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The Clinton administration has proposed major changes in the health care delivery system in an effort to control runaway medical costs and to provide greater access to quality health care. One of the issues being examined is whether costs might be decreased by converting more drugs from prescription to over-the-counter (OTC) status. The pharmaceutical industry has made overtures to add oral antimicrobials to the list of drugs available for purchase without prescription. The current application for OTC status for acyclovir may be the first of many moves in this direction. In this commentary, we consider whether such changes would be wise.

Glycine betaine is a powerful osmoprotectant molecule present in the inner medulla of the kidney and excreted into urine. It may be responsible for the ability of Escherichia coli to grow in hypertonic urine. Also, strains of E. coli that cause urinary tract infections may be more salt-tolerant than strains from other sites. To explore these questions, 301 isolates from blood, urine, or stool and 12 representative enteric strains were examined. Tolerance varied from 0.1 to 0.7 M NaCl (median, 0.5) in minimal medium. There were no significant differences in salt tolerance by site of isolation. A salt-sensitive enteric strain that responded poorly to glycine betaine and mutant strains lacking the ability to synthesize or transport glycine betaine did not grow well in hypertonic urine. Accumulation of glycine betaine appears to be a mechanism by which E. coli can adapt to external osmotic forces and grow in hypertonic urine.

The Antimicrobial Agents Committee of the Infectious Diseases Society of America (IDSA) was established in 1985. It was charged with the responsibility of developing initiatives that might help to improve the use of antimicrobial agents and delay the emergence of resistant microorganisms. The Committee and the Council have identified several areas that are considered to be of highest priority. The Committee endorses the Society's Statement on Ethics and has made additional recommendations for consideration by the membership. A series of position papers are being developed. These papers will include the following: Standards for Improving Use of Antibiotics in Hospitals; Clinical Trials of AntiInfective Drugs Before and After Licensure; Consensus Statements for Clinical Guidelines for Therapy and Prophylaxis; and Control of the Emergence of Antibiotic-Resistant Microorganisms. A contract proposal has been submitted to the U.S. Food and Drug Administration (FDA) to revise the current "Guidelines for Clinical Evaluation of Anti-Infective Drugs" and to develop new guidelines for evaluating antimicrobial agents for specific conditions. This report to the membership describes the progress

Growth of Escherichia coli was inhibited in a defined minimal medium by high concentrations of electrolytes and sugars in direct relation to their osmotic strength. Choline, betaine, proline, and human urine increased resistance to these substances. In contrast, the toxic effect of urea was not altered directly by betaine or urine, but was reduced in the presence of other osmolytes. The osmolyte protective effect was augmented by betaine. The osmoprotective effect of betaine and urine was confirmed with 40 strains of enteric bacteria. Urine from 19 healthy subjects contained osmoprotective activity greater than that observed with betaine. A methanol extract of urine was found to be highly protective. Although betaine was present in the extract, it could not account for all the protective activity. Urine contains additional low-molecular-weight osmoprotective agents.

Urinary concentrations of trimethoprim (TMP) and its metabolites were measured in eight healthy subjects after oral administration of 160 mg of TMP in two tablets of Septra@ (trimethoprim-sulfamethoxazole). Improved procedures for extraction of polar metabolites and for enzymic cleavage of conjugated products were applied. The 1-oxide and conjugates of demethylated metabolites were found in substantially higher concentrations than those previously reported. A new metabolite, the 3-oxide of TMP, was identified, and urinary levels of this product were also measured.

Persistent suppression of bacterial growth by certain antibiotics was tested by periodic counts of viable organisms in a culture of Staphylococcus aureus that had been incubated in media containing drugs for limited periods of time and then removed by centrifugation. During short (2 hr) periods of exposure of test cultures to penicillin G, cephalothin, erythromycin, clindamycin, vancomycin, and tetracyline, effects on the growth of S. aureus were produced that persisted after removal of the drug for periods of 1.7-4.1 hr. A persistent antibiotic effect was not observed with gentamicin. The persistent effects of penicillin G and erythromycin were directly related to duration of exposure and concentration of drug, up to a point of maximal response. The maximal durations of bacterial suppression after exposure to penicillin G and erythromycin were approximately 2 and 5 hr, respectively. These effects were observed over a wide range of inocula.

The distributions of trimethoprim (TMP) and nonacetylated sulfamethoxazole (SMZ) were studied in tissues of rhesus monkeys at equilibrium after establishment of serum levels comparable to those in man. Concentrations of nonacetylated SMZ in tissue were always lower than those in serum, with the highest concentrations in kidney, lung, and heart. In contrast, concentrations of TMP in tissue were greater than those in serum, except in brain, skin, and fat. The greatest uptake of TMP by tissues was observed in kidney and liver. The ratio of SMZ to TMP was significantly less in tissue than in serum and was lower than the optimal 20:1 ratio for antibacterial synergy. The rate of disappearance of both drugs from tissues was identical to their rate of elimination from serum. The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMZ) in animals and man have been previously reported [1-3]. Calculations of distribution have suggested significant uptake of TMP but not of SMZ by tissues. Biopsy material from patients and distribution studies in tissues of the rat, mouse, and rabbit have shown that the concentration of TMP in tissues exceeds that in serum, whereas levels of SMZ are lower in tissues than in serum [3-5]. We designed the following investigations to determine the distribution of these drugs in the tissues of primates at equilibrium with serum levels comparable to those in man.

The interaction between human erythrocyte lysates and antibiotics was studied, and the effect of intracellular components on the activity and binding of the drugs was determined. Lysates inhibited antibacterial activity of penicillin G, dicloxacillin, tetracycline, and minocycline to about the same extent as did human plasma. Dicloxacillin activity was the most inhibited, followed by the activities of penicillin G, minocycline, and tetracycline. All four antibiotics bound to human hemoglobin, as determined by gel filtration methods. Heme-free globin was also effective in binding the antibiotics. In addition, minocycline and tetracycline were bound to another erythrocytic protein, which, on the basis of electrophoretic mobility, molecular size, and localization, has been identified as carbonic anhydrase. Experiments with pure preparations of carbonic anhydrase revealed that the C isozyme is the major binder of the tetracyclines and that zinc is required for binding. Tetracyclines did not inhibit enzymatic activity of carbonic anhydrase.

This is the first in a series of reports being prepared by the Infectious Diseases Society of America (IDSA) that will deal with issues in antimicrobial therapy. Antimicrobial agents are often used inappropriately [1-19]. This may be attributed to their success in the treatment and prevention of serious infections, the complexity of the decision-making process in patients with infectious diseases, the desire of physicians to use the very best drugs available, and the promotional efforts of pharmaceutical manufacturers. The reasons for concern about excessive use of antibiotics are the burden of resistant organisms, adverse reactions to these drugs, and excessive costs. The issue of cost containment has become increasingly important as government and third-party payers seek to control expenditures in the health care system. The members and fellows of the IDSA were polled to obtain their views on the issues of optimum usage of antibiotics in hospitals. They registered concern about excessive and often inappropriate use of antibiotics in hospitals [20]. Effective antimicrobial agents are an essential part of patients' care. Intensive use of antimicrobial agents is associated with development of resistant strains [21-33], and excessive use increases costs unnecessarily [34-46]. Nevertheless, new agents are welcome that fill important therapeutic needs and overcome problems of resistance. To help hospitals provide the very best agents for care of patients by their staff, assure quality of care, and decrease the problems of emergence of resistant strains, the IDSA has prepared a series of general guidelines for evaluating and con

The polymyxin antibiotics are inactivated in vitro by tissues because they are bound to phospholipids of cell membranes. A method that liberates bound drug in an active form from tissues permitted study of distribution and persistence in vivo. Studies using single injections in the rabbit showed that bound drug persists in liver, kidney, brain, heart, muscle, and lung for as long as 72 hr. Accumulation in tissue but not in serum was noted on repeated injection, with persistence for at least five days after seven daily injections. Free polymyxin B was detectable in liver, kidney, muscle, and brain and persisted for many days in muscle and brain. Free colistimethate was detectable in all tissues other than brain and persisted for many days in liver, kidney, and muscle. Colistimethate appears to be incompletely converted in vivo to the parent compound, colistin. These observations may account for differences in toxicity and chemotherapeutic efficacy of polymyxin B and colistimethate.

Binding of metabolites and drugs, including antibiotics, to serum proteins has been extensively studied. This phenomenon has important biologic and therapeutic significance [1-3]. The ability of tissues to bind has also been explored, particularly with organic dyes and biologically active agents. In some instances, binding of drugs to specific sites in microorganisms can be linked closely with their mode of action. For example, the polymyxins owe their biologic activity to binding to polyphosphate groups of phospholipids in the bacterial cell membrane [4], and amphotericin B requires sterol binding sites in fungal cells [5]. Antitrypanosomal activity of acriflavine has been shown to depend upon binding of the drug to the parasite [6]. The receptor site theories of pharmacology and virology depend largely on evidence of specific combination between drug or virus and complementary structures on cell membranes. Some of these concepts of drug action were clearly visualized by Ehrlich and Morgenroth many years ago [7 p. 24]. Studies in this laboratory indicated that several antibiotics, particularly those in the polymyxin and aminoglycoside families, are inhibited by constituents of bacteriologic agar and various culture media [8]. The phenomenon appears to be related to the charge produced by free amino groups in the drugs and sulfate groups in the medium, since it can be overcome readily by addi