Quiz 2 Study Guide
Chapters reviewed: 48, 49, 52, 53, 54, 56, 57, 58, 64, 65, 66, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 87, 88, 89,
Antibiotics
Review terminology:
- selective toxicity—is defined as the ability of a drug to injure a target cell or target organism without injuring other cells or organisms that are
in intimate contact with the target. As applied to antimicrobial drugs, selective toxicity indicates the ability of an antibiotic to kill or suppress
microbial pathogens without causing injury to the host. Selective toxicity is the property that makes antibiotics valuable. pp651 (in other
words, if antibiotics were as harmful to the host as they are to infecting organisms- these drugs would have no therapeutic utility.
3 examples of how to achieve selective toxicity these include:
1. Disruption of the Bacterial Cell Wall
Unlike mammalian cells, bacteria are encased in a rigid cell wall. The protoplasm within this wall has a high concentration of
solutes, making osmotic pressure within the bacterium high. Several families of drugs such as penicillins and cephalosporins weaken
the cell wall and, hence, promote bacterial lysis. Because mammalian cells have no cell wall, drugs directed at this structure do not
affect humans.
2. Inhibition of an Enzyme Unique to Bacteria
The sulfonamides represent antibiotics that are selectively toxic because they inhibit an enzyme critical to bacterial survival but not to
our survival. Specifically, sulfonamides inhibit an enzyme needed to make folic acid, a compound required by all cells, both
mammalian and bacterial. Because we can use folic acid from dietary sources, sulfonamides are safe for human consumption. In
contrast, bacteria must synthesize folic acid themselves, because unlike us, they cannot take folic acid from the environment hence, in
order to meet their needs, bacteria first take up para-aminobenzoic acid (PABA), a precursor of folic acid and then convert the PABA
into folic acid. Sulfonamides block this conversion. Because mammalian cells do not make their own folic acid, sulfonamide toxicity
is limited to microbes.
3. Disruption of Bacterial Protein Synthesis
In bacteria, as in mammalian cells, protein synthesis is completed by ribosomes. However, bacterial and mammalian ribosomes are
not identical, and hence we can make drugs that disrupt function of one but not the other. As a result, we can impair protein synthesis
in bacteria while leaving mammalian proteins synthesis untouched.
- culture and sensitivity test pp. 658
o The quickest, simplest and most versatile technique for identifying microorganisms is microscopic examination of Gram-stained
preparation- this can be obtained by obtaining samples for examination such as exudate, sputum, urine, blood, and other bodily
fluids.
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, o Another new method known as Polymerase chain reaction (PCR) test or nucleic acid amplification test, can detect very low titers of
bacteria and viruses. Testing is done by using an enzyme—either DNA polymerase or RNA polymerase. Microbes that can be
identified with a PCR test include: C. Difficile, S. aureus, mycobacterium tuberculosis, neissseria gonorrhoeae, chlamydia
trachomatis, and helicobacter pylori, and important viral pathogens such as: HIV (human immunodeficiency virus). Compared with
Gram-staining, PCR test are both more specific and more sensitive.
- mechanisms of resistance
o bacterial resistance to antibiotics, which may be innate (natural and inborn) or acquired over time. As a rule, antibiotics resistance is
associated with extended hospitalization, significant morbidity, and excess mortality. Organisms for which drug resistance is currently
a serious problem include Enterococcid faecium, Staphylococcis aureus, Enterobacter species, Pseudomonas aeruginosa,
Acinetobacter baumannii, Klebsiealla species, and Clostridiodies difficile (C. difficile).
o Microbes have four basic mechanisms for resisting drugs.
They can DECREASE the concentration of a drug at its site of action.
ALTER the structure of drug target molecules
PRODUCE a DRUG ANTAGONIST
CAUSE DRUG INACTIVATION
o Spontaneous Mutation produce random changes in a microbe’s DNA. The result is a gradual increase in resistance. Low-level
resistance develops first. With additional mutations, resistance becomes greater. As a rule, spontaneous mutations confer resistance to
only one drug.
o Conjugation is a process by which extrachromosomal DNA is transferred from one bacterium to another. To transfer resistance by
conjugation, the donor organism must possess two unique DNA segments.
o one that codes for the mechanisms of drug resistance
o and one that codes for the “sexual” apparatus required fir DNA transfer. Together these two DNA segments constitute an R
factor (resistance factor).
o In contrast to spontaneous mutation, conjugation, frequently confers multiple-drug resistance. This can be achieved, for
example, by transferring DNA that codes for several different drug-metabolizing enzymes. Hence, in a single event, a drug-
sensitive bacterium can become highly drug resistant.
o If a drug-resistant organism is present, antibiotics will create selection pressure favoring its growth by killing off sensitive
organisms. In doing so, the drug will eliminate the toxins they produce and will, hence, facilitate survival of the microbe that is
drug resistant. In addition, elimination of sensitive organisms will remove competition for available nutrients, thereby making
conditions even more favorable for the resistant microbe to flourish. Hence, although drug resistance is of no benefit to an
organism when there are no antibiotics present, when antibiotics are introduced, they create selection pressure favoring
overgrowth of microbes that are resistant.
o Which antibiotics promote more resistance?
All antimicrobial drugs promote the emergence of drug-resistant organisms. However, some agents are more likely to
promote resistance than others. Because BROAD-SPECTRUM antibiotics kill more competing organisms than do
Narrow-spectrum drugs, BROAD-SPECTRUM agents do the most to facilitate emergence of resistance.
- CYP3A4 pp. 457-459 CYP3A4 are reversible inhibitors and are competitive inhibitors. These are enzymes that can be both reversible and
irreversible. Don’t consume Grapefruit! Inhibitors of CYP3A4 such as Ketoconazole, itraconazole, erythromycin, cimetidine, saquinavir,
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, ritonavir, grapefruit juice can SUPPRESS the metabolism of SILDENAFIL, thereby increasing its level. These combinations should be used
with caution. It is metabolized in the liver. This the most common metabolic enzyme involced in drug interactions. Metabolizes approx. 50%
of drugs
o Tadalafil – Is CONTRAINDICATED FOR USE WITH NITRATES IR a blockers (Except tamsulosin [Flomax]). As with sildenafil
and vardenafil, CYP3A4 Inhibitors can cause levels of tadalafil to rise. To avoid toxicity, men taking CYP3A4 inhibitors, should limit
tadalafil dosage to 10mg every 72 hours.
- CYP450
o Group of enzymes that are metabolized in the liver, but also located in the lungs, intestines, and kidneys.
- disulfiram-like effect pp. 670—is very dangerous and is brought on by accumulation of acetaldehyde secondary to inhibition of aldehyde
dehydrogenase. CEFAZOLIN & CEFOTETAN can induce a state of alcohol intolerance. Patients using these cephalosporins MUST NOT
CONSUME ALCOHOL IN ANY FORM WHILE TAKING THESE MEDICATIONS.
- Note—Cefotetan, cefazolin, and ceftriaxone—can promote bleeding!! Therefore, caution is needed when if these drugs are combined
with other agents that promote bleeding such as anticoagulants, thrombolytics, nonsteroidal anti-inflammatory drugs NSAIDs, and
other antiplatelet agents.
- Superinfection – is defined as a new infection that appears during the course of treatment for a primary infection. An example of a
superinfection is new infections develop when antibiotics eliminate the inhibitory influence of normal flora, thereby allowing a second
infectious agent to flourish. A common example of superinfection is the development of a vaginal Candida infection in a female treated with a
broad-spectrum antibiotic for a urinary tract infection. Because broad-spectrum antibiotics kill more normal flora than do narrow-spectrum
drugs, superinfections are more likely in patients who are receiving broad-spectrum agents. pp. 655
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