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Biomedical subjects

A R Tunkel

Publications and source records attributed to A R Tunkel.

At least 19 recordsLinked to original sources
PubMed1992

Azithromycin and clarithromycin: overview and comparison with erythromycin.

Azithromycin and clarithromycin are erythromycin analogues that have recently been approved by the FDA. These drugs inhibit protein synthesis in susceptible organisms by binding to the 50S ribosomal subunit. Alteration in this binding site confers simultaneous resistance to all macrolide antibiotics. Clarithromycin is several-fold more active in vitro than erythromycin against gram-positive organisms, while azithromycin is 2- to 4-fold less potent. Azithromycin has excellent in vitro activity against H influenzae (MIC90 0.5 microgram/ml), whereas clarithromycin, although less active against H influenzae (MIC90 4.0 micrograms/ml) by standard in vitro testing, is metabolized into an active compound with twice the in vitro activity of the parent drug. Both azithromycin and clarithromycin are equivalent to standard oral therapies against respiratory tract and soft tissue infections caused by susceptible organisms, including S aureus, S pneumoniae, S pyogenes, H influenzae, and M catarrhalis. Clarithromycin is more active in vitro against the atypical respiratory pathogens (e.g., Legionella), although insufficient in vivo data are available to demonstrate a clinical difference between azithromycin and clarithromycin. Superior pharmacodynamic properties separate the new macrolides from the prototype, erythromycin. Azithromycin has a large volume of distribution, and, although serum concentrations remain low, it concentrates readily within tissues, demonstrating a tissue half-life of approximately three days. These properties allow novel dosing schemes for azithromycin, because a five-day course will provide therapeutic tissue concentrations for at least ten days. Clarithromycin has a longer serum half-life and better tissue penetration than erythromycin, allowing twice-a-day dosing for most common infections. Azithromycin pharmacokinetics permit a five-day, single daily dose regimen for respiratory tract and soft tissue infections, and a single 1 g dose of azithromycin effectively treats C trachomatis genital infections; these more convenient dosing schedules improve patient compliance. Azithromycin and clarithromycin also are active against some unexpected pathogens (e.g., B burgdorferi, T gondii, M avium complex, and M leprae). Clarithromycin, thus far, appears the most active against atypical mycobacteria, giving new hope to what has become a difficult group of infections to treat. Gastrointestinal distress, a well known and major obstacle to patient compliance with erythromycin, is relatively uncommon with the new macrolides. Further clinical data and experiences may better define and expand the role of these new macrolides in the treatment of infectious diseases.

Azithromycin↗
PubMed1992

Candidal endophthalmitis after lithotripsy of renal calculi.

Candidal endophthalmitis is most commonly due to hematogenous seeding of the eye by Candida albicans. Although it is most often seen as a manifestation of disseminated candidiasis in patients who are seriously ill, other patients may have candidal endophthalmitis as the only evidence of fungal infection. We have presented a case of endophthalmitis due to C albicans in a patient who had bilateral renal calculi and who had received multiple antibiotics and extracorporeal shock wave lithotripsy.

Candidiasis↗
PubMed1992

Enterobacter endocarditis.

Endocarditis due to Enterobacter species is very rare. We recently cared for a patient who developed E. cloacae endocarditis following mitral valve replacement with a porcine heterograft, and was successfully treated with antibiotic therapy alone. A review of the literature disclosed an additional 17 well-described cases of enterobacter endocarditis. Two-thirds of the patients had underlying cardiac disease. The mitral valve was most frequently involved (10/16 cases) with 4 of the patients having concomitant aortic valve involvement. The overall mortality rate was 44.4%. Antibiotic therapy of enterobacter endocarditis should consist of the combination of a beta-lactam antibiotic and an aminoglycoside with careful monitoring of blood cultures to assure the adequacy of therapy. Resistance of enterobacter to previously susceptible antibiotics may occur during therapy due to induction of a chromosomally-mediated beta-lactamase, necessitating a change in antimicrobial therapy. Valvular surgery is indicated for patients failing medical management.

Endocarditis, Bacterial↗
PubMed1991

Blood-brain barrier alterations in bacterial meningitis: development of an in vitro model and observations on the effects of lipopolysaccharide.

To further examine the effects of purified Haemophilus influenzae type b lipopolysaccharide (LPS) on blood-brain barrier permeability, we have developed an in vitro model of the BBB. Microvascular endothelial cells were isolated from rat cerebral cortices by enzymatic digestion, dextran centrifugation, and separation on percoll gradients. The cells were determined to be endothelial in origin by positive fluorescent staining for Factor VIII-related antigen and the ability to take up acetylated low density lipoproteins, and their cerebral origin by the formation of junctional complexes in vitro. Cells were seeded onto semipermeable polycarbonate filters and permeability assessed by measuring traversal of radioactive albumin across the monolayer. Treatment of the cells with LPS at concentrations of 1.0 microgram/ml and 0.1 microgram/ml for 4 h led to statistically significant increases in albumin permeability of 4.6% (P = 0.001) and 5.6% (P less than 0.001), respectively, without evidence of cell death as assessed by release of lactate dehydrogenase into the media. These results indicate that LPS significantly increases albumin permeability across a monolayer of cerebral microvascular endothelial cells in the absence of host inflammatory cells. Future studies on the effects of LPS on intracellular regulation will determine the mechanisms responsible for these alterations.

Albumins↗
PubMed1991

Ofloxacin.

Ofloxacin is a newly licensed fluoroquinolone with an antimicrobial spectrum similar to ciprofloxacin. Compared with ciprofloxacin, the MIC90 values for ofloxacin are lower for S aureus, C trachomatis, and Ureaplasma urealyticum, but somewhat higher against gram-negative bacteria (especially P aeruginosa). Ofloxacin has favorable pharmacokinetics with almost 100% bioavailability; peak serum concentrations obtained one to two hours following oral dosing are higher than those achieved with ciprofloxacin. The oral bioavailability is decreased by the coadministration of antacids, but ofloxacin does not alter serum theophylline concentrations. Ofloxacin has demonstrated bacteriologic and clinical efficacy in the treatment of urinary tract infections, respiratory tract infections, prostatitis, and skin and soft tissue infections caused by susceptible organisms, although there are little data to recommend ofloxacin over ciprofloxacin for these indications. Ofloxacin should not be used alone to treat anaerobic or mixed aerobic/anaerobic infections, and a penicillin or cephalosporin is preferred for known or suspected streptococcal or pneumococcal infection. Ofloxacin is the only quinolone currently approved for the treatment of uncomplicated gonorrhea. It also is effective therapy for nongonococcal urethritis, although the tetracyclines are much less expensive. Ofloxacin has a good safety profile, but, as with other fluoroquinolones, it should not be used in children or in pregnant or nursing women. Further comparative trials may broaden the range of infections that can be treated with ofloxacin.

Clinical Trials as Topic↗
PubMed1990

Bacterial meningitis: recent advances in pathophysiology and treatment.

PURPOSE: To review recent advances in the understanding of pathogenic and pathophysiologic mechanisms underlying bacterial meningitis that may lead to the development of adjunctive strategies for treating this disorder. DATA IDENTIFICATION: Studies published from 1975 to 1989 were identified using Index Medicus and by reviewing the bibliographies of identified articles. STUDY SELECTION: We reviewed the experimental and human studies evaluating pathogenesis, pathophysiology, and antimicrobial treatment of bacterial meningitis, as well as those reviews that have contributed to our understanding of meningitis. DATA EXTRACTION: We evaluated the data on the pathogenesis, pathophysiology, and treatment of bacterial meningitis and considered in depth the information from animal models that may have potentially important applications in the treatment of human disease. RESULTS OF DATA SYNTHESIS: Penicillin and ampicillin remain the drugs of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third-generation cephalosporins have revolutionized the treatment of gram-negative bacillary meningitis; one such agent, ceftazidime, is also useful for treating Pseudomonas aeruginosa meningitis. Modification of subarachnoid space inflammation by anti-inflammatory agents may lessen many of the pathophysiologic consequences of bacterial meningitis. A recent study of adjunctive dexamethasone therapy in infants and children with bacterial meningitis showed that the incidence of long-term neurologic sequelae was lower in the corticosteroid group. CONCLUSION: Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease. Additional studies using monoclonal antibodies against specific virulence factors and investigations into the production of inflammatory cytokines in response to bacterial cell products may lead to additional treatments that decrease the high morbidity and mortality in patients with bacterial meningitis.

Animals↗
PubMed1990

Development of 5q- myelodysplasia in a patient with sarcoidosis.

Sarcoidosis has been observed in association with numerous blood dyscrasias including lymphoma, leukemia, and multiple myeloma. This report describes a patient with sarcoidosis and a refractory anemia whose bone marrow karyotype showed deletion of the long arm of chromosome 5, consistent with a myelodysplastic syndrome. Concurrent sarcoidosis and myelodysplasia may relate to the continued availability of cytokines as a consequence of repeated macrophage, T-cell, and B-cell interactions, with evolution to the 5q- abnormality. This association may merit specific attention in the future approach to the diagnostic evaluation in certain patients with sarcoidosis.

Aged↗
PubMed1990

Aztreonam.

Aztreonam, the first commercially available monobactam, has a wide range of activity against aerobic gram-negative bacilli. It can be administered two to three hours daily because its half-life is 1.6 to 2 hours. Excellent blood and tissue concentrations are attained. The MIC of aztreonam against most Enterobacteriaceae is less than or equal to 2 micrograms/ml and against P aeruginosa less than or equal to 16 micrograms g/ml. Aztreonam has been used in a wide array of infections of the urinary tract and respiratory tract, blood, intra-abdominal and gynecologic infections and infections of the skin, bones and joints. As empiric therapy, aztreonam is usually combined with another antimicrobial agent active against anaerobes and/or aerobic gram-positive cocci until culture results are available. One exception is empiric therapy for gram-negative urinary tract infections in which aztreonam can be used initially as monotherapy against susceptible gram-negative pathogens. In general, the efficacy of aztreonam is equal or superior to that of the aminoglycosides. Adverse reactions to aztreonam are unusual, and it as been shown to be a poor hapten, permitting its administration to patients with proven allergy to the penicillins and cephalosporins. Aztreonam is a useful addition to the available antibiotics for treatment of gram-negative infections.

Aztreonam↗
PubMed1990

Pathogenesis and pathophysiology of meningitis.

Advances in the understanding of the pathogenesis and pathophysiology of meningitis have occurred primarily through the use of experimental animal models. These models have proven to be particularly valuable in experimental bacterial meningitis, focusing on the bacterial virulence factors responsible for the initiation of infections, CNS invasion, and induction of SAS inflammation. Recent studies have examined the formation of host inflammatory cytokines in response to these virulence factors. These cytokines may be responsible for many of the pathophysiologic consequences of bacterial meningitis (eg. increased BBB permeability, cerebral edema, and increased intracranial pressure). Meningitis due to C. neoformans occurs most commonly in patients with defects in cell-mediated immunity (eg, AIDS), and the depletion of T helper cells in AIDS patients may allow unrestricted cryptococcal growth. Viral meningitis is an illness of low prevalence when compared with the overall occurrence of viral infections at other sites. CNS infection usually occurs by means of traversal across barriers that normally exclude viral invasion of the CNS, primarily through hematogenous dissemination from initial sites of infection. These advances in the pathogenesis and pathophysiology of bacterial, fungal, and viral meningitis may lead to the development of innovative treatment strategies for these disorders.

Animals↗
PubMed1990

Bacterial meningitis in adults.

Bacterial meningitis continues to be an important cause of morbidity and mortality despite the availability of effective bactericidal antibiotics. Penicillin or ampicillin remains the drug of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third generation cephalosporins have revolutionized the treatment of gram-negative meningitis. Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease.

Adult↗
PubMed1990

Meningitis in the neurosurgical patient.

In the patient with a basilar skull fracture and CSF leak, the risk of meningitis is greatly increased. The diagnosis of both leak and infection can be obscured by the patient's other injuries, and requires aggressive investigation of symptoms that suggest infection. Although the diagnosis is made with CSF cultures, when clinically suspected, treatment should begin after appropriate cultures have been obtained. Treatment should be directed against the most likely organisms, Streptococcus pneumoniae, Haemophilus influenzae, and the other organisms common to the upper respiratory tract. There are no good indications for prophylactic antibiotic usage in patients with known CSF leaks. The patient with a shunt or other CNS prosthetic device may have various manifestations of infection, depending on the type of device and its termination. Frank meningitis or ventriculitis is not always present. Diagnosis requires direct culturing of the shunt milieu, with the most frequent isolates being staphylococcal species and gram-negative enteric bacilli. The most effective therapy, for both eradication of the infection and minimization of the duration and morbidity of therapy, involves removal of the infected shunt, external drainage during parenteral antibiotic therapy, and complete replacement of hardware at the time of internalization. The postsurgical patient will not develop meningitis very frequently, but like the posttrauma patient, concurrent factors can make the diagnosis difficult. Differentiating infectious from chemical meningitis must often be initially based on CSF cell counts and chemistries alone. Treatment to cover the most likely organism, staphylococcal species and respiratory flora, should be started before the culture results are finalized.(ABSTRACT TRUNCATED AT 250 WORDS)

Central Nervous System↗
PubMed1989

Applications of therapy in animal models to bacterial infection in human disease.

Animal models have proven to be invaluable in bridging the gap between in vitro susceptibility testing of an antibiotic and anticipating results obtained in clinical studies. Variables such as antibiotic concentration, inoculum of organism, and pharmacokinetic parameters of the drug can be carefully controlled to provide information about the principles of treating infectious diseases as well as an evaluation of specific antimicrobial agents. End points of treatment can be precisely defined (that is, CSF sterility in meningitis, vegetation counts of bacteria in endocarditis) to allow a quantitative evaluation of a new antibiotic. However, it is important to realize that there may be differences in disease pathogenesis and antibiotic pharmacokinetics between experimental infections in animal models and infections in humans. Therefore, results in animal models should be interpreted with caution and compared with results obtained with antimicrobial regimens in clinical studies. Perhaps one of the most useful features of animal models is suggesting which antimicrobials would not be expected to be of therapeutic benefit in man.

Animals↗