant Enterobacteriaceae were the most frequently reported antibiotic-resistant bacteria with 69 (73%) and 67 (71%) participants reporting having treated at least one patient with such an infection during the preceding six months, respectively. Antibiotic-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae, were more frequently reported than any selected antibiotic-resistant Gram-positive bacteria, with the exception of MRSA. Fifty (53%) participants declared having treated at least one patient infected with a bacterium totally or almost totally resistant to available antibiotics during the past six months, with 8 participants having treated more than 10 such patients and 13 having treated from 3 to 10 such patients.

Pseudomonas aeruginosa: can studies in engineered cells tell us why is it such a problem in people with cystic fibrosis? Focus on “Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa”

PEOPLE WITH CYSTIC FIBROSIS (CF) are surviving in larger numbers into adulthood and even middle age. Over time, acquisition of antibiotic-resistant gram-positive and gram-negative bacteria in the airways leads to progressive inflammation and cycles of pulmonary exacerbations that drive obstructive lung disease and decline in lung function. CF patients have an exuberant immune system aided by ever more powerful antibiotics that prevent sepsis and death by limiting spread beyond the airways. Yet at the same time, despite aggressive intervention to improve mucociliary clearance and fight infection from infancy, the airways become chronically colonized with specific bacteria that are difficult to eradicate. Periodically, bacteria become more invasive causing pulmonary exacerbations that lead to progressive airways damage and irreversible structural changes. The paradox between a strong immune reaction and failure to eradicate infection supports the hypothesis that there is a primary defect in innate immunity in CF.

Linezolid for the treatment of skin and soft-tissue infections

Linezolid, a novel synthetic antibiotic compound with enhanced activity against Gram-positive infections, is at the center of much interest lately owing to the soaring prevalence of antibiotic-resistant Gram-positive bacteria. Since its inception, linezolid has been used successfully for the treatment of many different types of infections. Based on a number of clinical and pharmacokinetic trials, however, it seems that linezolid is particularly well suited to the treatment of skin and soft-tissue infections (SSTIs). Currently available evidence supports that the choice of linezolid should be considered as a valuable alternative, particularly for those cases where the patient presents with a complicated SSTI, has comorbid conditions or requires outpatient treatment. With serious adverse events being reported only in rare cases (mainly in those receiving longer courses of treatment) linezolid is furthermore considered to be a safe antibiotic agent for short therapeutic courses.

A new approach to treatment of resistant gram-positive infections: potential impact of targeted IV to oral switch on length of stay

BackgroundPatients prescribed intravenous (IV) glycopeptides usually remain in hospital until completion of this treatment. Some of these patients could be discharged earlier if a switch to an oral antibiotic was made. This study was designed to identify the percentage of inpatients currently prescribed IV glycopeptides who could be discharged earlier if a switch to an oral agent was used, and to estimate the number of bed days that could be saved. We also aimed to identify the patient group(s) most likely to benefit, and to estimate the number of days of IV therapy that could be prevented in patients who remained in hospital.MethodsPatients were included if they were prescribed an IV glycopeptide for 5 days or more. Predetermined IV to oral antibiotic switch criteria and discharge criteria were applied. A multiple logistic regression model was used to identify the characteristics of the patients most likely to be suitable for earlier discharge.ResultsOf 211 patients, 62 (29%) could have had a reduced length of stay if they were treated with a suitable oral antibiotic. This would have saved a total of 649 inpatient days (median 5 per patient; range 1–54). A further 31 patients (15%) could have switched to oral therapy as an inpatient thus avoiding IV line use. The patients most likely to be suitable for early discharge were those with skin and soft tissue infection, under the cardiology, cardiothoracic surgery, orthopaedics, general medical, plastic surgery and vascular specialities, with no high risk comorbidity and less than five other regularly prescribed drugs.ConclusionThe need for glycopeptide therapy has a significant impact on length of stay. Effective targeting of oral antimicrobials could reduce the need for IV access, allow outpatient treatment and thus reduce the length of stay in patients with infections caused by antibiotic resistant gram-positive bacteria.

Antimicrobial resistance in gram-positive bacteria

Gram-positive bacteria are common causes of bloodstream and other infections in hospitalized patients in the United States, and the percentage of nosocomial bloodstream infections caused by antibiotic-resistant gram-positive bacteria is increasing. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are of particular concern. In the United States, approximately 60% of staphylococcal infections in the intensive care unit are now caused by MRSA, and percentages continue to rise. Outbreaks of hospital-acquired MRSA (HA-MRSA) are typically the result of clonal spread by MRSA being transferred from patient to patient, frequently using healthcare personnel as intermediaries. HA-MRSA strains are generally multidrug resistant. Vancomycin is the standard treatment for serious MRSA infections, but a few cases of vancomycin-resistant S aureus (VRSA) have recently emerged in the United States. Community-acquired MRSA (CA-MRSA) is also increasing. Soft tissue infections are the most frequent presentations of CA-MRSA, but life-threatening invasive infections occur as well, including necrotizing pneumonia. The mechanisms of methicillin resistance are the same for CA-MRSA and HA-MRSA, but susceptibilities to non-â-lactam antibiotics often differ. CA-MRSA exhibits broader antibiotic susceptibility than does HA-MRSA. The proportion of enterococci resistant to vancomycin continues to rise in the hospital setting, with the overwhelming majority of infections due to Enterococcus faecium. Clonal spread of VRE has been documented, but polyclonal outbreaks associated with antimicrobial use are also common. The relations between antibiotic use and VRE colonization are complex and related to the antienterococcal activity, biliary excretion, and antianaerobic activity of the antibiotic. Recent results show a decline in invasive pneumococcal disease (IPD) since the introduction of 7-valent pneumococcal conjugate vaccine, and suggest that, where available, vaccines may be useful in the battle to slow the spread of resistant gram-positive cocci.