Antagonism of the antibacterial action of some penicillins by other penicillins and cephalosporins.

There are many examples of two penicillins acting synergistically, usually by one competitively inhibiting beta-lactamase, thus protecting the other from inactivation. There are few reports on penicillins antagonizing each other. Eight strains of three genera (Proteus, Escherichia, Pseudomonas) isolated at Boston City Hospital or Institut Pasteur, Paris, showed antagonism of carbenicillin or ampicillin by cephaloridine, cloxacillin, or 6-aminopenicillanic acid. Broth dilution tests showed that with seven of the eight strains the minimum inhibiting concentration (MIC) of the more active antibiotic was increased by 800-6,400% by low concentrations (often one-tenth the MIC) of the antagonist, whereas higher concentrations of "antagonist" were not as antagonistic, This suggested that two or more receptor sites of action for penicillins were present; the antagonist thus blocks the antibacterial action at the more sensitive site but acts additively with the antagonized antibiotic at the less sensitive site. The possibility that the mechanism of antagonism was induction of inactivating enzymes (beta-lactamase, penicillin acylase) was studied in two strains(one Escherichia coli and one Proteus rettgeri), and two antagonists were studied in detail. With E. coli cephaloridine was a poorer inducer of beta-lactamase than were the antagonized antibiotic and 6-aminopenicillanic acid. From these organisms, the good inducers of a beta-lactamase that acted on benzylpenicillin did not induce enzymes that inactivated carbenicillin. Thus, the mechanism of antagonism was not due to beta-lactamase induction.

Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections.

The distinction between bactericidal and bacteriostatic agents appears to be clear according to the in vitro definition, but this only applies under strict laboratory conditions and is inconsistent for a particular agent against all bacteria. The distinction is more arbitrary when agents are categorized in clinical situations. The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems. Bacteriostatic agents (e.g., chloramphenicol, clindamycin, and linezolid) have been effectively used for treatment of endocarditis, meningitis, and osteomyelitis--indications that are often considered to require bactericidal activity. Although bacteriostatic/bactericidal data may provide valuable information on the potential action of antibacterial agents in vitro, it is necessary to combine this information with pharmacokinetic and pharmacodynamic data to provide more meaningful prediction of efficacy in vivo. The ultimate guide to treatment of any infection must be clinical outcome.

Erythromycin and clindamycin absorption and elimination in pregnant women.

Thirty-nine pregnant women admitted for therapeutic abortions during early or mid pregnancy were given erythromycin estolate, erythromycin base, or clindamycin hydrochloride orally in single or multiple doses. Peak serum levels of clindamycin were 3.4 to 9.0 mug/ml following a single dose of 450 mg, whereas peak serum levels of erythromycin were 0.29 to 7.2 mug/ml following 500 mg in a single dose. The individual variability of serum concentrations of erythromycin was greater than that reported in normal men and nonpregnant women, whereas the serum levels of clindamycin were rather uniform, and similar to what has been reported in nonpregnant individuals. Following multiple doses of each antibiotic, high serum levels were obtained in virtually all subjects, and urine levels were also higher. Following single doses the mean urinary recovery was 2% for erythromycin and 16.8% for clindamycin.

The assay of antimicrobial compounds.

The earliest antibiotic assays evolved from attempts to qualitatively demonstrate antimicrobial activity in biological fluids. The need for rapid, selective, accurate assays of antibiotics present in blood arises from the fact that many potentially toxic, commonly used antibiotics have narrow toxic: therapeutic ratios; no single dosage regimen can insure adequate therapeutic levels that are not toxic, because of individual variation in excretory patterns and in susceptibility of infecting bacteria. This need for rapid quantitative information about the serum antibiotic concentration can be met by agar diffusion assays, enzymatic assay, or radioimmunoassay. Other assay techniques less commonly used to meet this clinical need are both dilution assay, turbidimetric assay, potentiometric assay, and chemical assay. Details for one agar diffusion assay are presented, as well as principles and references for other techniques.

Urinary tract infections in the female.

Special problems peculiar to urinary tract infections (UTIs) in the female include higher frequency than in males, recurrent infections, restrictions on antibiotic use during pregnancy, and the "urethral syndrome." Current concepts in the management of UTI include recognition of significant infection with total count of less than 100,000 organisms per milliliter; awareness that untreated UTI usually does not lead to progressive renal failure; importance of differentiating between upper and lower UTI; use of antibody coating of bacterial for distinguishing upper from lower UTI; evidence that 1-day (or single-dose) therapy may be adequate for cystitis, whereas pyelonephritis usually requires treatment beyond 2 weeks; evidence of effective prophylaxis; and indications that Chlamydia may be responsible for some cases of urethral syndrome.

Therapeutic and epidemiologic recommendations to reduce the spread of type-I beta-lactamase resistance.

The objectives of this United States Consensus Panel meeting were to evaluate the effectiveness of current surveillance systems for the detection of bacterial resistance as well as to formulate recommendations that can assist hospitals in determining actions that should be taken when a resistance problem is detected. These recommendations may be particularly helpful in controlling the emergence and spread of type-I beta-lactamase resistance. Numerous case reports of antimicrobial resistance among Enterobacter species, Pseudomonas aeruginosa, and other Gram-negative nosocomial pathogens known to produce type-I beta-lactamases have appeared in the literature since the introduction of the newer "third-generation" cephalosporins. The widespread use of these newer antimicrobial agents, often selected as standard therapy for serious hospital-acquired infections, has been associated with a corresponding increase in resistance to them. The failure of hospitalwide surveillance methods to describe the scope of this problem, especially among the most critically ill patients, may have resulted in a false sense of security among some infectious disease specialists and clinicians prescribing these antimicrobials as empiric therapy. High-level resistance in individual hospital units may be masked in hospitalwide antibiograms. A variety of conclusions and recommendations were formulated based on the collective experiences of the Consensus Panel members. Microbiology laboratories must make it a high priority to identify markers that will assist in rapidly identifying resistant organisms. Cooperative efforts are needed among users of commercial and automated microbiology test instruments to standardize results and to improve quality control, thereby making the data more directly comparable between laboratories.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian hypo- and hyper-amplitude-tension (CHAT) associated with putative pheochromocytoma and 12-hourly phenoxybenzamine treatment.

A 26-year-old white woman had an ablated sino-atrial node and ventricular pacemaker as an unusual feature of a pheochromocytoma-compatible history. Her status quo included, on three occasions, elevated 24-hour urinary epinephrine and metanephrine excretion. She monitored her blood pressure (BP) and heart rate (HR) at 15- to 60-minute intervals over several days, with interruptions, before and after the institution of 10 mg phenoxybenzamine per os every 12 hours (between 7:30 and 8:00 and between 19:30 and 20:00), with continued monitoring over several months. Her data were summarized for consecutive 3-day intervals by sphygmochron. Circadian parameters and original data are compared with gender- and age-specified reference values, yielding also non-parametric endpoints, such as the percentage time elevation, the extent of excess, and the timing of excess, that all can be acceptable for some days but unacceptable for other days. In her broader time structure, or chronome, cosinor analyses revealed a prominent and statistically significant circadian rhythm in BP and HR before and during the 12-hourly therapy. The 12-hour component of BP was more prominent during therapy than prior to it. A statistically significant decreasing trend occurred before therapy, and recurred during treatment. Chronomically interpreted monitoring revealed: 1) the persistence of a statistically significant circadian rhythm during 12-hourly phenoxybenzamine treatment; 2) days-long changes in BP MESOR, the duration of which could not be previously determined based on spotchecks; 3) changes in the circadian amplitude of BP, which can be either very small or very large, compatible with the diagnosis of intermittent circadian hyper-amplitude-tension (CHAT); and 4) a very wide range of BP and HR values, so that occasional (casual) measurements fail to convey the dynamics that may underlie this infrequently found clinical condition of an elevated catecholamine excretion compatible with a pheochromocytoma. All findings support the need for long-term monitoring of BP and HR that may account for controversy in earlier publications.

Achievements and problems from the view of a physician.

Penicillin made possible the cure of many common, and also the most serious, infections, such as meningococcal meningitis and bacterial endocarditis, often with few or no sequelae. Endocarditis had been invariably fatal. Semisynthetic penicillins added new dimensions of convenience of administration and a broader spectrum in the presence of many beta-lactamases. A quantum step forward was permitted by the derivatives of cephalosporin C. Specific clinical advances were (1) the opportunity to use these in some penicillin-allergic patients, (2) activity against wider range of Gram-negative bacilli, (3) activity against Bacteroides fragilis (cefoxitin), (4) more complete renal excretion after oral cephalosporins than with oral penicillins, and (5) delayed renal excretion. Major remaining problems limiting beta-lactam use are (1) allergy, (2) resistant organisms, (3) relatively poor entry into the cerebrospinal fluid (especially of cephalosporins, (4) some nephrotoxicity, (5) local irritation of veins and tissues during administration, and (6) poor results in patients with agranulocytosis.

Tissue penetration of antibiotics; an overview.

The recent development of several techniques has made it possible to more adequately study the tissue penetration of various antibiotics. The major technical advances making this possible have been various assay systems permitting measurement of antibiotics in very small amounts of fluid or tissue. In addition, various tissue cages and the use of skin blisters has been a popular means for testing antibiotic penetration into extra-cellular fluid.

Current status of treatment of pneumonia.

Proper treatment of pneumonia is dependent upon a correct diagnosis. Pneumonia may be due to infectious agents, allergic phenomena, or chemical causes. Treatment regimens are outlined for the various types of pneumonia--pneumococcal, staphylococcal, fungal, and pneumonia due to gram-negative and anaerobic gram-negative bacilli, to Blastomyces dermatitidis, and to the parasite Pneumocystis carinii. In discussing current concepts of treatment, several well-known methods are emphasized, as well as newer developments, knowledge of which is essential for optimal treatment of pneumonia.

Mechanisms of resistance to beta-lactam antibiotics in strains of Staphylococcus aureus.

There are three major mechanisms of resistance of Staphylococcus aureus to beta-lactam antibiotics: enzyme mediated (penicillinase or beta-lactamase) by which the antibiotic is inactivated; intrinsic, which is not due to drug inactivation, and accounts for methicillin-resistance; and tolerance, in which there is a dissociation of the inhibitory and killing actions of beta-lactam antibiotics. In enzyme-mediated resistance, there are at least three different staphylococcal beta-lactamases, which probably account for differences in the inoculum effect with different cephalosporins. The intrinsic resistance is associated with differences in the affinity of beta-lactams for penicillin-binding proteins, but intrinsic resistance is probably more complex, because the pH of the medium, chelating agents, visible light, and temperature also effect its expression. Tolerance is clearly due to decreased autolytic enzyme activity (reflecting persistence of an enzyme inhibitor) of those tolerant organisms that need 32 (or more) times as much antibiotic for a bactericidal effect as for simple inhibition.