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Biomedical subjects

W A Craig

Publications and source records attributed to W A Craig.

At least 55 records · Page 3Linked to original sources
PubMed1995

Parenteral versus oral antibiotic therapy.

The past decade has seen the increased use of oral therapy for a variety of serious infections that were previously treated exclusively by parenteral therapy. A variety of clinical trials in patients with pneumonia, urinary tract infections, skin and soft tissue infections, osteomyelitis, and bacteremia have demonstrated equal efficacy between oral and parenteral therapy. Much of this success is due to the availability of new oral agents, such as the fluoroquinolones and cephalosporins, with enhanced activity against gram-negative bacilli and improved pharmacokinetics. Oral therapy with certain of these drugs provides the same therapeutic serum levels required for efficacy that are obtained with parenteral therapy, that is, a 24-hour AUC/MIC above 125 for fluoroquinolones and levels constantly above the MIC for cephalosporins and other beta-lactams. Oral therapy can also reduce the costs of antimicrobial therapy.

Administration, Oral↗
PubMed1995

Once-daily versus multiple-daily dosing of aminoglycosides.

The pharmacodynamic characteristics of isepamicin and other aminoglycosides, both in terms of efficacy and toxicity, explain why once-daily administration of these agents should be the optimal dosing regimen. Isepamicin, as with other aminoglycosides, exhibits concentration-dependent bactericidal activity and produces prolonged post-antibiotic effects against susceptible organisms. High concentrations of these drugs would be expected to produce more rapid and extensive bacterial killing than lower levels. Furthermore, the post-antibiotic effect would protect against bacterial regrowth when serum and tissue concentrations fall below inhibitory levels. In animal models, the magnitude of the peak serum concentration or the area under the concentration-time curve, are the important determinants of efficacy for isepamicin and the other aminoglycosides. Isepamicin also exhibits the "first-exposure effect", i.e. initial exposure of bacteria to isepamicin down-regulates subsequent uptake of the drug. During this period of down-regulation, bacteria exhibit decreased killing and shorter post-antibiotic effects. Since the first-exposure effect lasts for several hours, once-daily administration of the aminoglycosides allows for this effect to dissipate completely between doses. High peak concentrations, greater than 8-10 times the minimum inhibitory concentration (MIC), will also decrease the emergence of resistant strains. With regard to toxicity, one of the first steps in the uptake of aminoglycosides into sites of toxicity is their binding to the brush borders of renal cells and to the cochlea and vestibular membranes. Binding to these membranes demonstrates saturable kinetics. As a result, uptake of the aminoglycosides is more efficient with low sustained concentrations than with high intermittent levels. Once-daily dosing of aminoglycosides has consistently been less toxic than more frequent dosing in animals. In clinical studies, once-daily dosing of aminoglycosides compared to two-or three-times daily administration has generally exhibited similar efficacy and toxicity. However, a few studies has shown greater efficacy or lower toxicity with once-daily dosing of aminoglycosides. Once-daily dosing of the aminoglycosides has the potential to enhance efficacy, reduce toxicity, and lower administration costs for this drug class.

Animals↗
PubMed1994

The postantibiotic effect of antifungal agents against common pathogenic yeasts.

A total of ten strains of Candida spp. and Cryptococcus neoformans were examined for the presence of the postantibiotic effect (PAE) after 0.5-2 h exposure to amphotericin B, 5-fluorocytosine, miconazole and ketoconazole. Significant PAEs were observed for amphotericin B and 5-fluorocytosine, but none for the imidazoles. The duration of the PAEs of amphotericin B ranged from 0.5-10.4 h for the Candida spp. and 2.8-10.6 h for the cryptococcos, while 5-fluorocytosine induced PAEs from 0.8-7.4 h and 2.4-5.4 h, respectively. Even though no PAEs were demonstrated for the imidazoles, the growth rate was persistently reduced by continuous exposure to concentrations as low as 1/1000 of the MIC of these agents. These findings may have implications for dosing antifungal agents in systemic yeast infections.

Amphotericin B↗
PubMed1994

Decreased bactericidal activity during the period of the postantibiotic effect.

Standard and clinical strains of Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae were subjected to continuous exposure to beta-lactams and aminoglycosides during the postantibiotic effect phase induced by rifampicin or erythromycin (for S. aureus). A significant inhibition of bactericidal activity by these agents during the PAE period was observed. The degree of inhibition was dependent both on the class of antimicrobial agent (beta-lactams > aminoglycosides) and the microorganism (Gram-negative bacilli > S. aureus).

Ampicillin↗
PubMed1994

A protective role for T lymphocytes in asbestos-induced pulmonary inflammation and collagen deposition.

Several lines of evidence have suggested that specific (i.e., lymphocyte) immunity plays a role in chemical-induced pulmonary diseases, including asbestosis. To evaluate the influence of cell-mediated immunity in pulmonary inflammation and fibrosis evoked by asbestos fibers, we compared the effects of asbestos in immunodeficient mice (Balb/c nu/nu and severe combined immunodeficient [C3H-SCID]), immunologically normal mice of the same genetic background, and immunodeficient mice reconstituted with syngeneic T lymphocytes. Increases in lavaged cell numbers occurred in asbestos-treated immunodeficient mice compared with asbestos-treated immunocompetent or immunodeficient mice that received T lymphocytes. Differential analysis of the collected cells in treated mice demonstrated a predominantly neutrophilic infiltrate that correlated with increased levels of leukotriene B4 and prostaglandin E2. There were no significant differences between immunocompetent and athymic asbestos-treated mice in bronchoalveolar lavaged total protein. However, asbestos-treated SCID mice revealed a significant increase in protein content and lactate dehydrogenase activity compared with asbestos-treated normal mice, which did not occur in T lymphocyte-reconstituted SCID mice. Fibronectin levels were elevated in asbestos-exposed athymic mice when compared with air-exposed athymic mice or asbestos-exposed immunocompetent mice. Both asbestos-treated athymic and SCID mice showed a significant increase in total lung hydroxyproline when compared with asbestos-treated immunocompetent mice. Lung hydroxyproline was also reduced in asbestos-exposed SCID mice after T lymphocyte reconstitution and, conversely, increased in T cell-depleted Balb/c mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Pharmacokinetic contributions to postantibiotic effects. Focus on aminoglycosides.

The postantibiotic effect (PAE) refers to a period of time after complete removal of an antimicrobial during which there is no growth of the target organism. The PAE appears to be a feature of most antimicrobial agents and has been documented with a variety of common bacterial pathogens. Various factors influence the presence or duration of the PAE including the type of organism, type of antimicrobial, concentration of antimicrobial, duration of antimicrobial exposure, antimicrobial combinations, and inoculum and medium used. beta-Lactams demonstrate a PAE against Gram-positive cocci, but produce only a short PAE with Gram-negative bacilli. Antimicrobial agents that inhibit RNA or protein synthesis have a PAE against Gram-positive cocci and Gram-negative bacilli. In vivo studies of aminoglycosides suggest that area under the plasma concentration-time curve is the pharmacokinetic parameter that best correlates with clinical efficacy. This is thought to be due to the concentration-dependent killing and PAE possessed by these antimicrobials. Animal and human studies have reported that once-daily administration of aminoglycoside is as effective as, or more effective than, and possibly less toxic than traditional multiple daily administration.

Aminoglycosides↗
PubMed1993

Outpatient parenteral antibiotic therapy. Management of serious infections. Part I: Medical, socioeconomic, and legal issues. Selecting the antibiotic.

Variations in antibiotic pharmacokinetics and pharmacodynamics allow therapy to be readily adapted to the outpatient setting. Factors to be taken into account when designing an outpatient parenteral regimen include minimal inhibitory and bactericidal concentrations, post-antibiotic effect, half-life, protein binding, drug stability, IM versus i.v. administration, and continuous versus intermittent infusion.

Ambulatory Care↗
PubMed1993

Post-antibiotic effects in experimental infection models: relationship to in-vitro phenomena and to treatment of infections in man.

Persistent suppression of bacterial growth, called the post-antibiotic effect (PAE), has been studied in six different animal infection models. Prolonged in-vivo PAEs are observed for all antimicrobials with staphylococci and for imipenem and inhibitors of protein and nucleic acid synthesis with streptococci and Gram-negative bacilli. Penicillins and cephalosporins produce short or no in-vivo PAEs with these latter organisms. The presence of neutrophils prolongs the in-vivo PAEs found with aminoglycosides and quinolones. Simulation of human pharmacokinetics also enhances the duration of in-vivo PAE for aminoglycosides. In-vivo PAEs tend to be longer than those observed in vitro. The in-vitro PAE for penicillin with streptococci has been observed in vivo in only one of four experimental infection models. The presence of a prolonged in-vivo PAE can allow wider dosing intervals. The primary clinical application of the in-vivo PAE has been with once-daily dosing of aminoglycosides.

Animals↗
PubMed1993

The post-antibiotic effect of antimicrobial combinations in a neutropenic murine thigh infection model.

The post-antibiotic effect (PAE) may allow for more widely spaced dosing of antibiotics than is currently employed without loss of efficacy. Antimicrobial combinations are widely used in clinical medicine. However, dosing schedules are usually based on pharmacological profiles of the drugs used alone. Previously we have demonstrated significant prolongation of the PAE induced by antimicrobial combinations in vitro as compared to PAEs induced by the agents alone. We examined this issue further in vivo in a neutropenic mouse thigh infection model, by exposing Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae to several antimicrobials, either singly or in combination. The PAE in vivo was defined as the difference in time needed for the organisms in the treated animals to grow 1 log10 as compared with controls after serum drug concentrations had fallen below the MIC. Drug concentrations exceeded the MIC for 1.2-3.2 h, but bactericidal activity occurred mainly during the first hour. When the agents were used singly a negative PAE was produced by ceftazidime against P. aeruginosa, a PAE of approximately 0 h by imipenem against E. coli and K. pneumoniae, a PAE of 2-4 h by cefazolin against S. aureus, gentamicin against E. coli and K. pneumoniae, and imipenem and tobramycin against P. aeruginosa, and a PAE of 6-7 h by gentamicin against S. aureus and rifampicin against P. aeruginosa. The beta-lactam/aminoglycoside combinations when used against S. aureus and P. aeruginosa prolonged the PAE by 1.0-3.3 h, compared with the longer of the individual drug PAEs, but no prolongation was observed against E. coli and K. pneumoniae. Ceftazidime reduced the PAE when used with tobramycin against P. aeruginosa. The long PAE of rifampicin against P. aeruginosa was 'carried over' to the combination, thus prolonging the growth suppression achieved by imipenem and tobramycin alone or in combination by 5.5-8.0 h. This effect on the PAE was additive only, and synergy was not observed. In conclusion, a potentially significant prolongation of the PAE by combination of drugs was observed in vivo, but only if both (or all) agents induced a PAE when used alone. The impact of this observation needs to be examined further in studies involving multiple and different dosing regimens in an infection model.

Animals↗
PubMed1993

Pharmacokinetics and ex vivo susceptibility of cefpodoxime proxetil in patients receiving continuous ambulatory peritoneal dialysis.

Pharmacokinetics of cefpodoxime, an extended-spectrum cephalosporin, were determined for eight noninfected patients on continuous ambulatory peritoneal dialysis (CAPD) and eight healthy volunteers. Subjects were matched for sex, age (+/- 6 years), and body weight (+/- 10 kg, except for one pair) and received a single 200-mg (cefpodoxime equivalents) oral dose of the prodrug cefpodoxime proxetil in an open-label, paired-design fashion. Dialysate (CAPD group only), plasma, and urine samples were collected and assayed for cefpodoxime by a microbiologic method. In addition, mean bactericidal titers of the effluent dialysate against selected bacterial strains often associated with CAPD-related peritonitis were determined at 6 and 24 h after the dose. There was a significant difference (P < 0.05) in all pharmacokinetic parameters between healthy and CAPD subjects, except for lag time to absorption. The mean peak plasma cefpodoxime concentration of 1.88 +/- 0.6 micrograms/ml occurred at 2.44 +/- 0.5 h for healthy volunteers, while the peak concentration of 3.25 +/- 1.4 micrograms/ml occurred at 12.0 +/- 4.2 h for patients on CAPD. The average elimination half-life in CAPD patients was approximately 12 times greater than that seen in healthy volunteers. Peritoneal dialysis had a minimal effect on cefpodoxime clearance. In healthy volunteers, 24.2% +/- 13% of the dose was recovered from the urine, in contrast to only 5.59% +/- 6.9% for CAPD patients. The mean bactericidal titers for all CAPD patients, at 6 and 24 h, were mostly less than 1:2 and did not exceed 1:4 for any of the isolates. Because of the decreased renal clearance and negligible dialysate clearance of cefpodoxime, and delayed drug absorption, the dosage interval for cefpodoxime proxetil may need to be extended in CAPD patients.

Administration, Oral↗
PubMed1993

The pharmacokinetics of cefpirome--rationale for a twelve-hour dosing regimen.

Cefpirome is a new broad-spectrum beta-lactam antibiotic that exhibits minimal concentration dependent killing and produces prolonged postantibiotic effects only with Staphylococcus aureus. These pharmacodynamic characteristics suggest that the goal of optimal dosing regimens for cefpirome is to provide serum levels above the MIC of infecting pathogens for most of the dosing interval. Cefpirome has a half-life of 2.0 hours in normal volunteers that increases to 3.1 to 4.4 hours in elderly patients. Serum concentrations following 0.5, 1.0 and 2.0 grams of cefpirome are above the MIC of common pathogens for more than half of the dosing interval. For many of the Enterobacteriaceae, serum concentrations are above the MIC for over 12 hours. The drug distributes primarily into extracellular fluid and does provide potentially therapeutic concentrations in cerebrospinal fluid (CSF). The drug is eliminated primarily by the kidney and requires dosage modification when the creatinine clearance is below 50 ml/min. The half-life of the drug is not significantly altered in patients with cystic fibrosis and hepatic dysfunction. The integration of the drug's pharmacokinetic and pharmacodynamic characteristics support the use of a 12-hour dosing interval for the treatment of serious infection.

Adult↗
PubMed1992

Pentamidine blocks the pathophysiologic effects of endotoxemia through inhibition of cytokine release.

Pentamidine isethionate, an antiprotozoal agent with therapeutic value against Pneumocystis carinii pneumonia, has been used for over 30 years without a precise understanding of its mechanism of pharmacologic action. We have previously reported that pentamidine has the capacity to inhibit the release of cytokines from macrophages through a post-translational processing event. The present studies were undertaken to assess the ability of pentamidine to modulate the detrimental effects of murine endotoxemia, a disease with a pathophysiology clearly linked to host-produced cytokines. Under conditions where normal B6C3F1 mice succumbed to the lethal effects of endotoxin, mice pretreated with pentamidine were significantly protected from both mortality and loss of thermoregulatory control. The EC50 for protection from mortality by pentamidine was approximately 11.4 mg/kg. These observations correlated with decreased serum levels of tumor necrosis factor (TNF) and interleukin 6. Inhibition of cytokines was not manifested as part of a generalized inhibition of protein synthesis as demonstrated by the lack of significant modulation of serum albumin in pentamidine-treated animals. In addition to decreased serum concentrations of cytokines, lungs isolated from mice treated with both pentamidine and endotoxin exhibited a decreased release of TNF compared to lungs isolated from mice treated with vehicle and endotoxin. The lower levels of TNF released from lung tissue in pentamidine-treated mice correlated with a lesser degree of alveolar deterioration than was observed in vehicle-treated mice. These data indicate that following endotoxin administration, pentamidine has a protective and antiinflammatory role both systemically and in the lung and suggest that inhibition of inflammatory cytokines may be one mechanism operable in the therapeutic activity of the drug against P carinii pneumonia.

Animals↗
PubMed1992

Pneumocystis carinii induction of tumor necrosis factor-alpha by alveolar macrophages: modulation by pentamidine isethionate.

Pneumocystis carinii, and the inflammatory response it provokes, together contribute to irreversible lung damage in immunocompromised patients. P. carinii cysts were found to be capable of inducing tumor necrosis factor-alpha (TNF) release from alveolar macrophages in a concentration-dependent manner. At physiologically achievable concentrations, pentamidine isethionate (pentamidine) substantially reduces such production. Pretreatment of alveolar macrophages (AM phi) with interferon-gamma (IFN-gamma) synergizes with P. carinii to produce increased levels of TNF, a condition which pentamidine was also able to antagonize. Pentamidine treatment did not interfere with the phagocytic ability of AM phi. Considering clinical reduction of TNF could lessen P. carinii pneumonia (PCP) induced inflammation, the efficacy of pentamidine in the treatment of PCP may be partially associated with its ability to inhibit the release of inflammatory mediators such as TNF.

Animals↗
PubMed1992

Modulation of tumor necrosis factor release from alveolar macrophages treated with pentamidine isethionate.

Alveolar macrophages in AIDS patients have a marked increase in tumor necrosis factor release in active Pneumocystis carinii pneumonia. We have demonstrated that pentamidine, an aromatic diamidine currently used to treat AIDS-related P. carinii pneumonia, is an effective inhibitor of cellular tumor necrosis factor release from lipopolysaccharide-stimulated rat alveolar macrophages at concentrations greater than 10(-8) M. Inhibition of release is not dependent upon the continued presence of pentamidine in the culture medium during the release phase. In addition, this blockage occurs at neither the transcriptional level as determined by Northern blot analysis nor the translational level as determined by Western blot analysis. Timed addition studies suggest that pentamidine is targeting relatively early events following lipopolysaccharide administration. Pentamidine appears to alter early lipopolysaccharide-induced cellular processes associated with the release of tumor necrosis factor from macrophages.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Two dimensional gel electrophoresis of cellular and secreted proteins from rat alveolar macrophages after lipopolysaccharide treatment.

Two dimensional gel electrophoresis (2-D PAGE) and automated image analysis were used to study the effects of bacterial lipopolysaccharide (LPS) activation on secreted and cellular rat alveolar macrophage proteins. Primary alveolar macrophages were cultured and exposed to LPS in the presence of [35S]-methionine for 24 h. Image analysis of 2-D PAGE revealed that LPS treatment primarily modulated the proportions of several alveolar macrophage cellular proteins versus control in addition to limited protein induction and repression. The differential effect of LPS was more pronounced on secreted proteins where qualitative and quantitative differences from control cells were found. Immunoblots of secreted proteins with anti-tumor necrosis factor alpha (TNF alpha) and anti-interleukin-1 alpha(IL-1 alpha) antibodies identified these monokines from protein fluorographic patterns. IL-1 alpha was detected as a single polypeptide of 17 kD at pI = 5. Use of recombinant TNF alpha and monoclonal and polyclonal antibodies for immunodetection revealed the 17 kD form of TNF alpha as well as higher molecular weight species at 18 kD and 22 kD. Thus, analysis of radiolabeled rat macrophages treated with LPS reveals quantitative modulation of several cellular proteins as well as a distinctive pattern of secreted proteins which contain multiple monokine forms resolvable by 2-D PAGE.

Animals↗
PubMed1991

Pentamidine: an inhibitor of interleukin-1 that acts via a post-translational event.

Pharmacologic inhibition of cytokines, particularly interleukin-1 (IL-1), potentially has numerous therapeutic applications in inflammatory diseases. We demonstrate that pentamidine, an aromatic diamidine currently used to treat Pneumocystis carinii pneumonia, is a specific and effective inhibitor of cellular IL-1 release from macrophages, and we have shown that this blockage occurs at neither the transcriptional nor the translational level. Pentamidine induced inhibition of IL-1 occurs via an alteration in the post-translational modification of the protein, altering the intracellular and/or membrane cleavage of the 31-kDa pro-IL-1 to the 17-kDa secreted form. In addition, pentamidine exhibited less broad immunosuppressive actions when compared to a corticosteroid, the classical therapeutics utilized for inhibition of cytokine production.

Animals↗
PubMed1991

Factors affecting duration of in-vivo postantibiotic effect for aminoglycosides against gram-negative bacilli.

A murine thigh-infection model was used to determine the effect of certain host- and drug-related factors on the duration of the in-vivo postantibiotic effect (PAE) observed with aminoglycosides against Gram-negative bacilli. The role of neutrophils (PMNs), pharmacokinetics and variation among species and strains were studied. PAEs were quantitated after a single injection of gentamicin or amikacin. PAEs were several hours longer in normal mice than in neutropenic mice, in mice with renal impairment than in those with normal renal function, and with strains of Klebsiella pneumoniae than with strains of Escherichia coli, Serratia marcescens and Enterobacter cloacae. Among the 15 strains of Enterobacteriaceae studied, the duration of the in-vivo PAE did not correlate with MIC, duration of in-vitro PAE, and extent of in-vivo bactericidal activity. We conclude that prolonged PAEs are consistently observed in vivo with aminoglycosides against Enterobacteriaceae, and that this duration is enhanced in the presence of PMNs and by pharmacokinetic properties simulating those observed in humans.

Amikacin↗