Anti-infective research and development--problems, challenges, and solutions.
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Anti-Bacterial Agents↗
Biomedical subjects
Ethan Rubinstein
Publications and source records attributed to Ethan Rubinstein.
Comparison of community-acquired methicillin-resistant Staphylococcus aureus bacteremia to other staphylococcal species in a neonatal intensive care unit.
Hospital acquired infections including staphylococcal species are common in neonatal intensive care units. Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) was recently observed in our unit. The clinical and laboratory characteristics of all neonates with Staphylococcus aureus bacteremia during an 11-year period were retrospectively reviewed. Three groups of patients were compared: 1. Patients with CA-MRSA defined as MRSA-resistant only to beta-lactams, but sensitive to all other antibiotic groups and carried SCCmec IV. 2. Patients with multi-drug-resistant (MDR)-MRSA and 3. Patients with MSSA (methicillin-sensitive S. aureus). Forty-three neonates with documented S. aureus bacteremia were included. Of these 41 were preterm babies. Eleven infants had CA-MRSA, 20 had MDR-MRSA and 12 had MSSA bacteremia, the Panton-Valentine-Leukocidine gene (pvl-gene) was not present in any of these strains. Risk factors, clinical manifestations and laboratory tests were similar in all three groups studied. Although neonates infected with CA-MRSA were more premature and had more related diseases, the mortality rate was similar in all groups (9.1% in the CA-MRSA group). Skin infections, osteomyelitis or pneumatocele were not observed more frequently in the CA-MRSA group. We did not find significant differences in risk factors or outcomes in neonates in the three groups. One possible explanation for this observation is that the CA-MRSA outbreak strain did not contain the pvl-gene, which has been suggested to be a significant virulence factor.
Anti-Bacterial Agents↗
Tigecycline: a novel glycylcycline antibiotic.
Tigecycline, the first-in-class glycylcycline, was developed to recapture the broad spectrum of activity of the tetracycline class and to treat patients with difficult-to-treat bacterial infections. Tigecycline's in vitro spectrum of activity encompasses aerobic, facultative and anaerobic Gram-positive and -negative bacteria, including antimicrobial-resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and Enterococcus faecium, and extended-spectrum beta-lactamase-producing Enterobacteriaceae. Clinical trials involving patients with complicated skin and skin-structure infections and complicated intra-abdominal infections, including patients infected with methicillin-resistant S. aureus, demonstrated that tigecycline was bacteriologically and clinically effective with mild-to-moderate gastrointestinal adverse events (i.e., nausea, vomiting and diarrhea) the most commonly reported. Tigecycline is a promising new broad-spectrum parenteral monotherapy for the treatment of patients with Gram-positive and -negative bacterial infections.
Adolescent↗
A Review of New Fluoroquinolones : Focus on their Use in Respiratory Tract Infections.
The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.
Anti-Infective Agents↗
Staphylococcus aureus endocarditis: a consequence of medical progress.
CONTEXT: The global significance of infective endocarditis (IE) caused by Staphylococcus aureus is unknown. OBJECTIVES: To document the international emergence of health care-associated S aureus IE and methicillin-resistant S aureus (MRSA) IE and to evaluate regional variation in patients with S aureus IE. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational cohort study set in 39 medical centers in 16 countries. Participants were a population of 1779 patients with definite IE as defined by Duke criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to December 2003. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: S aureus was the most common pathogen among the 1779 cases of definite IE in the International Collaboration on Endocarditis Prospective-Cohort Study (558 patients, 31.4%). Health care-associated infection was the most common form of S aureus IE (218 patients, 39.1%), accounting for 25.9% (Australia/New Zealand) to 54.2% (Brazil) of cases. Most patients with health care-associated S aureus IE (131 patients, 60.1%) acquired the infection outside of the hospital. MRSA IE was more common in the United States (37.2%) and Brazil (37.5%) than in Europe/Middle East (23.7%) and Australia/New Zealand (15.5%, P<.001). Persistent bacteremia was independently associated with MRSA IE (odds ratio, 6.2; 95% confidence interval, 2.9-13.2). Patients in the United States were most likely to be hemodialysis dependent, to have diabetes, to have a presumed intravascular device source, to receive vancomycin, to be infected with MRSA, and to have persistent bacteremia (P<.001 for all comparisons). CONCLUSIONS: S aureus is the leading cause of IE in many regions of the world. Characteristics of patients with S aureus IE vary significantly by region. Further studies are required to determine the causes of regional variation.
Cross Infection↗
An outbreak of Phialemonium infective endocarditis linked to intracavernous penile injections for the treatment of impotence.
BACKGROUND: In March 2002, a patient in Tel Aviv, Israel, died of endocarditis caused by Phialemonium curvatum. As part of his therapy for erectile dysfunction, the patient had been trained to self-inject a compound of vasoactive drugs provided by an impotence clinic into his penile corpus cavernosous. METHODS: We identified the used prefilled syringes as the source of his infection. Similar cases were investigated as a putative outbreak of P. curvatum invasive disease among customers of this impotence clinic. P. curvatum isolates, cultured from samples obtained from the patients and from prefilled syringes, were compared by DNA sequencing of the nuclear ribosomal internal transcribed spacer. RESULTS: We identified 2 additional customers at the impotence clinic who had P. curvatum endocarditis. In addition, cultures of unused, prefilled syringes and bottles provided by the same clinic to 5 asymptomatic customers tested positive for pathogenic molds (P. curvatum in 4 cases and Paecilomyces lilacinus in 1). All P. curvatum isolates were of a single genetic type that is known only from this outbreak but is closely related to 3 other P. curvatum genotypes associated with pathogenicity in humans. CONCLUSIONS: P. curvatum is an emerging pathogen that can be readily isolated from blood. We identified an outbreak of P. curvatum endocarditis among men who had erectile dysfunction treated by intracavernous penile injections from contaminated prefilled syringes.
Aged↗
Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis.
The management challenges of patients with nosocomial pneumonia are great because of resistance among the responsible pathogens. In this issue of Critical Care, Argyris Michalopoulos and colleagues describe the use of inhaled colistin in the treatment of multidrug-resistant Gram-negative nosocomial pneumonia in a small group of patients. Although seven of eight patients who received nebulized colistin showed clinical improvement, some patients also received other active antibiotics. Microbiological eradication was demonstrated in only four of the eight patients. Serum levels of colistin were not measured. In addition, although adverse events were not documented in patients receiving colistin, formal assessments for bronchoconstriction and neurological toxicity were not completed in this retrospective study. Although resistance to colistin in Gram-negative organisms has not evolved, the risk of breakthrough infection with Gram-positive and inherently resistant Gram-negative bacteria remains a concern. The results of this limited study do, however, suggest that further studies examining the use of nebulized colistin are merited.
Aerosols↗
Resistant organisms and otitis media.
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Acute Disease↗
Is in vitro antibiotic combination more effective than single-drug therapy against anthrax?
Antibiotic combinations are used to enhance antibacterial efficacy and to prevent the development of resistance. We have tested a possible synergistic effect of several antibacterial combinations on Bacillus anthracis. The in vitro activities of antibiotic combinations against two strains of B. anthracis, strain Sterne and the Russian anthrax vaccine strain STi, were tested by the fractional inhibitory concentration (FIC) method, derived from the MICs of the agents in combination, and by measuring the rate of bacterial killing over time by several antibiotic combinations. The FIC results showed that synergism against both B. anthracis strains was observed only with the combination of rifampin and clindamycin. The telithromycin-amoxicillin combination showed synergism against strain Sterne only. All other combinations were either indifferent or antagonistic. The results of the bacterial time-kill study demonstrated indifferent effects for all combinations. These in vitro results demonstrate the difficulties in obtaining synergistic combinations of antibiotics against B. anthracis.
Anti-Bacterial Agents↗
Excision of nucleoside analogs from DNA by p53 protein, a potential cellular mechanism of resistance to inhibitors of human immunodeficiency virus type 1 reverse transcriptase.
We investigated the ability of p53 in cytoplasm to excise nucleoside analogs (NAs). A decrease in incorporation of NAs by human immunodeficiency virus type 1 reverse transcriptase and their excision from DNA by p53, provided by the cytoplasmic fraction of LCC2 cells, suggest that p53 in cytoplasm may act as an external proofreader for NA incorporation.
Anti-HIV Agents↗
Tigecycline: a novel glycylcycline.
Antibacterials have been in clinical use for almost 60 years; however, the effectiveness of these valuable agents has been diminished by widespread emergence of bacterial resistance. Tigecycline is the first in a new class of glycylcyclines with activity against a wide range of clinically important pathogens. Tigecycline has demonstrated potent microbiological activity and excellent therapeutic response in animal infection models and in recently reported phase III human clinical trials. It is effective against intra-abdominal and skin and soft tissue infections caused by susceptible or multidrug-resistant staphylococci, enterococci or streptococci as well as most Enterobacteriaceae and anaerobic pathogens. In clinical trials nausea and vomiting were the most common adverse events and were of a magnitude typical of those observed with tetracyclines in general. Additionally, tigecycline has proven to be efficacious in animal models of infection, including pneumonia, endocarditis and peritonitis. Tigecycline is only available as an intravenous agent and distributes extensively in tissues. Administration of a 100mg loading dose of tigecycline followed by twice-daily doses of 50mg yielded an apparent volume of distribution of 7-10 L/kg. Systemic clearance ranged from 0.2 to 0.3 L/h/kg and its half-life varied from 37 to 67 hours. The pharmacokinetics of tigecycline appear unaffected by sex, age, renal disease or the presence of food. Data from animal studies would suggest that time above the minimum inhibitory concentration is the pharmacodynamic factor that best correlates with bacterial eradication. The efficacy, safety profile and pharmacodynamic attributes of tigecycline support its continuing clinical development as empirical parenteral treatment of challenging nosocomial and community-acquired infections, including those caused by proven or suspected resistant pathogens.
Animals↗
Methicillin-resistant Staphylococcus aureus in neonatal intensive care unit.
A neonatal intensive care unit outbreak was caused by a strain of methicillin-resistant Staphylococcus aureus previously found in the community (ST45-MRSA-IV). Fifteen infected neonates were identified, 2 of whom died. This outbreak illustrates how a rare community pathogen can rapidly spread through nosocomial transmission.
Anti-Bacterial Agents↗
Association between carriage of Streptococcus pneumoniae and Staphylococcus aureus in Children.
CONTEXT: Widespread pneumococcal conjugate vaccination may bring about epidemiologic changes in upper respiratory tract flora of children. Of particular significance may be an interaction between Streptococcus pneumoniae and Staphylococcus aureus, in view of the recent emergence of community-acquired methicillin-resistant S aureus. OBJECTIVE: To examine the prevalence and risk factors of carriage of S pneumoniae and S aureus in the prevaccination era in young children. DESIGN, SETTING, AND PATIENTS: Cross-sectional surveillance study of nasopharyngeal carriage of S pneumoniae and nasal carriage of S aureus by 790 children aged 40 months or younger seen at primary care clinics in central Israel during February 2002. MAIN OUTCOME MEASURES: Carriage rates of S pneumoniae (by serotype) and S aureus; risk factors associated with carriage of each pathogen. RESULTS: Among 790 children screened, 43% carried S pneumoniae and 10% carried S aureus. Staphylococcus aureus carriage among S pneumoniae carriers was 6.5% vs 12.9% in S pneumoniae noncarriers. Streptococcus pneumoniae carriage among S aureus carriers was 27.5% vs 44.8% in S aureus noncarriers. Only 2.8% carried both pathogens concomitantly vs 4.3% expected dual carriage (P =.03). Risk factors for S pneumoniae carriage (attending day care, having young siblings, and age older than 3 months) were negatively associated with S aureus carriage. CONCLUSIONS: Streptococcus pneumoniae carriage, specifically of vaccine-type strains, is negatively associated with S aureus carriage in children. The implications of these findings in the pneumococcal vaccine era require further investigation.
Carrier State↗
Type II topoisomerase mutations in Bacillus anthracis associated with high-level fluoroquinolone resistance.
OBJECTIVES: To identify and characterize the mechanisms of high-level fluoroquinolone resistance in two strains of Bacillus anthracis following serial passage in increasing concentrations of fluoroquinolones. METHODS: Fluoroquinolone-resistant isolates of the Sterne and Russian Anthrax Vaccine STi strains were obtained following serial passage in the presence of increasing concentrations of four different fluoroquinolones. The quinolone-resistance-determining regions of the type II topoisomerase genes from the resistant strains were amplified by PCR and characterized by DNA sequence analysis. The MICs in the presence and absence of reserpine were determined using broth microdilution as a means of detecting active efflux. RESULTS: Single and double amino acid substitutions in the GyrA (Ser-85-Leu; Glu-89-Arg/Gly/Lys) and GrlA (Ser-81-Tyr; Val-96-Ala; Asn-70-Lys) were most common. A single amino acid substitution in GyrB (Asp-430-Asn) was also identified. Efflux only applied to isolates selected for by either levofloxacin or ofloxacin. CONCLUSIONS: Specific amino acid substitutions in the type II topoisomerase enzymes significantly contributed to the development of high-level fluoroquinolone resistance in B. anthracis. However, notable differences between the strains and the drugs tested were identified including the role of efflux and the numbers and types of mutations identified.
Amino Acid Substitution↗
Nasopharyngeal carriage of Streptococcus pneumoniae by adults and children in community and family settings.
The rate of Streptococcus pneumoniae carriage among adults was compared with that among children (age, < or =6 years) in the same population. Nasopharyngeal culture results for 1300 adults and 404 children were analyzed. S. pneumoniae was carried by only 4% of the adults, compared with 53% of children in the same community. Young age, day care center attendance, having young siblings, and no antibiotic use during the month before screening were associated with the high carriage rate among children, whereas the only risk factor associated with carriage among adults was the presence of a respiratory infection on the screening day. S. pneumoniae serotype distribution and antibiotic resistance patterns differed between adults and children. Isolates of the same serotype--even of the same clone--differed in their antibiotic susceptibility patterns between children and adults. In a subanalysis of 151 pairs of children and their parents and of 32 pairs of siblings, intrafamilial transmission of S. pneumoniae could not be demonstrated.
Adolescent↗
Fungal Endocarditis.
Recent advances in medicine have caused fungal endocarditis (FE) to be a more common disease entity. Many fungi are potential pathogens in FE, although Candida species and Aspergillus species are the most common. Valvular heart disease is the necessary underlying condition for FE, with intravenous devices and antibiotic use being the predisposing factors for yeast endocarditis, whereas immunosuppression in patients with valvulopathy predisposes for mold endocarditis. Better prognosis of FE depends on fast and accurate diagnosis and subsequent treatment. Echocardiography was the most valuable recent technique in the past two decades that allowed early diagnosis of FE and is probably responsible for the improved prognosis of patients with FE. In the future, development of nonculture-based diagnostic tests may further improve the sensitivity, specificity, and rapidity of microbiologic diagnosis of FE. Novel approaches in treatment, such as new antifungal drugs, also may assist in achieving cure and further improving the prognosis of this disease entity.
Journal Article↗
Vaccination and autoimmune diseases: the argument against.
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Autoimmune Diseases↗
Reply to: Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones.
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Animals↗