Antibacterial Drugs: Principles of Chemotherapy

Question 1

Learning Objectives

Answer 1

1) Categorize drugs as bactericidal and bacteriostatic and explain when you would prefer to use bactericidal drugs
2) Identify patient factors which affect drug absorption, distribution, metabolism, and excretion
3) Differentiate between prophylactic,pre-emptive, empiric, suppressive, and definitive therapy
4) Identify properties which limit usefulness of a drug class and drugs within a class (toxicity)
5) Identify mechanism through which drugs develop resistance
6) Explain strategies that minimize or prevent drug resistance

Question 2

Antimicrobial Terminology

Answer 2

Antimicrobial therapy includes
antibacterial, antifungal, antiparasitic, and antiviral drugs
Original antibiotics were natural substances made by micro-organisms that are antibacterial
Now most antibiotics are semisynthetic modifications of natural substances and can refer to antimicrobials in general or to antibacterials specifically

Question 3

Create the “ideal” drug

Answer 3

If emperical, broad spectrum.

absorption, distribution

low interactions

Specific is beneficial –> lower disruption of normal flora

low interactions

Question 4

Why more challenging to develop antifungal drugs than antibiotics?

Answer 4

Fungi/parasites are more resembling to EK’s; adverse events more harmful to humans

Question 5

Antibiotics are ligands, microbial targets are receptors

Answer 5

Cell wall (pep) synth

mucleic acid synth

cell membrane integrity

…

…

Question 6

Toxicity

Answer 6

Extension of mechanism of action
Trimethoprim can inhibit folate metabolism in humans resulting in bone-marrow suppression
2) Unintended consequences
Vancomycin can stimulate histamine release resulting in red man syndrome

Question 7

Therapeutic index- high therapeutic index means fewer adverse effects

Answer 7

Which of the drugs discussed on the previous slide would you predict to have a high therapeutic index?

Cell Wall synth - we don’t have cell walls!

Low therapeutic index example: TMP and those acting on bacterial ribosomes

Question 8

Spectrum of Activity

Answer 8

Drugs are classified generally as narrow, extended, or broad spectrum antibiotics.

Narrow – Gram negative cocci

Extended – Gram negative rods and cocci

Broad – Many gram positive and gram negative organisms

Question 9

Antimicrobial strategies

Answer 9

Prophylaxis treat an infection that has not yet developed in individuals at a high risk of developing an infection.

Pre-emptive- have lab test indicating infection but no symptoms. Advantage decreases amount of antibiotics being used.

Empiric Therapy- take cultures, patients have an infection with serious potential consequences but the organism has not been identified (broad spectrum)

Definitive Therapy- pathogen identified (monotherapy, narrow spectrum)

Suppressive Therapy- after initial disease is controlled therapy is continued

Question 10

Which of the following situations describes empiric antibiotic therapy?

A. Beginning nitrofurantoin for a patient with a history of repeated urinary tract infections to prevent another infection

B. Beginning nitrofurantoin for a patient with signs and symptoms of a urinary tract infection with a positive urinalysis

C. Beginning nitrofurantoin for a patient with signs and symptoms of a urinary tract infection with E. coli growing in the urine that are susceptible to nitrofurantoin

D. Beginning nitrofurantoin for a patient with signs and symptoms of a urinary tract infection with E. coli growing in the urine that are resistant to nitrofurantoin

Answer 10

B

Question 11

Pharmacokinetics

Answer 11

Pharmacokinetics- body’s effect on a drug

**Must treat the individual with the right drug, right dose, right route, and right duration to kill enough bacteria to eliminate the infection.

• *Absorption**- movement of drug into the vascular system
• *Distribution**- transfer of drug from intravascular to extravascular, blood brain barrier presents a challenge
• *Metabolism**- irreversible transformation of parent compound into daughter metabolites often in the liver
• *Excretion**- elimination of the drug from the body through urine or feces

Question 12

Which drugs will have a harder time with absorption?

What’s a common concern affecting pharmacokinetics?

Answer 12

Large, charged ones

Drug- drug interactions often occur when one drug inhibits or induces the uptake or
clearance of another drug.

Question 13

Drug administration- oral, intravenous, intramuscular, subcutaneous, inhalant, sublingual, intrathecal, rectal, or topical

Answer 13

Question 14

6-year old patient presents to you in clinic with a high fever and inflamed throat. The mother is asking for antibiotics. What will you do?

Answer 14

Strep test if symptoms are consistent with Group A streptococcal infection. (age 5-15, fever, headache, tender nodes). Cough coincides with viral infection and step test is not recommended.

If positive treat. If negative, fluids and rest.

Most pharyngitis is caused by viruses.

If viral, don’t give an antibacterial drug!

Responsible writing of prescriptions is important since:
1. Need to minimize the development of antibiotic resistant microorganisms

2. Minimize harm to the patient caused by toxicity due to the use of an
   unnecessary or inappropriate drug.
3. Provide cost effective treatment. Hospital purchases of antibiotics usually
   represent 25-30% of the drug budget.

Question 15

Do a rapid strep test? Yes or no?

Answer 15

Question 16

List methods that can be used to confirm the identify of the organism causing the infection

Answer 16

A positive rapid antigen detection test is diagnosticspecific (>95%) available in minutes but sensitivity is (80-90%)

• Serologic test- characteristic proteins or polysaccharides are detected with antibodies
• May have a false negative or infection could be due to another bacterial organism

Question 17

A backup culture of a throat swab for all children with a negative result takes 24-48 hours Gram stain and morphologic analysis (cocci vs. bacilli)

Answer 17

purple v pink, single, chain, cluster… remember, strep pneumo is diplococci (just two, not long chain like strep pyogenes). staphylococcus = purple clusters

Question 18

Biochemical Tests

Answer 18

Catalase test- monitors degradation of H2O2; differentiates between staphylococci (present) and streptococci (absent)

Coagulase test- differentiates Staphylococcus strains

Hemolysis- clearing around colonies on a blood agar plate differentiates between streptococci
α-hemolytic form green ring
β-hemolytic clearing around colonies on agar plates
γ-hemolysis no hemolysis

Glucose/lactose fermentation

www.wisc-online.com/Objects/ViewObject.aspx?ID=MBY4307

Question 19

Dichotomous Key

Answer 19

Question 20

Why is it important to initiate therapy in Group A Strep infections>

Answer 20

Important to treat to prevent sequelae like damage to heart valves (rheumatic fever)

Question 21

Group A streptococcal (GAS) pharyngitis:

Answer 21

In absence of positive test, Need 3 of 4 findings to favor GAS diagnosis:

Fever
Tonsillar exudates
No cough
Tender cervical lymphadenopathy

Question 22

Is there a history of drug reaction/allergy?

Answer 22

*Beta-lactams (penicillin) and sulfonamides
*In some cases, allergy to a particular drug will predict allergies to other drugs in the class.
*Must be careful about labeling a patient as allergic since this can result in treatment with inferior drugs
*Can do a skin test to confirm and try penicillin desensitization.

Question 23

How old is the patient?

Does the patient have any other diseases?

Answer 23

In the elderly, kidney function is reduced. With decreased excretion, the half life of beta-lactams, aminoglycosides and fluoroquinolones increasing likelihood of adverse effects.

Chloramphenicol is inactivated by liver metabolism.
With impaired liver function, dose should be reduced.

Question 24

What is the status of the patient’s immune system?

When use bactericidal?

Answer 24

• *Bacteriostatic**- limits growth and if removed the organism can grow again. Usually successful because allows immune system to catch up.
• *Bactericidal**- 99.9% reduction in bacterial inoculums within 24 hr period of exposure. Cell-wall inhibitors

Drug may be bacteriostatic against one organism and bactericidal against another.
Many bactericidal drugs do not work well if the cells are not actively dividing.

In immunocompromised patients, may want to use bactericidal b/c patient

Lastly, if bacteria is in spore form, or isn’t actively dividing, wouldn’t want to use something that targets ribosomes or replication.

Question 25

If your patient was undergoing cancer chemotherapy and had a suppressed immune system, would you choose drug A or drug B to treat the infecting organism? Why?

Question 26

Are there genetic factors which make the patient more susceptible to toxic side effects?

Answer 26

Sulfonamides may cause hemolysis of red blood cells in individuals with glucose-6-phosphate dehydrogenase deficiency.

Question 27

Is the patient pregnant?

What is the pregnancy category for Penicillin?

Answer 27

Table 1. US FDA Pregnancy Category Definitions

A Studies in pregnant women. No Risk
B Animal studies indicate no risk, but human studies are not adequate; or animal toxicity but human studies indicate no risk.
C Animal studies show toxicity, human studies inadequate but benefit of use may exceed risk
D Evidence of human risk, but benefits may outweigh risk

X Fetal abnormalities in humans, risk exceeds benefit

Question 28

Has the patient recently been on an antibiotic?

Propose some mechanisms associated with bacterial resistance to antibiotics.

Answer 28

Suspect drug resistance or possible superinfection

Eflux pumps, beta lacatamse, change in target site

Question 29

Mechanisms of Resistance

Answer 29

Add pics

intrinsic resistance = absence or inaccessibility of the target for the drug action. E.g. Mycoplasma lack cell wallsso they are intrinsically resistant to cell wall inhibitors
No change in the genetics of the bacteria occurs.

Acquired Drug Resistance
The bacteria change their DNA (mutation) or acquire new DNA resulting in resistance to a drug.

VERY IMPORTANT to understand that the drug itself is not causing the resistance

Question 30

Ways bacteria take up mutations from environment

Answer 30

Transformation: Taking up nearby DNA w/ Strep resistance on it. –> After replication, one daughter cell has resistant DNA; other does not. Those that do would survive in the presence of antibiotic.

TRansduction: From bacteriophage

Conjugation: Often, amoungst Gram-‘s. F+ cell passes to F- cell. Info is passed & both have it b/c the plasmid is replicated b4 being passed.

Transposition:Transposition can then cause the movement of the genetic material within the genome

Question 31

Example of how antibiotic resistance is transferred from Enterococcus to Staphylococcus

Answer 31

Question 32

Increasing resistance is coupled with less new antibiotic development.

Question 33

Antibiotic Susceptibility Testing

Answer 33

Antibiotic Susceptibility Testing- results can be at least as important as determining the etiologic agent

Some organisms have predictable susceptibility to antimicrobial agents (ie, Streptococcus pyogenes to penicillin). Therefore, antibiotic susceptibility testing for such pathogens is seldom required or performed

Question 34

MIC

Answer 34

*Minimum Inhibitory concentration (MIC) lowest concentration of antibiotic that prevents visible growths in culture, usually reported as ug/mL

*If MIC is lower than the breakpoint then the bacterium is considered susceptible. The breakpoint is determined by looking at the pharmacokinetics, achievable antibiotic concentration, and clinical efficacy.

*Advantage of agar testing over broth testing- contamination and heterogenous populations are more obvious

Example of phenotypic test: Kirby Bauer test - measurement of antimicrobial inhibition…can also do genotypic test

Question 35

12 steps to prevent antimicrobial resistance in hospitalized adults

Answer 35

Question 36

Consequences of overly broad antibiotic treatment-

Answer 36

The balance of the normal residents of the bowel, skin, etc. is maintained by competition for nutrients and the production by bacteria of compounds that inhibit the growth of other bacteria. When an antibiotic kills an important resident bacterium, other harmful bacteria may be able to multiply and cause a secondary infection or superinfection.

• The broader the spectrum of activity and the longer time period of antibiotic treatment, the more likely that treatment with the antibiotic will cause superinfection*.
• Symptoms of superinfection range from mild diarrhea to acute enteritis.*

Question 37

Mutualistic partnerships with commensal bacteria may be important for our health

Answer 37

Use antibiotics in a way that limits
harm to microbiome

Restore indigenous microbiota
(prebiotics and probiotics)

Discover protective mechanisms used
by the microbiome

Question 38

NBME question: A patient being treated with clindamycin for aspiration pneumonia develops diarrhea. A stool sample from the patient contains a toxin that kills cultured epithelial cells. Stool culture grows an anaerobic gram-positive rod. The same organism is cultured from the patients’ bed pan. Which of the following will be effective to sterilize the bed pan?

Question 39

How prevalent are Clostridium difficile infections? Identify what risk factors increase the likelihood of an infection. (Epidemiology)

What are most common symptoms associated with C.diff infection and what other infections present with similar symptoms? (Microbiology)

What tests are used to diagnose C. diff infection? (Biochemistry)

How can the transmission of C. diff infections be prevented? (Microbiology)

Draw a picture to explain the underlying cause of patients’ symptoms. (Pathology)

What are potential therapeutic options for individuals with C. diff infection and what is the mechanism of action at which the treatments intervene? (Pharmacology)