Pharmacology: advantages and disadvantages.
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Review of the 4-quinolones.
Improvements in antimicrobial activity and pharmacokinetics have moved the 4-quinolones into the forefront of antibiotic research. The 4-quinolones are analogues of nalidixic acid, and there are presently at least six agents in this group under investigation in the United States. It is difficult to generalize their clinical usefulness, since these agents exhibit different pharmacokinetic profiles, antimicrobial activity (with varied minimum inhibitory concentrations among similar organisms), and dosage regimens. The 4-quinolones are potential therapeutic alternatives for infections caused by a variety of organisms. They include: Neisseria gonorrhoeae; Pseudomonas aeruginosa; Haemophilus influenzae; Staphylococcus aureus; common enteric pathogens (salmonella, shigella, campylobacter, etc); and intracellular bacteria (legionella, chlamydia, mycobacteria, etc). Clinical efficacy has been demonstrated in urinary tract infections, respiratory tract infections, and sexually transmitted diseases. Future studies will undoubtedly demonstrate effectiveness in numerous additional infectious processes. The purpose of this article is to compare the 4-quinolones in regards to pharmacokinetics and spectrum of activity and review the clinical studies involving these agents.
Anti-Bacterial Agents↗
Mercury pollution may contribute to antibiotic resistance.
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Adaptation, Physiological↗
Enhanced antitumor activity and selectivity of lactoferrin-derived peptides.
A number of peptide analogs derived from the N-terminal alpha-helical region of bovine lactoferrin (LFB 14-31), were designed in order to investigate how deviating numbers and positions of positively charged residues and numbers of aromatic residues affected their activity against prokaryotic, normal and transformed eukaryotic cells. Most of the LFB derivatives were highly active against both Escherichia coli and Staphylococcus aureus. The peptides were more active against the tumor cell lines MethA, HT-29 and MT-1 than normal eukaryotic cells. The peptides that were most active against the tumor cell lines had all cationic residues concentrated in one sector of the helical structure. These peptides were less selective against the tumor cell lines than against normal fibroblasts. Quantitative structure-activity relationship studies showed that certain structural parameters affected toxicity against the tumor cell lines more than against fibroblasts. Peptides encompassing these parameters were slightly less active against tumor cells, but gained significant selectivity.
Amino Acid Sequence↗
Possible mechanisms for the relative efficacies of ortho-phthalaldehyde and glutaraldehyde against glutaraldehyde-resistant Mycobacterium chelonae.
AIMS: This investigation compared glutaraldehyde (GTA)-sensitive and -resistant strains of Mycobacterium chelonae and examined the effects of pretreatment of GTA-sensitive and -resistant strains of Myco. chelonae with chemical agents that interfere with cell wall synthesis. METHODS AND RESULTS: When exposed to 2% (v/v) GTA at 25 degrees C, GTA-resistant strains of Myco. chelonae dried on to glass carriers were not inactivated to any significant extent. By contrast, GTA-sensitive strains of Myco. chelonae and a strain of Myco. terrae suffered a > 6 log reduction in viability in 5 min. However, ortho-phthalaldehyde (OPA; 0.5% w/v) achieved a corresponding inactivation against two GTA-resistant strains within 5-10 and 10-20 min, respectively. Electron microscopy, using a non-aldehyde fixation process and also negative staining, failed to detect any extensive changes in GTA-sensitive and -resistant cultures exposed to GTA or OPA. Thin-layer chromatography was unsuccessful in detecting differences between GTA-resistant and -sensitive strains of Myco. chelonae. However, pretreatment of GTA-resistant cells with mycobacterial cell wall synthesis inhibitors increased their subsequent susceptibility further to OPA but not to GTA. CONCLUSION: Ortho-phthalaldehyde is an effective new biocidal agent that, at its in-use concentration, is rapidly bactericidal to non-sporulating bacteria, including GTA-sensitive and -resistant mycobacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Pretreatment of GTA-resistant cells with mycobacterial cell wall synthesis inhibitors increased their subsequent susceptibility to OPA but not to GTA.
Antitubercular Agents↗
Prediction of growth of Bacillus megaterium spores as affected by gamma radiation dose and spore load.
AIMS: To provide data on the interaction of radiation dose (x1) and microbial contamination load (x2), as predictor variables, on the percentage of vials exhibiting growth of Bacillus megaterium spores (y). METHODS AND RESULTS: The influence of a wide range of spore loads (1-50 000 spores of B. megaterium vial-1) and gamma radiation doses (0.2-10 kGy) on the contaminated samples was determined. Each contamination load was studied by adding the specified number of spores to 100 vials containing nutrient broth and exposing them to various doses of gamma radiation. Curves representing the number of contaminated vials against the dose of radiation were sigmoidal in shape and the data showed an indirect relationship. Data were analysed by regression analysis which revealed a significant correlation (R2=0.85). The relationship among the tested variables is exponential and can be described by the following equation: y = 1 - (1 - e(0.0173x(1)))(x(2)) It was also estimated that, for each increase of 1 in the number of spores per vial, there is an increase of 1 in the number of contaminated vials. CONCLUSION: The two variables (x1 and x2) have great influence on the radiation sterilization efficiency and the proposed mathematical model is valid for the prediction of this efficiency. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of the present investigation can be of useful industrial application and can help to set acceptance and rejection limits for the production of materials vulnerable to microbial contamination.
Bacillus megaterium↗
Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA.
The macrolide antibiotic erythromycin and its 6-O-methyl derivative (clarithromycin) bind to bacterial ribosomes primarily through interactions with nucleotides in domains II and V of 23S rRNA. The domain II interaction occurs between nucleotide A752 and the macrolide 3-cladinose moiety. Removal of the cladinose, and substitution of a 3-keto group (forming the ketolide RU 56006), results in loss of the A752 interaction and an approximately 100-fold drop in drug binding affinity. Within domain V, the key determinant of drug binding is nucleotide A2058 and substitution of G at this position is the major cause of drug resistance in some clinical pathogens. The 2058G mutation disrupts the drug-domain V contact and leads to a further > 25 000-fold decrease in the binding of RU 56006. Drug binding to resistant ribosomes can be improved over 3000-fold by forming an alternative and more effective contact to A752 via alkyl-aryl groups linked to a carbamate at the drug 11/12 position (in the ketolide antibiotics HMR 3647 and HMR 3004). The data indicate that simultaneous drug interactions with domains II and V strengthen binding and that the domain II contact is of particular importance to achieve binding to the ribosomes of resistant pathogens in which the domain V interaction is perturbed.
Anti-Bacterial Agents↗
New functions for the ancient globin family: bacterial responses to nitric oxide and nitrosative stress.
Globin-like oxygen-binding proteins occur in bacteria, yeasts and other fungi, and protozoa. The simplest contain protohaem as sole prosthetic group, but show considerable variation in their similarity to the classical animal globins and plant globins. Flavohaemoglobins comprise a haem domain homologous to classical globins and a ferredoxin-NADP+ reductase (FNR)-like domain that converts the globin into an NAD(P)H-oxidizing protein with diverse reductase activities. In Escherichia coli, the prototype flavohaemoglobin (Hmp) is clearly involved in responses to nitric oxide (NO) and nitrosative stress: (i) the structural gene hmp is upregulated by NO and nitrosating agents; (ii) purified Hmp binds NO avidly, but also converts it to nitrate (aerobically) or nitrous oxide (anaerobically); (iii) hmp mutants are hypersensitive to NO and nitrosative stresses. Here, we review recent advances in E. coli and the growing number of microbes in which globins are known, draw particular attention to the essential chemistry of NO and related reactive species and their interactions with globins, and suggest that microbial globins have additional functions unrelated to 'NO' stresses.
Animals↗
In vitro activity of propyl gallate-azole drug combination against fluconazole- and itraconazole-resistant Candida albicans strains.
AIMS: The influence of an antioxidant, propyl gallate (PG), on the in vitro antifungal activity of itraconazole and fluconazole, was investigated to determine whether PG could increase the antifungal activity and reduce strain resistance. METHODS AND RESULTS: Susceptibility tests were performed against azole-resistant isolates of Candida albicans by the microbroth dilution method in the presence of PG at 400 microg ml-1. PG-triazole combination brought about a marked reduction of inhibitory azole concentration. In particular, the MIC90 for itraconazole and fluconazole dropped from 1 microg ml-1 to 0.125 microg ml-1 and from > 64 microg ml-1-8 microg ml-1, respectively. CONCLUSION: It is likely that more than one mechanism is involved in the above synergistic interaction, including effects of PG on ATP synthesis, thus reducing the ABC transporters activity, or an effect on the target of azole, i.e. the P-450 cytochrome. SIGNIFICANCE AND IMPACT OF THE STUDY: The PG-triazole combination may have a role in future topical antifungal strategies but other studies are warranted.
Antifungal Agents↗
Acne therapy: clinical pearls.
Several classes of medications successfully treat acne. Systemic and topical retinoids, systemic and topical antimicrobials, and systemic hormonal therapy are the major categories. Failure of therapy may result from drug interactions, antibiotic resistance, or coexisting conditions; therefore, a detailed history including these points should be used to decide which therapy is appropriate for each patient. Furthermore, one must consider the potential side effects of each treatment and make sure that (1) the benefits outweigh the risks of the treatment, (2) the side effects can be avoided by adding another agent, or (3) the side effects can be safely treated.
Acne Vulgaris↗
Trimethoprim-sulfamethoxazole.
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Administration, Oral↗
Oral azole drugs as systemic antifungal therapy.
The oral azole drugs--ketoconazole, fluconazole, and itraconazole--represent a major advance in systemic antifungal therapy. Among the three, fluconazole has the most attractive pharmacologic profile, including the capacity to produce high concentrations of active drug in cerebrospinal fluid and urine. Ketoconazole, the first oral azole to be introduced, is less well tolerated than either fluconazole or itraconazole and is associated with more clinically important toxic effects, including hepatitis and inhibition of steroid hormone synthesis. However, ketoconazole is less expensive than fluconazole and itraconazole--an especially important consideration for patients receiving long-term therapy. All three drugs are effective alternatives to amphotericin B and flucytosine as therapy for selected systemic mycoses. Ketoconazole and itraconazole are effective in patients with the chronic, indolent forms of the endemic mycoses, including blastomycosis, coccidioidomycosis, and histoplasmosis; itraconazole is also effective in patients with sporotrichosis. Fluconazole is useful in the common forms of fungal meningitis--namely, coccidioidal and cryptococcal meningitis. In addition, fluconazole is effective for selected patients with serious candida syndromes such as candidemia, and itraconazole is the most effective of the azoles for the treatment of aspergillosis.
Antifungal Agents↗
The chemotherapy of rodent malaria, XXVII. Studies on mefloquine (WR 142,490).
Mefloquine (WR 142,490) is a potent blood schizontocide active against drug-sensitive and drug-resistant lines of Plasmodium berghei. The ED50 and ED90 against the P. berghei N strain in albino mice are 1.5 and 3.8 mg/kg respectively. The highly chloroquine-resistant RC line is less sensitive and mefloquine is not fully effective at the maximum tolerated dose in the '4-day test'. Mefloquine has a similar mode of action to quinine both in vitro and (as demonstrated by the morphological changes it induces in P. berghei) in vivo, but is some 100 times more potent. Unlike quinine and WR 122,455 it appears not to interact with DNA. It has no causal prophylactic effect. Mixtures of mefloquine with pyrimethamine, sulphaphenazole or primaquine have an additive effect.
Animals↗
Remediable causes of failure of "appropriate" antimicrobial therapy.
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Abscess↗
Ciprofloxacin. Best use of this new broad-spectrum antibiotic.
Resistance to traditional antibiotics is an increasing problem. The introduction of ciprofloxacin (Cipro) has been welcome, because it is safe and effective against many organisms (including drug-resistant ones), can be taken orally, and is well tolerated. Dr Fass provides a complete description of the drug, including its use for infections of the urinary, respiratory, and gastrointestinal tracts; skin and skin structures; and bones and joints.
Bacterial Infections↗
Tuberculosis. The primary care physician's role in eradication.
The resurgence of tuberculosis in the United States presents a challenge for primary care physicians. The disease remains concentrated in the growing population of socioeconomically disadvantaged persons, immigrants from areas where drug resistance is common, certain racial groups, persons in extended-care facilities, alcohol and drug abusers, and persons infected with the human immunodeficiency virus. Because people in these groups are much less likely than others to seek regular medical care, it is difficult to identify and treat active tuberculosis in these populations. Contacts of patients with tuberculosis are equally difficult to identify. Active intervention by primary care physicians--including tuberculin screening, prophylactic therapy, treatment of active disease, and follow-up--is needed to help achieve the goal of eradicating tuberculosis.
Adolescent↗
Contribution of efflux to cefuroxime resistance in clinical isolates of Escherichia coli.
Retrospective data showed that resistance to cefuroxime among clinical blood culture isolates of Escherichia coli (2.67%) was more common than resistance to cefotaxime (0.59%) and ceftazidime (1.48%). 30 clinical isolates of E. coli with various degrees of resistance to cefuroxime were selected for the present studies. Antibiotic susceptibility to beta-lactam antibiotics was determined with the disc-diffusion method and for cefuroxime also with the E-test. The ability to grow in the presence of organic solvents was determined as a phenotypical measure of efflux. The organic solvent tolerance (OST) was graded on a scale from 1 to 5. Antibiotic susceptibility to cefuroxime, cefotaxime, ceftazidime and loracarbef was also determined in the presence of a known efflux pump inhibitor, MC-207,110. The strains that were organic solvent tolerant had significantly higher minimal inhibitory concentration (MIC) values for cefuroxime than the other E. coli strains (median 24 mg/l, range 4 to > 256 mgn/l vs median 4 mg/l, range 2-64 mg/l) and significantly lower cefuroxime zone diameters (p < 0.02). In the strains with most pronounced organic solvent tolerance, i.e. the cyclohexane-tolerant strains, the cefuroxime MIC values were decreased 2-fold (p < 0.03) and the zone diameters increased (p < 0.02) by the addition of an efflux pump inhibitor, MC-207,110. The findings supported the hypothesis that efflux contributes to cefuroxime resistance in E. coli.
Anti-Bacterial Agents↗
Some molecular properties of Citrobacter diversus beta-lactamases.
Citrobacter diversus ULA-27, a clinical isolate showing a broad resistance pattern towards both penicillins and cephalosporins, produces chromosome encoded beta-lactamases. However, the strain remains susceptible to some cephamycins, imipenem, ceftazidime and tetracyclines. Crude bacterial extracts analyzed by isoelectric focusing on polyacrylamide gels, revealed the presence of two main isoforms and some "satellite" bands focusing in the pH range 5.7-7.2. The isoform showing the pIs 6.8 and 6.2 were characterized as class "A" beta-lactamases (according to Ambler's classification) based on the rate of interaction of beta-iodopenicillanate and the amino acid sequence around the active site serine. The substrate specificity of the Citrobacter diversus beta-lactamases explains the resistance phenomenon of this bacterium to penicillins and cephalosporins.
Cephamycins↗