Return to Pharmacology Problem Sets<\/a><\/p>\nExperimental data for a new antibacterial agent, Drug A, are presented below.<\/p>\n
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<\/em>, Drug A irreversibly loses all of its antibacterial potency.<\/p>\nThe in vitro<\/em> 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.<\/p>\n\n\n\n| Table I<\/th>\n<\/tr>\n |
\n| Organism<\/th>\n | MEC (\u00b5g\/ml)<\/th>\n<\/tr>\n |
\n| Drug A<\/th>\n | Penicillin G<\/th>\n<\/tr>\n |
\nStreptococcus pneumoniae
\nStreptococcus hemolyticus<\/em> (Patient 1)
\nStreptococcus hemolyticus<\/em> (Patient 2)
\nStreptococcus hemolyticus<\/em> (Patient 3)
\nStreptococcus hemolyticus<\/em> (Patient 4)
\nStaphylococcus aureus<\/em> (Patient 5)
\nStaphylococcus aureus<\/em> (Patient 6)
\nStaphylococcus aureus<\/em> (Patient 7)
\nStaphylococcus aureus<\/em> (Patient 8)
\n<\/em><\/td>\n0.15
\n0.28
\n0.17
\n0.10
\n0.35
\n2.00
\n4.00
\n2.50
\n3.10<\/td>\n | 0.040
\n0.025
\n0.019
\n0.008
\n0.037
\n0.190
\n0.250
\n100.000
\n70.00<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\nThe 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.<\/p>\n \n\n\n| Table II<\/th>\n<\/tr>\n | \n| Antibiotic Added To Broth<\/th>\n | Number of Viable Bacterial Colonies
\nper ml of broth after 8 hours of incubation<\/th>\n<\/tr>\n | \nNone
\nPenicillin G (10mg\/ml)
\nVancomycin (10mg\/ml)
\nDrug A (10mg\/ml)
\nBacitracin (10mg\/ml)<\/td>\n | 10^12.0
\n10^11.5
\n10^5.0
\n10^4.5
\n10^3.5<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\nI. It can be inferred from the data in Table I that drug A is:<\/p>\n a. Effective against penicillin G-resistant streptococci<\/h4><\/p>\n No. The data really provide no evidence on this point, inasmuch as none of the Streptococcal strains appear to have been particularly resistant to penicillin G. The rank orders of sensitivities to the two drugs are identical, in fact. Go back to Item I.<\/p>\n <\/div>\n<\/div>\n\n b. Effective against penicillin G-resistant streptococcus pneumoniae<\/h4><\/p>\n Come now. With only one patient, you have no convincing evidence that his Streptococcus pneumoniae were, in fact, resistant to penicillin G. Go back to Item I.<\/p>\n <\/div>\n<\/div>\n\n c. Effective against penicillin G-resistant staphylococci<\/h4><\/p>\n Yes, because the two bacterial isolates which required massive amounts of penicillin G to achieve efficacy were effectively suppressed by relatively small concentrations of Drug A. Go on to Item II.<\/p>\n <\/div>\n<\/div>\n\n d. Ineffective against penicillin G-resistant staphylococci<\/h4><\/p>\n No, to the contrary, as you\u2019ll find when you look at Table I again.<\/p>\n \n\n\n| Table I<\/th>\n<\/tr>\n | \n| Organism<\/th>\n | MEC (\u00b5g\/ml)<\/th>\n<\/tr>\n | \n| Drug A<\/th>\n | Penicillin G<\/th>\n<\/tr>\n | \n| <\/td>\n<\/tr>\n | \nStreptococcus pneumoniae
\nStreptococcus hemolyticus<\/em> (Patient 1)<\/em><\/p>\nStreptococcus hemolyticus (Patient 2)
\nStreptococcus hemolyticus<\/em> (Patient 3)
\nStreptococcus hemolyticus<\/em> (Patient 4)
\nStaphylococcus aureus<\/em> (Patient 5)
\nStaphylococcus aureus<\/em> (Patient 6)<\/em><\/p>\nStaphylococcus aureus (Patient 7)
\nStaphylococcus aureus<\/em> (Patient 8)
\n<\/em><\/td>\n0.15
\n0.28
\n0.17
\n0.10
\n0.35<\/p>\n2.00
\n4.00
\n2.50
\n3.10<\/td>\n | 0.040
\n0.025
\n0.019
\n0.008
\n0.037<\/p>\n0.190
\n0.250
\n100.000
\n70.00<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n <\/div>\n<\/div>\n\n e. Two of the above<\/h4><\/p>\n You may be half-right, but that\u2019s not enough. Go back to the table and restudy the data there.<\/p>\n <\/div>\n<\/div>\n\n 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:<\/p>\n a. The median curative dose of vancomycin would be less than the median curative dose of Drug A.<\/h4><\/p>\n No, if anything the data available in the two Tables suggest that Drug A and vancomycin are nearly equipotent. Go back to Item II.<\/p>\n <\/div>\n<\/div>\n\n b. The median curative dose of Drug A would be less than the median curative dose of penicillin G.<\/h4><\/p>\n Yes, of course, because equivalent concentrations of Drug A and penicillin G permitted very different bacterial growth rates. Go on to Item III.<\/p>\n <\/div>\n<\/div>\n\n c. The median curative dose of Drug A would be greater than the median curative dose of penicillin G.<\/h4><\/p>\n No. Go back and restudy the data in Table II.<\/p>\n <\/div>\n<\/div>\n\n d. The therapeutic index of bacitracin would be greater than that of Drug A.<\/h4><\/p>\n No; we have absolutely no evidence that permits us to make this inference. In fact your knowledge of bacitracin\u2019s toxicity should have prevented you from making this inference in the first place. Try again.<\/p>\n <\/div>\n<\/div>\n\n e. None of the above.<\/h4><\/p>\n Well, you might be 75% correct, but you still missed. Study the data again.<\/p>\n <\/div>\n<\/div>\n\n III. From the data available, you can conclude that:<\/p>\n a. 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<\/h4><\/p>\n No. You\u2019re right about the sulfonamides, but the data suggest that, after eight half-lives, as much as 70% of the dose of Drug A was metabolized. Try again.<\/p>\n <\/div>\n<\/div>\n\n b. The administration of probenecid would be expected to decrease the fraction of Drug A that is metabolized, as is true for penicillin G<\/h4><\/p>\n Come now, probenecid inhibits the renal tubular secretion of organic acids, not their metabolism, which might well be increased if they remain in the body longer in the presence of probenecid. However, probenecid does prolong the duration of penicillin G action. Go back to Item III.<\/p>\n <\/div>\n<\/div>\n\n c. When, administered orally, Drug A would be ineffective as an antibacterial agent, as is true for penicillin V or ampicillin<\/h4><\/p>\n No. We don\u2019t really know whether all of an orally administered dose of Drug A would be destroyed in the stomach or not, do we? Only 80% of penicillin G is destroyed by this mechanism. At any rate, the virtues of penicillin V and ampicillin include their stability at gastric pH. Try again.<\/p>\n <\/div>\n<\/div>\n\n d. It would require much greater doses of Drug A for effective oral administration than for effective parenteral administration, as is true for penicillin G<\/h4><\/p>\n Yes. This would seem to be a perfectly reasonable inference. Go on to Item IV.<\/p>\n <\/div>\n<\/div>\n\n e. Drug A will be effective in the treatment of brain abscesses caused by penicillin G-resistant staphylococci, when administered intravenously<\/h4><\/p>\n No. We really don\u2019t have any evidence that Drug A can cross the blood-brain barrier, although we cannot be sure that it cannot. Try again.<\/p>\n <\/div>\n<\/div>\n\n IV. From the data available in the Tables above, and from your knowledge of other bacterial agents, it can be concluded that:<\/p>\n a. Drug A, like methicillin and oxacillin, is hydrolyzed by beta-lactamase<\/h4><\/p>\n No. There is good reason, from the data in Table I, to infer that Drug A is NOT susceptible to beta-lactamase; moreover, methicillin and oxacillin are known not to be susceptible to beta-lactamase. Go back to Item IV.<\/p>\n <\/div>\n<\/div>\n\n b. Drug A, like ampicillin, tetracycline, and ciprofloxacin, is a broad-spectrum antibiotic<\/h4><\/p>\n No. Well, you\u2019re right that ampicillin and the others have wide spectra of antibacterial efficacies, but we have no evidence for Drug A beyond a few Gram-positives, do we? Try again.<\/p>\n <\/div>\n<\/div>\n\n c. Drug A, like erythromycin, is effective against Gram-positive organisms<\/h4><\/p>\n Well, you\u2019re half-right. Now identify the other correct answer. Go back to Item IV.<\/p>\n <\/div>\n<\/div>\n\n d. Drug A, like chloramphenicol, inhibits protein synthesis at the transcriptional level<\/h4><\/p>\n No. You\u2019re right about chloramphenicol , but we can\u2019t make any such inference about Drug A yet. Go back to Item IV.<\/p>\n <\/div>\n<\/div>\n\n e. Drug A, like streptomycin, is bacteriocidal<\/h4><\/p>\n No. You are right about streptomycin and Drug A being bacteriocidal (for Drug A because the number of organisms following incubation was less than at the beginning of the experiment). However, you are only half-way to answering the question. Go back to Item IV.<\/p>\n <\/div>\n<\/div>\n\n f. Two of the above are equally plausible<\/h4><\/p>\n Good, if you identified answer choices c and e as correct, you can now go on to Item V.<\/p>\n <\/div>\n<\/div>\n\n 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:<\/p>\n a. Shorter than that in the normal subject, as would be expected for chloramphenicol<\/h4><\/p>\n No. Come now, renal insufficiency is not known to shorten the half-life of any substance. At any rate, renal insufficiency does not affect the persistence of microbiologically active chloramphenicol in the body, because it is primarily cleared by glucuronide conjugation in the liver. Go back to Item V.<\/p>\n <\/div>\n<\/div>\n\n b. Longer than that in the normal subject, as would be expected for tetracycline<\/h4><\/p>\n Very likely; in fact, renal disease is a contraindication to the use of tetracycline (but not of demeclocycline or doxycycline). However, you still haven\u2019t completely answered this question. Go back to Item V.<\/p>\n <\/div>\n<\/div>\n\n c. Shorter than that in the normal subject, as would be expected for the naturally occurring penicillins<\/h4><\/p>\n No. You should have recognized this as a nonsense answer. The half-lives of penicillins can be prolonged (not shortened!) in anuria, because penicillins are primarily cleared by renal tubular secretion. Adjustments in dose are usually unnecessary in lesser degrees of renal impairment.<\/p>\n <\/div>\n<\/div>\n\n d. Longer than that in the normal subject, as would be expected for erythromycin<\/h4><\/p>\n No, little or no change in dose or schedule is required for erythromycin in the presence of renal disease, because the antibiotic is metabolized in the liver. Go back to Item V.<\/p>\n <\/div>\n<\/div>\n\n e. Longer than that in the normal subject, as would be expected for streptomycin and the sulfonamides<\/h4><\/p>\n Yes, both drug groups are excreted chiefly through the kidney, However, you haven\u2019t really completely answered the question, so go back to Item V.<\/p>\n <\/div>\n<\/div>\n\n f. Two of the above<\/h4><\/p>\n Yes, you\u2019re entirely correct. Tetracycline, streptomycin and sulfonamides are all excreted principally through the kidney. Go on to Item VI.<\/p>\n <\/div>\n<\/div>\n\n VI. Agents which provide effective treatment for tuberculosis include:<\/p>\n a. Isoniazid and rifampin, because M. tuberculosis<\/em> does not develop resistance to either agent<\/h4><\/p>\n No. Well, both drugs are effective in tuberculosis, but resistance to both can impair their effectiveness. Go back to Item VI.<\/p>\n <\/div>\n<\/div>\n\n b. Isoniazid and rifampin, because both are relatively lipid-soluble<\/h4><\/p>\n Quite true, which means that both can be expected to be effective against intracellular organisms like M. tuberculosis<\/em>. But is this all? Go back to Item VI.<\/p>\n<\/div>\n<\/div>\n\n c. Streptomycin, because the tuberculosis organism is unable to develop resistance to aminoglycosides<\/h4><\/p>\n No, M. tuberculosis<\/em> strains, which can overcome the inability to read the genetic code induced by streptomycin, often develop during therapy with this antibiotic. Go back to Item VI.<\/p>\n<\/div>\n<\/div>\n\n d. Streptomycin, because the vestibular nerve is more sensitive to the antibiotic's toxic effect than is the acoustic nerve<\/h4><\/p>\n Quite true. Vestibular dysfunction may well develop during streptomycin therapy, but it can be better tolerated than can deafness (which more often developed during therapy with the now unavailable dihydrostreptomycin). However, you\u2019re only half correct on this question. Go back to Item VI.<\/p>\n <\/div>\n<\/div>\n\n e. Pyrazinamide and ethambutol, because both are potent inhibitors of DNA gyrase<\/h4><\/p>\n No, although both are effective in tuberculosis, pyrazinamide is an antimetabolite, and we have no good clues to ethambutol\u2019s mode of action. Go back to Item VI.<\/p>\n <\/div>\n<\/div>\n\n f. Two of the above<\/h4><\/p>\n Yes, if you\u2019ve perceived that isoniazid and rifampin, being lipid-soluble, are especially useful for treating intracellular organisms, and that streptomycin\u2019s side effects on the vestibular nerve can be better tolerated than its effects on the acoustic nerve. Go on to Item VII.<\/p>\n <\/div>\n<\/div>\n\n VII. The acetylated biotransformation products of sulfonamides:<\/p>\n a. Non-competitively inhibit dihydrofolate reductase<\/h4><\/p>\n No, no! On three counts. One, the acetylated biotransformation products are microbiologically inactive. Two, the parent compounds are competitive inhibitors, and three, they are competitive inhibitors of dihydrofolate synthetase. It makes a difference. Go back to Item VII.<\/p>\n <\/div>\n<\/div>\n\n b. Cannot oxidize hemoglobin<\/h4><\/p>\n No. It\u2019s a fine point, but the metabolites are just as effective in producing methemoglobinemia as the parent drugs. Try again.<\/p>\n <\/div>\n<\/div>\n\n c. Are more effective than their parent drugs in the treatment of lower urinary tract infections<\/h4><\/p>\n No, the metabolites are microbiologically ineffective. That is why, for instance, sulfisoxazole is useful in treating lower urinary tract infections, because it is not extensively metabolized, as well as the fact that it has a low pKa, and so is very soluble in the urine. Back to Item VII.<\/p>\n <\/div>\n<\/div>\n\n d. Are responsible for the renal side effects of these agents<\/h4><\/p>\n True. The acetylated metabolites are, by and large, less soluble in urine, especially when its pH is about 7.5, so they tend to crystallize out in the renal tubules. Go on to Item VIII.<\/p>\n <\/div>\n<\/div>\n\n e. None of the above<\/h4><\/p>\n No, you\u2019ve missed something. Try again.<\/p>\n <\/div>\n<\/div>\n\n VIII. Which of the following would you expect to have the smallest therapeutic index in man:<\/p>\n a. Agents that cross-link murein-peptide fragments, like the cephalosporins<\/h4><\/p>\n Come now. Which cells in man contain murein? Go Directly to Jail. Do not Collect $200. Then, try again.<\/p>\n <\/div>\n<\/div>\n\n b. Agents that interfere with the incorporation of p-aminobenzoic acid into dihydrofolic acid<\/h4><\/p>\n Come now. To what extent are human cells dependent on PABA for their vital processes? What are some examples of drugs which act in this fashion? Do you still persist in this answer? If so, go back to Item VIII and reconsider.<\/p>\n <\/div>\n<\/div>\n\n c. Agents that inactivate DNA, like bleomycin or actinomycin D.<\/h4><\/p>\n Well, of course, because DNA is common to all organisms. That is why these two true antibiotics \u2013 bleomycin and actinomycin D \u2013 are more appropriately used in cancer chemotherapy than for treating infectious diseases. Go on to Item IX.<\/p>\n <\/div>\n<\/div>\n\n d. Agents that inhibit the synthesis of RNA, like the aminoglycosides<\/h4><\/p>\n No. Well, drugs that inhibit protein synthesis at the transcriptional level ARE more likely to be toxic than most others, but the aminoglycosides (can you name at least three?) do not exert their effects in this way. Try again.<\/p>\n <\/div>\n<\/div>\n\n e. Agents that prevent the repair of bacterial DNA, like ciprofloxacin<\/h4><\/p>\n No. Because mammalian cells lack the enzyme DNA gyrase, the fluorinated quinolones will not affect your patient\u2019s DNA. Indeed, they are relatively free of side effects in man. Go back to Item VIII.<\/p>\n <\/div>\n<\/div>\n\n 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:<\/p>\n a. Penicillins, the most frequent cause of drug-induced allergies<\/h4><\/p>\n No. Yes, penicillins ARE the most frequent cause of drug-induced allergy, but they are excreted via renal tubular secretion, and need not be withheld from patients with liver disease. Go back to Item IX.<\/p>\n <\/div>\n<\/div>\n\n b. Tetracycline, which inhibits peptidyl transferase<\/h4><\/p>\n No, you\u2019ve confused tetracycline with drugs that bind to the 50 S ribosomal subunit, like chloramphenicol and erythromycin. Now, try again.<\/p>\n <\/div>\n<\/div>\n\n c. Chlortetracycline and oxytetracycline, which can cause liver damage<\/h4><\/p>\n You\u2019re exactly right. Both of these tetracycline derivatives are metabolized in the liver, and their toxicity is increased markedly if your patient is unable to metabolize them completely. Go on to Item X.<\/p>\n <\/div>\n<\/div>\n\n d. Aminoglycosides, some of which permit the development of malabsorption and\/or superinfection by organisms not usually pathogenic in humans<\/h4><\/p>\n No, streptomycin and its relatives are excreted chiefly in the urine. Go back to Item IX.<\/p>\n <\/div>\n<\/div>\n\n e. Erythromycin base, which can produce jaundice<\/h4><\/p>\n No. Fortunately, only erythromycin esters, such as the estolate, produce cholestatic hepatitis. Erythromycin base, even if it cannot be concentrated in the liver for emptying in to the bile, is not sufficiently toxic to necessitate withholding it from even a jaundiced patient who is infected with bacteria that are sensitive to it. Go back to Item IX<\/p>\n <\/div>\n<\/div>\n\n X. Delayed hypersensitivity following the administration of penicillin is attributable to :<\/p>\n a. The drug's binding to red cell membranes<\/h4><\/p>\n No, this is a cause of the hemolytic anemia that may, rarely, be caused by peniclillin, but not of skin rash. Try again.<\/p>\n <\/div>\n<\/div>\n\n b. The products of acid hydrolysis of the beta-lactam ring<\/h4><\/p>\n No, no! This occurs only in the stomach. Try again.<\/p>\n <\/div>\n<\/div>\n\n c. The products of enzymatic hydrolysis of the beta-lactam ring<\/h4><\/p>\n No, opening the beta-lactam ring results from the action of bacterial B-lactamase, and, unless the resulting penicilloic acid becomes a haptene, it will not cause hypersensitivity. Go back to Item X.<\/p>\n <\/div>\n<\/div>\n\n d. The products of enzymatic hydrolysis to penicillenic acid<\/h4><\/p>\n No, penicillenic acid itself does not function as an antigen or as a haptene. Go back to Item X.<\/p>\n <\/div>\n<\/div>\n\n e. The conjugates of penicilloic acid with tissue proteins<\/h4><\/p>\n Yes, you\u2019ve remembered that it is penicilloic acid, a metabolite of penicillenic acid, which conjugates with terminal lysine groups to form the essential antigen complex in penicillin allergy.<\/p>\n This concludes this Workshop Program on Antibiotics. Obviously, it could have included hundreds of questions. Those you have answered exemplify a few of the problems you will have to answer in choosing a drug for your patients\u2019 infectious diseases.<\/p>\n <\/div>\n<\/div>\n\n","protected":false},"excerpt":{"rendered":" J. Worth Estes, M.A.,M.D. Professor of Pharmacology Boston University School of Medicine Questions or comments should be mailed to Carol Walsh Return to Pharmacology Problem Sets 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 […]<\/p>\n","protected":false},"author":2,"featured_media":0,"parent":69,"menu_order":4,"comment_status":"closed","ping_status":"closed","template":"page-templates\/no-sidebars.php","meta":[],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/78"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/comments?post=78"}],"version-history":[{"count":25,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/78\/revisions"}],"predecessor-version":[{"id":18796,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/78\/revisions\/18796"}],"up":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/pages\/69"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/ppb\/wp-json\/wp\/v2\/media?parent=78"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}} | | | | |