Boston University Medical Campus
Pharmacology and Experimental Therapeutics

Problem 4

PROGRAMMED PROBLEM SET ON ANTIBIOTICS

Questions or comments should be mailed to Carol Walsh

Experimental data for a new antibacterial agent, Drug A, are presented below.

Toxicity studies in uninfected mice indicate that the LD50 of Drug A is about the same as that for penicillin G. Drug A is distributed, in man, in the extracellular fluid compartment, and has a half-life in the plasma of 1.5 hours. Approximately 30% of a rapidly injected intravenous dose of Drug A is found unchanged in the urine within 12 hours of its administration. At pH 2.5, in vitro, Drug A irreversibly loses all of its antibacterial potency.

The in vitro antibacterial effectiveness of Drug A and penicillin G was studied using microorganisms isolated from patients ill with bacterial infections. The minimally effective concentration (MEC) for Drug A and penicillin G are given in Table I. Suppression of growth for 24 hours after inoculation was the criterion of effectiveness.

Table I
Organism			MEC (µg/ml)
			Drug A	Penicillin G
Streptococcus pneumoniae Streptococcus hemolyticus (Patient 1) Streptococcus hemolyticus (Patient 2) Streptococcus hemolyticus (Patient 3) Streptococcus hemolyticus (Patient 4) Staphylococcus aureus (Patient 5) Staphylococcus aureus (Patient 6) Staphylococcus aureus (Patient 7) Staphylococcus aureus (Patient 8)			0.15 0.28 0.17 0.10 0.35 2.00 4.00 2.50 3.10	0.040 0.025 0.019 0.008 0.037 0.190 0.250 100.000 70.00

The effects of penicillin G, vancomycin, Drug A, and bacitracin on bacterial growth and viability were measured using a bacterial strain (called no. 28) isolated from a patient. The data obtained are given in Table II. The control culture medium contained no antibacterial agent. All the culture media contained p-aminobenzoic acid in excess of the normal requirements for bacterial growth. All cultures contained 10^7 viable colonies per ml of broth at the start of incubation. After 8 hours of incubation each culture contained the number of colonies listed in Table II.

Table II
Antibiotic Added To Broth	Number of Viable Bacterial Colonies per ml of broth after 8 hours of incubation
None Penicillin G (10mg/ml) Vancomycin (10mg/ml) Drug A (10mg/ml) Bacitracin (10mg/ml)	10^12.0 10^11.5 10^5.0 10^4.5 10^3.5

---

I. It can be inferred from the data in Table I that drug A is:

1. Effective against penicillin G-resistant streptococci
2. Effective against penicillin G-resistant streptococcus pneumoniae
3. Effective against penicillin G-resistant staphylococci
4. Ineffective against penicillin G-resistant staphylococci
5. Two of the above

II. Vancomycin, bacitracin, Drug A, and penicillin G were administered parenterally to mice experimentally infected with the bacterial strain isolated from Patient No. 7. The available data suggest that, with optimum treatment schedules:

1. The median curative dose of vancomycin would be less than the median curative dose of Drug A.
2. The median curative dose of Drug A would be less than the median curative dose of penicillin G.
3. The median curative dose of Drug A would be greater than the median curative dose of penicillin G.
4. The therapeutic index of bacitracin would be greater than that of Drug A.
5. None of the above

III. From the data available, you can conclude that:

1. Less than 50% of Drug A is metabolized in the body after its parenteral administration, as is true for sulfisoxazole and other commonly used sulfonamides
2. The administration of probenecid would be expected to decrease the fraction of Drug A that is metabolized, as is true for penicillin G
3. When, administered orally, Drug A would be ineffective as an antibacterial agent, as is true for penicillin V or ampicillin
4. It would require much greater doses of Drug A for effective oral administration than for effective parenteral administration, as is true for penicillin G
5. Drug A will be effective in the treatment of brain abscesses caused by penicillin G-resistant staphylococci, when administered intravenously

IV. From the data available in the Tables above, and from your knowledge of other bacterial agents, it can be concluded that:

1. Drug A, like methicillin and oxacillin, is hydrolyzed by beta-lactamase
2. Drug A, like ampicillin, tetracycline, and ciprofloxacin, is a broad-spectrum antibiotic
3. Drug A, like erythromycin, is effective against Gram-positive organisms
4. Drug A, like chloramphenicol, inhibits protein synthesis at the transcriptional level
5. Drug A, like streptomycin, is bacteriocidal
6. Two of the above are equally plausible

V. You can infer, from the available data, that the plasma half-life of Drug A in a patient with renal insufficiency (after parenteral administration) would be:

1. Shorter than that in the normal subject, as would be expected for chloramphenicol
2. Longer than that in the normal subject, as would be expected for tetracycline
3. Shorter than that in the normal subject, as would be expected for the naturally occurring penicillins
4. Longer than that in the normal subject, as would be expected for erythromycin
5. Longer than that in the normal subject, as would be expected for streptomycin and the sulfonamides
6. Two of the above

VI. Agents which provide effective treatment for tuberculosis include:

1. Isoniazid and rifampin, because M. tuberculosis does not develop resistance to either agent
2. Isoniazid and rifampin, because both are relatively lipid-soluble
3. Streptomycin, because the tuberculosis organism is unable to develop resistance to aminoglycosides
4. Streptomycin, because the vestibular nerve is more sensitive to the antibiotic’s toxic effect than is the acoustic nerve
5. Pyrazinamide and ethambutol, because both are potent inhibitors of DNA gyrase
6. Two of the above

VII. The acetylated biotransformation products of sulfonamides:

1. Non-competitively inhibit dihydrofolate reductase
2. Cannot oxidize hemoglobin
3. Are more effective than their parent drugs in the treatment of lower urinary tract infections
4. Are responsible for the renal side effects of these agents
5. None of the above

VIII. Which of the following would you expect to have the smallest therapeutic index in man:

1. Agents that cross-link murein-peptide fragments, like the cephalosporins
2. Agents that interfere with the incorporation of p-aminobenzoic acid into dihydrofolic acid
3. Agents that inactivate DNA, like bleomycin or actinomycin D.
4. Agents that inhibit the synthesis of RNA, like the aminoglycosides
5. Agents that prevent the repair of bacterial DNA, like ciprofloxacin

IX. Which of the following is (are) contraindicated in the treatment of infections caused by appropriately sensitive organisms in patients who also have elevated plasma bilirubin concentrations, prolonged prothrombin times, and low serum albumin concentrations:

1. Penicillins, the most frequent cause of drug-induced allergies
2. Tetracycline, which inhibits peptidyl transferase
3. Chlortetracycline and oxytetracycline, which can cause liver damage
4. Aminoglycosides, some of which permit the development of malabsorption and/or superinfection by organisms not usually pathogenic in humans
5. Erythromycin base, which can produce jaundice

X. Delayed hypersensitivity following the administration of penicillin is attributable to :

1. The drug’s binding to red cell membranes
2. The products of acid hydrolysis of the beta-lactam ring
3. The products of enzymatic hydrolysis of the beta-lactam ring
4. The products of enzymatic hydrolysis to penicillenic acid
5. The conjugates of penicilloic acid with tissue proteins