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Michael R Jacobs

Publications and source records attributed to Michael R Jacobs.

At least 19 recordsLinked to original sources
PubMed2005

A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus.

There is an urgent medical need for novel antibacterial agents to treat hospital infections, specially those caused by multidrug-resistant Gram-positive pathogens. The need may also be fulfilled by either exploring antibacterial agents having new mechanism of action or expanding known classes of antibacterial drugs. The paper describes a new chemical entity, compound 21, derived from hitherto little known "floxacin". The choice of the entity was made from a series of synthesized prodrugs and salts of the active chiral benzoquinolizine carboxylic acid, S-(-)-nadifloxacin. The chemistry, physicochemical characteristics, and essential bioprofile of 21 qualifies it for serious consideration as a novel drug entity against hospital infections of multi-drug-resistant Staphylococcus aureus, and its progress up to clinical phase I trials in humans is described.

Animals↗
PubMed2005

Sinusitis.

Explore the source record for details and available documents.

Anti-Bacterial Agents↗
PubMed2005

The epidemiology of childhood pneumococcal disease in the United States in the era of conjugate vaccine use.

In 2000, a heptavalent pneumococcal conjugate vaccine was licensed and included in the schedule of routine childhood immunizations in the United States. The vaccine contains the serotypes most commonly associated with invasive and noninvasive pneumococcal infection in children and the serotypes most commonly expressing antibiotic resistance. Since the introduction of the vaccine, the incidence of invasive pneumococcal disease has declined dramatically in the United States, particularly among children younger than 2 years of age. The incidences of pneumonia and acute otitis media also have declined, but less substantially. Several factors may blunt the future effectiveness of the vaccine, however, particularly the emergence of noninvaccine pneumococcal serotypes and the propensity for pathogenic pneumococci to switch their capsular types, evading vaccine-conferred immunity.

Bacteremia↗
PubMed2005

Efficacy of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) in adults with community-acquired pneumonia caused by Streptococcus pneumoniae, including penicillin-resistant strains.

Community-acquired pneumonia (CAP) is a common respiratory illness, frequently caused by Streptococcus pneumoniae. The prevalence of S. pneumoniae resistance to common antimicrobials has increased over recent years. A new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) has been developed, designed to combat infections caused by S. pneumoniae, including penicillin-resistant (PRSP, penicillin minimum inhibitory concentrations (MICs) >or=2mg/l) isolates, and those with elevated amoxicillin/clavulanic acid MICs, while maintaining coverage of beta-lactamase-producing pathogens. A pooled efficacy analysis of four randomized (1:1) and one non-comparative clinical trials of amoxicillin/clavulanate, 2000/125 mg, given twice daily, was conducted in adult patients with CAP. Comparator agents were conventional amoxicillin/clavulanate formulations. At follow-up (days 16-39), efficacy (eradication of the initial pathogen or clinical cure in patients for whom no repeat culture was performed) in patients with S. pneumoniae infection was 92.3% (274/297) for amoxicillin/clavulanate, 2000/125 mg and 85.2% (46/54) for comparators (P=0.11). Twenty-four of 25 PRSP-infected patients receiving amoxicillin/clavulanate, 2000/125 mg were treated successfully. Both amoxicillin/clavulanate, 2000/125 mg and comparators were well tolerated, with few patients withdrawing from the studies.

Adolescent↗
PubMed2005

Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria.

The development of resistance in the major pathogenic Gram-positive genera Staphylococcus and Streptococccus has led to the need for new agents that are able to overcome existing resistance mechanisms or that have novel mechanisms of action. There is currently a dearth of new agents that are active against resistant bacterial species. Agents that have recently been approved for clinical use include linezolid, the first oxazolidinone in clinical use, daptomycin, the first lipopeptide in clinical use, and telithromycin, a ketolide that is derived from clarithromycin. Agents currently in clinical development include tigecycline, a broad-spectrum intravenous tetracycline, ceftobiprole, a broad-spectrum cephalosporin that has activity against methicillin-resistant staphylococci, DX-619 and WCK-771, which are potent quinolones that have activity against quinolone-resistant staphylococci, oritavancin and dalbavancin, both of which are new glycopeptides, and iclaprim, which is a diaminopyrimidine. Additional agents that are in preclinical development against Gram-positive pathogens include quinoline-naphthyridine agents, which target novel DNA gyrase sites, other novel quinolones that have high potency, peptide deformylase inhibitors, and new lincosamide, oxazolidinone, lipopeptide and cephalosporin derivatives. Misuse of potent new agents will, however, result in the inevitable development of resistance to these agents; responsible use of potent new agents is required to prevent continuation of this vicious cycle.

Anti-Bacterial Agents↗
PubMed2005

Evaluation of the Scansystem method for detection of bacterially contaminated platelets.

BACKGROUND: Platelet (PLT) bacterial contamination occurs in approximately 1 in 2000 PLT units. The College of American Pathologists recommends and AABB requires procedures to detect PLT bacterial contamination. Although two methods, BacT/ALERT (bioMerieux) and Pall BDS (Pall Corporation), have FDA approval for quality control testing, additional methods are in development. One such method was evaluated, the Scansystem (Hemosystem), which has been developed for use on leukoreduced PLT components between 30 and 72 hours after collection. STUDY DESIGN AND METHODS: Leukoreduced, single-donor apheresis PLT units (LR-SDPs) were inoculated with 10 bacterial species (low and high inocula) associated with PLT contamination. Bacterial detection was compared with the Scansystem and BacT/ALERT. Testing was initiated (10 replicates performed) when LR-SDPs were experimentally inoculated with bacteria. The Scansystem was evaluated 30 hours later, the shortest manufacturer recommended time after PLT collection. RESULTS: All replicates were positive with the Scansystem at 30 hours and with the BacT/ALERT, at 9.3 to 24.0 hours after inoculation. The Scansystem detected bacteria in 83 of 200 replicates (42%) at the time of inoculation indicating a potential for earlier application. CONCLUSIONS: The Scansystem, used to test LR-SDPs 30 hours after bacterial inoculation, detected all 20 replicates with a sensitivity equal to the BacT/ALERT system. Based on use of Scansystem with LR-SDPs 30 hours after collection and the BacT/ALERT being inoculated 24 hours after collection and incubated for an additional 24 hours before being determined to be negative, the Scansystem will potentially provide results at an earlier time point (32 hr) than provided by the BacT/ALERT system (48 hr).

Bacteria↗
PubMed2005

Enhancement of a culture-based bacterial detection system (eBDS) for platelet products based on measurement of oxygen consumption.

BACKGROUND: An enhanced bacterial detection system (Pall eBDS) was developed that distinguishes itself from its predecessor (Pall BDS) by removal of the platelet (PLT)-retaining filter allowing for optimal bacterial transfer, modification of the culture tablet to reduce the confounding effects of respiring PLTs while enhancing bacterial growth, and facilitation of nutrients and gas exchange by agitating the sample pouch during incubation at 35 degrees C. The objective was to evaluate the performance of the new eBDS. STUDY DESIGN AND METHODS: Leukoreduced whole blood-derived PLT concentrates (LR-PCs) and LR single-donor PLTs (LR-SDPs) were inoculated with 1 to 15 colony-forming units (CFUs) of bacteria per mL in studies of each of 10 bacterial species associated with fatal transfusion-transmitted bacterial infection. Immediately after inoculation and after 24 hours of storage at 22 degrees C, samples of inoculated LR-PCs were aseptically transferred into the eBDS pouches. Pouches were then incubated for 24 hours at 35 degrees C with agitation and oxygen concentration was then measured. RESULTS: Median inoculation levels ranged from 5 to 13 CFUs per mL for each species studied. No significant differences in oxygen concentration were found when comparing LR-PCs with LR-SDPs. When sampling occurred from the PLTs 24 hours after inoculation, all 280 cases (24-33 replicates of each species) were detected as contaminated by the device (100% sensitivity). No false-positives were obtained with 713 uninoculated PLT units. CONCLUSIONS: The eBDS demonstrated improved detection sensitivity in the range of 1 to 15 CFUs per mL with no observed false-positives compared to the original BDS (detection range 100 to 500 CFUs/mL) with no false-positives.

Bacteria↗
PubMed2005

Relationship between surface accessibility for PpmA, PsaA, and PspA and antibody-mediated immunity to systemic infection by Streptococcus pneumoniae.

Antibodies to capsular polysaccharide (PS) are protective against systemic infection by Streptococcus pneumoniae, but the large number of pneumococcal serogroups and the age-related immunogenicity of pure PS limit the utility of PS-based vaccines. In contrast, cell wall-associated proteins from different capsular serotypes can be cross-reactive and immunogenic in all age groups. Therefore, we evaluated three pneumococcal proteins with respect to relative accessibility to antibody, in the context of intact pneumococci, and their ability to elicit protection against systemic infection by encapsulated S. pneumoniae. Sequences encoding pneumococcal surface adhesin A (PsaA), putative protease maturation protein A (PpmA), and the N-terminal region of pneumococcal surface protein A (PspA) from S. pneumoniae strain A66.1 were cloned and expressed in Escherichia coli. The presence of genes encoding PsaA, PpmA, and PspA in 11 clinical isolates was examined by PCR, and the expression of these proteins by each strain was examined by Western blotting with antisera raised to the respective recombinant proteins. We used flow cytometry to demonstrate that PspA was readily detectable on the surface of the pneumococcal strains analyzed, whereas PsaA and PpmA were not. Consistent with these observations, mice with passively or actively acquired antibodies to PspA or type 3 PS were equivalently protected from homologous systemic challenge with type 3 pneumococci, whereas mice with passively or actively acquired antibodies to PsaA or PpmA were not effectively protected. These experiments support the hypothesis that the extent of protection against systemic pneumococcal infection is influenced by target antigen accessibility to circulating host antibodies.

Adhesins, Bacterial↗
PubMed2005

Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles.

Acute bacterial respiratory tract infections cause a great deal of human morbidity and mortality. Treatment guidelines for these infections include macrolides, doxycycline, beta-lactams and beta-lactam/beta-lactamase inhibitor combinations such as amoxicillin/clavulanic acid to provide coverage for the common respiratory pathogens, including penicillin and macrolide nonsusceptible Streptococcus pneumoniae, as well as beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. In response to recent guidelines recommending higher dose amoxicillin to extend coverage to a higher percentage of S. pneumoniae, a new formulation of amoxicillin/clavulanic acid was developed. This formulation includes a higher amoxicillin dose, with part of the amoxicillin dose being in an extended release formulation, without increasing the clavulanate dose, for twice-daily oral treatment of these infections. Clinical studies of community-acquired pneumonia and acute rhinosinusitis have shown that the new formulation is well tolerated and highly efficacious, with clinical outcomes equivalent to comparators.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2005

Antimicrobial Agents And Resistance--Fifth International Symposium.

The Fifth International Symposium on Antimicrobial Agents and Resistance (ISAAR) provided a comprehensive review of current developments, with emphasis on new antimicrobial agents in development, novel vaccines, and public health concerns about respiratory virus pandemics and bioterrorism. This report describes new antimicrobial agents in clinical development or those recently approved, as well as progress in development of antibacterial agents with novel targets. Other agents under development include antimicrobial peptides, bactericidal permeability-increasing proteins, self-assembling peptide nanotubes, and antisense nucleotides.

Anti-Bacterial Agents↗
PubMed2004

Streptococcus pneumoniae: epidemiology and patterns of resistance.

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, otitis media, and sinusitis; it results in significant morbidity and mortality in patients with pneumonia and meningitis. The pneumococcus is a common colonizing bacterium in the respiratory tract; it is especially common in the respiratory tracts of children, where it is frequently exposed to antimicrobial agents. This exposure can lead to resistance. Penicillin nonsusceptibility is found in nearly 40% of strains causing disease in adults, although often these cases are treatable with appropriate dosing regimens of many oral and parenteral beta-lactam agents. In the United States resistance to macrolides is widespread--averaging approximately 28%--but geographically variable, ranging from 23% in the northwest to 30% in the northeast. Resistance to tetracyclines and trimethoprim-sulfamethoxazole are reported in approximately 20% and 35% of isolates, respectively, and resistance to multiple classes of agents is increasingly common. Amoxicillin, amoxicillin-clavulanate, respiratory fluoroquinolones, and clindamycin are currently the most effective agents for treatment of respiratory tract infections caused by S pneumoniae, with >90% of isolates in the United States being susceptible. Vancomycin is the only agent against which resistance has not emerged. Patient groups that are at increased risk for developing resistant pneumococcal infections have been identified and include patients with malignancies, human immunodeficiency virus infection, and sickle-cell disease. Judicious use of antimicrobials is the key to preventing the emergence of further resistance, particularly as few new classes of agents are likely to become available for clinical use in the short term.

Acute Disease↗
PubMed2004

Four antibiotic-resistant Streptococcus pneumoniae clones unrelated to the pneumococcal conjugate vaccine serotypes, including 2 new serotypes, causing acute otitis media in southern Israel.

This study examined the prevalence of antibiotic-resistant clones that belong to serotypes not included in the pneumococcal conjugate vaccines and that cause a significant percentage of acute otitis media (AOM) in children in southern Israel. During 1998-2001, 2467 pneumococcal isolates, obtained from middle-ear fluid of children <3 years old with AOM, were characterized by antimicrobial susceptibility testing, serotype testing, and pulsed-field gel electrophoresis. Non-vaccine type (NVT) strains constituted 477 (19%) of the 2467 isolates, of which 173 (36%) belonged to only 4 serotypes: 35B, 33F, 21, and 15B/C. For serotype 35B, 47 (96%) of 49 strains were penicillin nonsusceptible, and 93% constituted a single clone; for serotype 33F, 31 (82%) of 38 strains were penicillin nonsusceptible, and 95% constituted a single clone; for serotype 21, 38 (93%) of 41 strains were penicillin nonsusceptible, and 93% constituted a single clone; for serotype 15B/C, 22 (49%) of 45 strains were penicillin nonsusceptible, and 42% constituted a single clone. Two of these clones have not been described elsewhere. The high prevalence of NVT clones should increase the awareness of the potential for replacement of the vaccine strains with these NVT antibiotic-resistant strains.

Acute Disease↗
PubMed2004

Evolution of amoxicillin/clavulanate in the treatment of adults with acute bacterial rhinosinusitis and community-acquired pneumonia in response to antimicrobial-resistance patterns.

Current treatment guidelines for community-acquired respiratory tract infections no longer depend solely on the characteristics of the patient and the clinical syndrome, but on those of the offending pathogen, including presence and level of antimicrobial resistance. The most common respiratory tract pathogens known to cause acute bacterial rhinosinusitis (ABRS) and community-acquired pneumonia (CAP) include Streptococcus pneumoniae and Haemophilus influenzae. The prevalence of antimicrobial resistance, especially b-lactum and macrolide resistance, among S pneumoniae and H influenzae has increased dramatically during the past 2 decades, diminishing the activity of many older antimicrobials against resistant organisms. A pharmacokinetically enhanced formulation of amoxicillin/clavulanate has been developed to fulfill the need for an oral b-lactam antimicrobial that achieves a greater time that the serum drug concentration exceeds the minimum inhibitory concentration (T > MIC) of antimicrobials against pathogens than conventional formulations to improve activity against S pneumoniae with reduced susceptibility to penicillin. The b-lactamase inhibitor clavulanate allows for coverage of b-lactamase-producing pathogens, such as H influenzae and M catarrhalis. This article reviews the rationale for, and evolution of, oral amoxicillin clavulanate for ABRS and CAP

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2004

Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to 17 oral antimicrobial agents based on pharmacodynamic parameters: 1998-2001 U S Surveillance Study.

Pharmacokinetic/pharmacodynamic parameters were used to interpret susceptibility data for the oral agents tested in a clinically meaningful way. Among S pneumoniae isolates, >99% were susceptible to respiratory fluoroquinolones, 91.6% to amoxicillin, 92.1% to amoxicillin/clavulanic acid (95.2% at the extended-release formulation breakpoint), 90.6% to clindamycin, 80.4% to doxycycline, 71.0% to azithromycin, 72.3% to clarithromycin, 71.8% to cefprozil and cefdinir, 72.6% to cefuroxime axetil, 66.3% to cexime, 63.7% to trimethoprim/sulfamethoxazole, and 19.7% to cefaclor. Among H influenzae isolates, 28.6% were b-lactamase positive, but virtually all were susceptible to amoxicillin/clavulanic acid (98.3%, with 99.8% at the extended-release formulation breakpoint), cexime (100%), and uoroquinolones (99.8%), whereas 93.5% were susceptible to cefdinir, 82.8% to cefuroxime axetil, 78.1% to trimethoprim/sulfamethoxazole, 70.2% to amoxicillin, 25.1% to doxycycline, 23.2% to cefprozil, and 5% to cefaclor, azithromycin and clarithromycin. Most isolates of M catarrhalis were resistant to amoxicillin, cefaclor, cefprozil, and trimethoprim/sulfamethoxazole. Thus significant b-lactam and macrolide/azalide resistance in Streptococcus pneumoniae and b-lactamase production and trimethoprim/sulfamethoxazole resistance in untypeable Haemophilus influenzae are still present. The results of this study should therefore be applied to clinical practice based on the clinical presentation of the patient, the probability of the patient's having a bacterial rather than a viral infection, the natural history of the disease, the potential of pathogens to be susceptible to various oral antimicrobial agents, the potential for cross-resistance between agents with S pneumoniae, and the potential for pathogens to develop further resistance. Antibiotics should be used judiciously to maintain remaining activity and chosen carefully based on activity determined by pharmacokinetic/pharmacodynamic-based breakpoints to avoid these bacteria developing further resistance, particularly to fluoroquinolones.

Administration, Oral↗
PubMed2004

Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of respiratory tract infections.

The pharmacologic field that studies antimicrobial pharmacokinetics and pharmacodynamics (PK/PD) has had a major impact on the choice and dosing regimens used for many antibiotics especially those used in the treatment of respiratory tract infections. PK/PD parameters are particularly important in light of increasing antimicrobial resistance. Drug pharmacokinetic features, such as serum concentrations over time and area under the concentration-time curve, when integrated with minimum inhibitory concentration (MIC) values of antibiotics against pathogens, can predict the probability of bacterial eradication and clinical success. These pharmacokinetic and pharmacodynamic relationships also are important in preventing the selection and spread of resistant strains and have led to the description of the mutation prevention concentration, which is the lowest concentration of antimicrobial that prevents selection of resistant bacteria from high bacterial inocula. b-lactams are time-dependent agents without significant post-antibiotic effects, resulting in bacterial eradication when unbound serum concentrations exceed MICs of these agents against infecting pathogens for >40% to 50% of the dosing interval. Macrolides, azaolides, and lincosamides are time-dependent agents with prolonged post-antibiotic effects, and fluoroquinolones are concentration-dependent agents, resulting in both cases in bacterial eradication when unbound serum area-under-the-curve to MIC ratios exceed 25 to 30. These observations have led to changes in recommended antimicrobial dosing against respiratory pathogens and are used to assess the role of current agents, develop new formulations, and assess potency of new antimicrobials.

Anti-Bacterial Agents↗
PubMed2004

Mechanisms of resistance among respiratory tract pathogens.

Antimicrobial resistance among respiratory tract pathogens represents a significant health care threat. Identifying the antimicrobial agents that remain effective in the presence of resistance, and knowing why, requires a thorough understanding of the mechanisms of action of the various agents as well as the mechanisms of resistance demonstrated among respiratory tract pathogens. The primary goal of antimicrobial therapy is to eradicate the pathogen, via killing or inhibiting bacteria, from the site of infection; the defenses of the body are required for killing any remaining bacteria. Targeting a cellular process or function specific to bacteria and not to the host limits the toxicity to patients. Currently, there are four general cellular targets to which antimicrobials are targeted: cell wall formation and maintenance, protein synthesis, DNA replication, and folic acid metabolism. Resistance mechanisms among respiratory tract pathogens have been demonstrated for all four targets. In general, the mechanisms of resistance used by these pathogens fall into one of three categories: enzymatic inactivation of the antimicrobial, prevention of intracellular accumulation, and modification of the target site to which agents bind to exert an antimicrobial effect. Resistance to some agents can be overcome by modifying the dosage regimens (e.g., using high-dose therapy) or inhibiting the resistance mechanism (e.g., b-lactamase inhibitors), whereas other mechanisms of resistance can only be overcome by using an agent from a different class. Understanding the mechanisms of action of the various agents and the mechanisms of resistance used by respiratory tract pathogens can help clinicians identify the agents that will increase the likelihood of achieving optimal outcomes.

Anti-Bacterial Agents↗
PubMed2004

In vitro selection of resistance in haemophilus influenzae by 4 quinolones and 5 beta-lactams.

We tested abilities of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, amoxicillin, amoxicillin/clavulanate, cefixime, cefpodoxime, and cefdinir to select resistant mutants in 5 beta-lactamase positive and 5 beta-lactamase negative Haemophilus influenzae strains by single and multistep methodology. In multistep tests, amoxicillin, amoxicillin/clavulanate and cefpodoxime exposure did not cause >4-fold minimum inhibitory concentration (MIC) increase after 50 days. One mutant selected by cefdinir had one amino acid substitution (Gly490Glu) in PBP3 and became resistant to cefdinir. Cefixime exposure caused 8-fold MIC-increase in 1 strain with TEM but the mutant remained cefixime susceptible and had no alteration in PBP3 or TEM. Among 10 strains tested, ciprofloxacin, moxifloxacin, gatifloxacin, levofloxacin caused >4-fold MIC increase in 6, 6, 5, and 2 strain, respectively. Despite the increases in quinolone MICs, none of the mutants became resistant to quinolones by established criteria. Quinolone selected mutants had quindone resistance-determining region (QRDR) alterations in GyrA, GyrB, ParC, ParE. Four quinolone mutants had no QRDR alterations. Among beta-lactams cefdinir and cefixime selected one mutant each with higher MICs however amoxicillin, amoxicillin/clavulanate, and cefpodoxime exposure did not select resistant mutants.

Drug Resistance, Bacterial↗