PubMed Health⌕ Search

Biomedical subjects

William A Craig

Publications and source records attributed to William A Craig.

13 recordsLinked to original sources
PubMed2006

Tigecycline: a critical analysis.

Tigecycline (GAR-936) is the first glycylcycline antibiotic to be approved by the US Food and Drug Administration (FDA). The drug overcomes the 2 major resistance mechansisms of tetracycline: drug-specific efflux pump acquisition and ribosomal protection. Tigecycline is active against many gram-positive and -negative organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate and -resistant enterococci, and extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. It is also active against many anaerobic bacteria, as well as atypical pathogens, including rapidly growing, nontuberculous mycobacteria. Tigecycline is concentrated in cells and is eliminated primarily via biliary excretion. Diminished renal function does not significantly alter its systemic clearance. Furthermore, tigecycline does not interfere with common cytochrome P450 enzymes, making pharmacokinetic drug interactions uncommon. It provides parenteral therapy for complicated skin/skin-structure and intra-abdominal infections. The only prominent adverse effects are associated with tolerability, most notably nausea and vomiting. Tigecycline will be most useful as empirical therapy for polymicrobial infections, especially in cases in which deep tissue penetration is needed or in which multidrug-resistant pathogens are suspected.

Anti-Bacterial Agents↗
PubMed2006

Outcomes evaluation of patients with ESBL- and non-ESBL-producing Escherichia coli and Klebsiella species as defined by CLSI reference methods: report from the SENTRY Antimicrobial Surveillance Program.

As extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae continue to emerge worldwide, selection of empiric treatment modalities is an increasing challenge. Data describing the clinical outcomes associated with different treatment regimens have been limited. Using data from centers with confirmed ESBL- and non-ESBL-producing Escherichia coli and Klebsiella species isolates in North America, Latin America, and Europe, potential risk factors for the occurrence of invasive ESBL- and non-ESBL-producing Enterobacteriaceae infections and factors associated with clinical outcome were evaluated. Of the 175 cases considered evaluable, 77% were ESBL-producing organisms. Underlying comorbidities and potential risk factors were generally similar between ESBL and non-ESBL cases with a statistically greater proportion of ESBL cases requiring gastrostomy or jejunostomy tubes, ventilatory assistance, or care in the intensive care unit before culture (P<or=0.008). Among ESBL cases, carbapenem monotherapy and combination therapy were often selected for treatment (32.6% and 13.3%, respectively). Among non-ESBL cases, fluoroquinolones and beta-lactam/beta-lactamase inhibitor combination agents accounted for the highest proportion of treatment regimens (25.0% and 22.5%, respectively), whereas cephalosporin monotherapy and combination therapy were each used as treatment for 10% of cases. Clinical success was similar between patients with ESBL and non-ESBL-producing isolates (83% and 80%, respectively). Although infections arising from E. coli and Klebsiella species are associated with significant mortality, ESBL production alone did not appear to be an independent risk factor for treatment failure.

Adolescent↗
PubMed2005

Inhibition of mutation and combating the evolution of antibiotic resistance.

The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.

Animals↗
PubMed2005

Reevaluation of Enterobacteriaceae MIC/disk diffusion zone diameter regression scattergrams for 9 beta-lactams: adjustments of breakpoints for strains producing extended spectrum beta-lactamases.

Validity of the current susceptibility breakpoint criteria for 9 beta-lactam antimicrobials and performance of proposed alternative breakpoints to improve prediction of clinical outcomes were analyzed by testing a contemporary collection of 350 Enterobacteriaceae, enriched for an overrepresentative collection of 70 (20.0%) strains producing extended-spectrum beta-lactamases (ESBLs). The majority of the strains were isolated from bloodstream infections (83.7% of the entire collection and 85.7% of the ESBL subset). The 9 beta-lactam antimicrobials analyzed were aztreonam, cefepime, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftriaxone, ceftizoxime, and cefuroxime. Reference broth microdilution MIC results were compared with those zone diameters obtained by the standardized disk diffusion test. The correlation coefficient (r) was acceptable for all antimicrobials, ranging from 0.87 (cefotetan) to 0.97 (aztreonam, cefotaxime, and ceftazidime). Using the current susceptible breakpoint criteria for Enterobacteriaceae, the intermethod categorical agreement ranged from 90.6% (cefotaxime) to 98.0% (ceftazidime). Very major (false-susceptible by disk test) and major errors (false-resistant) were nil (0.0%) for 6 of the 9 beta-lactams. Minor error rates ranged from only 0.9% (cefotetan) to 9.4% (cefotaxime). The proposed MIC breakpoint criteria (generally lower) adjusted to levels to accurately detect ESBL-producing strains and better predict clinical outcomes, also had acceptable intermethod concordance ranging from 90.6% (cefotetan) to 100.0% (ceftazidime). Remarkably, an improvement in the intermethod categorical agreement ranging from +1.7% to +8.3% was observed for 7 of the 9 antimicrobials, including the ESBL index or screening compounds (aztreonam, ceftazidime, cefotaxime, and ceftriaxone). No change in the breakpoint criteria, with removal of the intermediate category was tentatively proposed for cefoxitin and cefuroxime, resulting in an increase of the serious intermethod errors (very major and major), but the absolute intermethod agreement remained highly acceptable at 90.6% to 93.4%. Although the current breakpoint criteria remain acceptable in minimizing intermethod discords, the alternative susceptible breakpoint criteria proposed by combining pharmacokinetic/pharmacodynamic (PK/PD), microbiology MIC population analyses, and clinical success parameters possess improved intermethod agreement for the ESBL screening drugs and 5 other broad-spectrum beta-lactam compounds. The Clinical Laboratory Standards Institute (formerly, the National Committee for Clinical Laboratory Standards) should consider these changes to facilitate the detection of all Enterobacteriaceae with low PK/PD target attainment rates, therefore having the potential for suboptimal responses with usual therapeutic dosing.

Anti-Bacterial Agents↗
PubMed2004

The importance of bactericidal drugs: future directions in infectious disease.

BACKGROUND: Although a considerable amount of research has gone into the study of the role of bactericidal versus bacteriostatic antimicrobial agents in the treatment of different infectious diseases, there is no accepted standard of practice. METHODS: A panel of infectious diseases specialists reviewed the available literature to try to define specific recommendations for clinical practice. RESULTS: In infections of the central nervous system, the rapidity with which the organism is killed may be an important determinant, because of the serious damage that may occur during these clinical situations. The failure of bacteriostatic antibiotics to adequately treat endocarditis is well documented, both in human studies and in animal models. CONCLUSION: The bulk of the evidence supports the concept that, in treating endocarditis and meningitis, it is important to use antibacterial agents with in vitro bactericidal activity. This conclusion is based on both human and animal data. The data to support bactericidal drugs' superiority to bacteriostatic drugs do not exist for most other clinical situations, and animal models do not support this concept in some situations. Clinicians should be aware that drugs that are bacteriostatic for one organism may in fact be bactericidal for another organism or another strain of the same organism.

Animals↗
PubMed2004

Overview of newer antimicrobial formulations for overcoming pneumococcal resistance.

The pharmacokinetic (PK) and pharmacodynamic (PD) profile of an antimicrobial agent provides important information that can be used to maximize bacteriologic and clinical efficacy, minimize selective pressure for the development of antimicrobial resistance, and determine an optimal dosing regimen. Judicious selection of an antimicrobial based on local susceptibility data and PK and PD parameters is imperative in this era of increasing resistance among Streptococcus pneumoniae, a leading cause of community-acquired respiratory tract infections. The beta-lactam antimicrobials display time-dependent bacterial killing with minimal to no persistent effects. Ketolides and fluoroquinolones display concentration-dependent bacterial killing, and tetracyclines and macrolides display time-dependent killing. All have prolonged persistent effects (e.g., postantibiotic effect) that retard or prevent bacterial regrowth when free drug levels fall below the minimum inhibitory concentration (MIC). New high-dose and/or extended-release formulations of traditional antimicrobials have been added to the current armamentarium for treatment of community-acquired respiratory tract infections. These formulations include amoxicillin-clavulanate potassium powder for oral suspension 90/6.4 mg/kg per day divided every 12 hours (Augmentin ES-600; GlaxoSmithKline, Research Triangle Park, NC), amoxicillin-clavulanate potassium extended-release tablets 2 x 1,000 mg/62.5 mg every 12 hours (Augmentin XR; GlaxoSmithKline), clarithromycin extended-release tablets 2 x 500 mg once daily (Biaxin XL; Abbott Laboratories, North Chicago, IL), and cefaclor extended-release tablets 375 mg or 500 mg every 12 hours (Ceclor CD; Eli Lilly Pharmaceuticals, Indianapolis, IN). Of these agents, only amoxicillin-clavulanate potassium powder for oral suspension and amoxicillin-clavulanate potassium extended-release tablets were designed to treat infections caused by penicillin-resistant pneumococci (penicillin MIC < or =2 microg/mL). Extended-release clarithromycin does not provide higher daily doses than its immediate-release counterpart; rather, it allows for once-daily dosing of this agent because of its slower absorption following oral administration. Extended-release cefaclor is considered clinically equivalent to 250 mg of immediate-release cefaclor pulvules administered 3 times daily; it cannot be used interchangeably with 500 mg 3-times-daily dosages of other cefaclor formulations. Thus, despite providing a similar or higher total daily dose than its immediate-release counterpart, extended-release cefaclor is indicated only for the treatment of patients with mild to moderate infections caused by susceptible strains of certain organisms.

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↗
PubMed2003

Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid.

Time above MIC for free drug concentrations is the important PK-PD parameter correlating with the efficacy of beta-lactam antibiotics. The duration of time plasma concentrations needed to exceed the MIC is relatively similar for most organisms except staphylococci. Neutrophils contribute very little to the overall activity of beta-lactams. The appearance of increasing antimicrobial resistance can challenge the efficacy of these drugs when concentrations do not exceed the MIC for 40% to 50% of the dosing interval. Time above MIC with oral amoxicillin and amoxicillin-clavulanate can be enhanced with high-dose formulations. Time above MIC with parenteral preparations can be enhanced by longer intravenous infusions or even continuous infusion. The 24-hour AUC-MIC is probably the important PK-PD parameter correlating with the efficacy of vancomycin and teicoplanin. It clearly is the important parameter for the efficacy of linezolid. Usual doses of these drugs generally provide adequate plasma concentrations to treat effectively infections in which plasma concentrations are predictive of tissue concentrations. Penetration of these drugs into respiratory secretions, such as ELF, is enhanced for linezolid and reduced for vancomycin. This may give linezolid an advantage over vancomycin in certain respiratory infections.

Acetamides↗
PubMed2003

mecA-blaZ corepressors in clinical Staphylococcus aureus isolates.

The presence and nucleotide sequences of the two mecA repressors, mecI and blaI, were assessed in 73 clinical Staphylococcus aureus isolates. Isolates with mecI mutations were grouped into unique clonal types based on their spa nucleotide repeat patterns. Forty-three of the 45 (96%) isolates with mutant mecI or with a deletion of mecI contained blaI, while blaI was present in only 21 of 28 (78%) isolates with wild-type mecI (P < 0.05). Among 22 additional isolates that did not contain blaI, all had wild-type mecI sequences. We conclude that oxacillin-resistant S. aureus must have at least one of the two functional mecA regulators.

Bacterial Proteins↗
PubMed2003

Quantitation of mecA transcription in oxacillin-resistant Staphylococcus aureus clinical isolates.

The transcription of mecA, the gene required for oxacillin resistance in staphylococci, was quantified in a collection of 65 geographically and genetically diverse clinical and 8 defined laboratory Staphylococcus aureus isolates. mecA transcription was measured by real-time reverse transcription-PCR, confirmed by Northern blot analysis, and correlated with the presence and DNA sequence of the two mecA repressors, mecI and blaI. Isolates were first examined that contained mecI and/or blaI with wild-type sequence. BlaI provided significantly more repression of mecA transcription than did MecI, unrelated to blaI genetic location. Both together repressed mecA better than either one alone. In clinical isolates containing only wild-type mecI, mecA transcription repression was 10- to 25-fold less effective than that seen in previously studied constructs derived from strain N315. There was a difference in the mecI ribosomal binding site (RBS) between the clinical isolates (GGAA) and N315 (GGAG). The GGAA RBS was associated with 5.5- to 7.3-fold less mecA repression than GGAG in isogenic constructs. The values generated for wild-type repressors were compared to those in 26 isolates containing mecI mutations. mecA transcription appeared to be repressed only by BlaI in isolates with mecI nonsense and frameshift mutations. In contrast, mecI repression seemed to be partially or fully retained in many of the isolates with mecI and one isolate with blaI missense mutations, providing structure-function correlates with the site and type of mutation. We conclude that mecA repressor activity is highly variable in clinical S. aureus isolates due to mecI mutations, RBS polymorphisms, and unidentified genomic adaptations.

Bacterial Proteins↗
PubMed2002

A comparison of cefditoren pivoxil and amoxicillin/ clavulanate in the treatment of community-acquired pneumonia: a multicenter, prospective, randomized, investigator-blinded, parallel-group study.

BACKGROUND: Cefditoren pivoxil is a broad-spectrum cephalosporin that is approved for the treatment of pharyngitis, acute exacerbations of chronic bronchitis, and skin and skin-structure infections. OBJECTIVE: This study was conducted to examine the efficacy and tolerability of cefditoren in the treatment of community-acquired pneumonia (CAP). Amoxicillin/clavulanate was chosen as a comparator because of its established efficacy and general acceptance as a standard of care in CAP. METHODS: This multicenter, prospective, randomized, investigator-blinded, parallel-group trial compared oral cefditoren 200 and 400 mg BID with oral amoxicillin/clavulanate 875/125 mg BID for 14 days in adult outpatients with CAP. RESULTS: Eight hundred two patients (404 men, 398 women; mean age, 50 years; age range, 12-93 years) with CAP were enrolled. Comparable clinical cure rates were observed among evaluable patients in all treatment groups at both the posttreatment and follow-up visits: 88.0% (125/142) for cefditoren 200 mg, 89.9% (143/159) for cefditoren 400 mg, and 90.3% (130/144) for amoxicillin/clavulanate at the posttreatment visit, and 86.5% (128/148), 86.8% (138/159), and 87.8% (129/147) for the respective groups at the follow-up visit. Of 82 Streptococcus pneumoniae strains isolated before treatment, 22 (26.8%) had reduced susceptibility to penicillin, 12 (14.6%) of them penicillin resistant. Overall eradication rates at the posttreatment visit for pathogens isolated from microbiologically evaluable patients were 84.0%, 88.6%, and 82.6% for cefditoren 200 mg, cefditoren 400 mg, and amoxicillin/clavulanate, respectively. In the respective treatment groups, 80.6%, 88.6%, and 88.0% of Haemophilus influenzae strains and 95.0%, 96.2%, and 89.5% of S pneumoniae strains were eradicated. The rates of resolution of or improvement in clinical signs and symptoms were comparable between treatment groups. The treatment regimens were well tolerated, with 4.9%, 3.0%, and 5.2% of patients in the respective treatment groups requiring discontinuation of study drug due to an adverse event. CONCLUSIONS: In this study in adult outpatients with CAP, both doses of cefditoren demonstrated equivalence to amoxicillin/clavulanate based on rates of clinical and microbiologic cure. All 3 regimens were effective in resolving or improving the clinical signs and symptoms of CAP. Both cefditoren and amoxicillin/ clavulanate were well tolerated.

Adolescent↗