DENT 601 Dental Pharmacology Final Exam

What is acquired ß-lactam resistance?

(rare) - have altered PBP (transpeptidase) - antibiotic no longer binds (MRSA is an example)

How we make the distinction between true penicillin allergy and other things

1. Rashes that involve hives (raised, intensely itchy spots that come and go over hours), or occur with other allergic symptoms like wheezing or swelling of the skin or throat, suggest a true allergy 2. Rashes that are flat, blotchy, spread over days but do not change by the hour are less likely to represent a dangerous allergy. These rashes typically start after several days of treatment. 3. Rashes follow the administration of ampicillin in nearly all patients with infectious mononucleosis.

Mechanisms of resistance to cephalosporins?

1. Inability of drug to reach site of action (innate resistance) 2. Destruction by cephalosporinases - It is an *acquired resistance - most common*

ß-lactams are bactericidal or bacteristatic?

Bactericidal

Are there issues to consider when treating an immunocompromised patient (choice between a bacteriostatic versus bactericidal antimicrobial)?

Bacteriostatic antibiotics rely on the patient's immune system to eliminate the infection to a large extent.

Why is Amphotericin B associated with severe toxicities when given systemically?

Because it can bind the cholesterol in our cell membranes along with the ergosterol in the fungal cell membranes.

Tetracycline drug interactions

Bind divalent cations (Ca2+, Mg 2+) or trivalent cations (Fe 3+Al 3+) found in dairy products and antacids. When taken together, absorption will be impeded.

What is the mechanism of action of all Macrolides

Bind to 50S ribosomal subunit to inhibit peptide chain elongation (bacteriostatic)

Tetracycline mechanism of action

Bind to the 30S ribosomal subunit and blocks protein synthesis. *Bacteriostatic* Short acting: tetracycline (avoid in patients with poor kidney function) Long acting: doxycyline, minocycline

Mechanism of Action of aminoglycosides

Bind to the 30S ribosomal subunit and interfere with protein synthesis 1) block initiation 2) cause premature termination of elongation 3) cause misincorporation of amino acids into growing peptide chain.

What are the "broad spectrum penicillins" as oppose to the "natural penicillin"?

Broad spectrum penicillins (ampicillin, amoxicillin - more polar) are broad spectrum because they can *diffuse through Porin channels better than regular penicillins* (like Penicillin G)

How are Peptidoglycan chains joined together?

By a pentapeptide extending from the NAM residue - Existing peptidoglycan cell wall is selectively cleaved through the action of *autolysins* - so that it is possible to add new peptidoglycan monomers

How can we combat ß-lactamases?

Can give penicillins in combination with *ß-lactamase inhibitors* to combat drug resistance

Other than hypersensitivity, what are some of the other adverse reactions to penicillin?

Diarrhea - disruption of normal GI bacteria o *Pseudomembranous colitis (occurs with use of broad spectrum amoxicillin) - outgrowth of c. difficile - shut down GI tract* Pain and discomfort at site of IM injection

What are the adverse effects of clindamycin?

Diarrhea and skin rashes (10-20%) Severe but rare Adverse effect: Pseudomembranous colitis (Clindamycin is most associated with this rare but serious effect due to the overgrowth of Clostridium difficile during or after antibiotic treatment.

What is the unique pharmacokinetic feature of azithromycin?

Displays a unique tissue distribution by accumulating in cells and then released slowly from tissues over time - allows for a shortened dosing schedule (Z packs).

How can we prevent the emergence of drug resistance?

Don't treat viral infections with antibiotics!

Therapeutic uses of aminoglycosides

Due to the toxicity, aminoglycosides are reserved for use in serious infections that do not respond well to other less toxic agents

What is significant about the absorbability of erythromycin?

Erythromycin is inactivated in the stomach and must be coated for protection. Clarithromycin and Azithromycin are more acid stable and orally bioavailable.

Are anaerobic or aerobic bacteria vulnerable to aminoglycosides?

For both gram(+) and gram(-), transport across the cell membrane into the cell is Oxygen and energy dependent (*anaerobic bacteria are therefore resistant to aminoglycosides*).

Fluoroquinilones side effects

GI (nausea & vomiting) CNS (mainly at high concentrations) photosensitivity QTc prolongation (levofloxacin & moxifloxacin) *Cartilage toxicity* and joint swelling in children *Increased risk of tendonitis & tendon rupture (esp. Achilles tendon)* *Pseudomembranous Colitis by overgrowth of Clostridium difficile.* *Not recommended as drug of 1st choice in pediatric patients (<18 yrs) due to cartilage toxicity.*

Tetracycline adverse of effects

GI problems (diarrhea), *tooth staining, photosensitivity, liver/kidney toxicity at high doses* - *pseudomembranous colitis is a rare but serious side effect*. Broad Spectrum but declining in use because of plasmid mediated resistance (through a variety of mechanisms, especially through drug efflux)

What are the symptoms of hypersensitivity to penicillin?

Get rash, fever, itchy eyes, hives, wheezing, maculopapular rush, *anaphylaxis - severe adverse reaction* *If a patient is allergic to penicillin, assume allergy to all penicillins and cephalosporins!!*

Explain how metabolism of isoniazid can be different in various people?

Metabolized in the liver acetylation, *renal excretion*. *Plasma half life in fast acetylators is 70 min and in slow acetylators is 2-5 hr*

Macrolide Adverse Effects

Nausea, vomitting, diarrhea Abdominal pain Liver toxicity (estolate related) *Erythromycin inhibits P450* Drug interactions & Prolonged QT interval

What is the absorption of Vancomycin?

Not absorbed orally. Needs to be administered *slowly* by IV - Drug is well-distributed - Little metabolism (6 hours half-life) - Glomerular filtration - excreted unchanged in urine mostly. Once again need to adjust dose to patients liver functioning.

Aminoglycoside Side Effects

OTOTOXICITY • Irreversible damage to hearing and balance. • Ringing in the ears (tinnitus) is one of the first signs of trouble. NEPHROTOXICITY • Damage is usually reversible upon drug withdrawal. • Any loss in renal function can spiral into further complications (Ototoxicity and more Nephrotoxicity) due to increased accumulation of Aminoglycosides in the body. *Doses must be modified when renal fuction is poor)*

Rifampin Side Effects

Orange red colored urine, sweat, tears and feces (harmless, but patients should be warned) Flu like symptoms *Hepatotoxicity (avoid alcohol)!* *DRUG INTERACTIONS!*

What determines the activity of penicillins?

The R-group - Penicillin G has a benzene ring as R group - Amoxicillin has a phenyl ring (more polar so more permeable through the gram(-) walls) - Cloxacillin has a bulky R group - penicillinase resistant The bulkier the R-group the more resistant it is to being inactivated

What needs to be kept in mind about the excretion or aminoglycosides?

The absorption from the GI tract is negligible because they are so polar (have very poor CSF penetration). The majority is excreted unchanged in the urine. *The half life can increase to 24-48 hours in patients with severe renal impairment!*

Which drugs block the production of folic acid?

The antifolates (Sulfonamides and Trimethoprim) Blocks folate production by bacteria

What's the difference between the human eukaryotic cell and the fungal eukaryotic cell?

The fungi have *ergosterol* in their cell walls and that's what anti-fungal drugs target.

What are the Delayed Absorption Penicillins and what are their benefits?

These are used for increasing the half life and when prolonged concentrations of penicillin G are desired. - Benzathine penicillin G (maintains a low steady blood level for more than 24 hours) - Procaine salt - higher level in blood but stable for 18 hours only.

What are the adverse effects of vancomycin?

- Fever, chills - Rapid infusion can cause thrombophlebitis (vein blood clots) and wide spread reddening of skin due to histamine release (*red man syndrome*) - Ototoxicity and nephrotoxicity associated with high dose regimens

Clindamycin mechanism of action

*Bacteriostatic* Inhibition of peptide chain elongation - binds to the same site as the macrolides in the ribosomal 50S subunit.

Which macrolides show drug interactions with enzyme CYP 3A4?

*Erythromycin and Clarithromycin are potent inhibitors of CYP 3A4* and have the potential to cause serious toxicities when given with other drugs that are metabolized by CYP 3A4. *Azithromycin does not appear to inhibit CYP3A4.*

What is important to keep in mind about the metabolism and excretion of penicillins?

*Infants and individuals with impaired kidney function will require lower doses to avoid toxicity!* - 30-60 min half life - rapidly eliminated by glomerular filtration and tubular secretion; majority excreted unchanged in urine

What are the rifampin drug interactions to keep in mind?

*Strong inducer of P-450 enzymes*, which increases the elimination of other drugs including (makes them less effective): Anticoagulants Anticonvulsants (some) HIV 1 protease inhibitors, nevirapine (NNRTI) Contraceptives Methadone Antirejection medications (tacrolimus, cycosporine) Cardiac medication

What is the selectivity of sulfonamides?

*Targets dihydropteroate synthase* Only Bacteria express dihydropteroate synthase - we obtain folate from our diets Inhibits bacterial Dihydrofolate Reductase, but not human Dihydrofolate Reductase

What determines sensitivity of bacteria to penicillin?

- Ability to enter through outer membrane - Resistance of penicillin to degradation by ß-lactamases produced by bacterium - Affinity of penicillin to PBPs

What is the mechanism of action of vancomycin?

- Binds directly to the pentapeptide chain (termini) and intereferes with peptide crosslinking during cell wall synthesis - It is *bactericidal* - Can only get through gram(+) walls; not effective against gram(-) -Vanomycin does not inhibit transpeptidases but binds to and 'traps' their substrate- no product can be formed

What are Cefazolin, Cephalexin, and Omnicef?

- Cefazolin - (Gen. 1) widely used for prophylaxis before surgical procedures where gram+ skin microbes are likely pathogens - *Cephalexin* - (Gen. 1) most frequently prescribed 1st generation - *Omnicef* - (Gen. 3) most frequently prescribed 3rd generation

What are some examples of ß-lactamase inhibitors?

- Clavulonic acid, sulbactam and tazobactam - irreversible "suicide" inhibitors of many (but not all) bacterial ß-lactamases - *Augmentin (amoxicillin + clavulanic acid)*

How do ß-lactamases function to create resistance?

- Cleave ß-lactam ring to inactivate the drug - ß-lactamases could be narrow spectrum or broad spectrum (inactivate many if not all ß-lactam drugs no matter what the R group is)

What is the ß-lactam ring?

- Common core structure for antibiotics (penicillins, cephalosporins, monobactams and carbapenems) - Resistant bacteria produce enzymes which destroy ß-lactam ring (penicillinases, carbapenases, ß-lactamases)

How does drug resistance to vancomycin (VRE - vancomycin-resistant enterococci) develop?

- Emerged in 1990s - *VRE acquired a new pathway for synthesizing peptidoglycan monomer* -High level resistance to Vancomycin arises through reprogramming the drug target to D-Ala-D-Lac. This substitution significantly reduces vancomycin binding affinity without interfering with peptide crosslinking and cell wall integrity.

There aren't many penicillin drug interactions, but what are the drug interactions with NSAIDs, oral contraceptives, and bacteriostatic penicillins?

- NSAIDs, aspirin and probenecid: competition for elimination by the kidney resulting in penicillin toxicity - Oral contraceptives: effectiveness reduction - Bacteriostatic Penicillins: Bactericidal penicillins can only function only active penicillins so combing a bacteriostatic and bactericidal would cancel the bactericidals affects

Adverse effects of cephalosporins

- Nausea, cramping, vomiting - Also associated with *pseudomembranous colitis (due to c. difficile)* - Oral contraceptives efficiency is reduced - Allergies o Individuals allergic to one cephalosporin should avoid all o *Anaphylactic reactions are more rare (0.0001%-0.1%)* o Some studies suggest that 10% of patients allergic to penicillins are cross-allergic to cephalosporins • Never ever never give cephalosporins to patients with a history of severe reactions to penicillin

What are the cephalosporins?

- One of the largest and most prescribed classes of antibiotics - Share the same basic structure with penicillins - ß-lactam ring

What are the absorption, distribution, metabolism and excretion of cephalosporins?

- Oral, parenteral absorption - Good distribution, some penetrate CSF - 0.5-8 hrs half life - Excretion is through kidneys - same thing, patients with impaired kidney function need to be careful.

What are the ß-lactam antibiotics?

- Penicillins - Cephalosporins

When do we use vancomycin?

- Serious infections in patients with severe penicillin allergies - Serious infections caused by multidrug resistant gram+ (c. difficile, MRSA, pseudomonas, enterococcus faecalis)

What is Vancomycin resistant s. aureus (VRSA)?

- VanA gene likely transferred from e. faecalis to s. aureus - Several identified in Michigan

Biochemistry of action of ß-lactam

- ß-lactam ring mimics the amino acid substrate for transpeptidases - Binds to the transpeptidase covalently and does not dissociate easily o Bacterial cell has to build a new transpeptidase

4 generations of cephalosporins

1st generation - cephalosporinase sensitive, affects gram+ more than gram- 2nd generation - broader spectrum of activity, increased penetration through gram-, increased resistance 3rd generation - cephalosporinase resistant, penetrate CNS, affect more gram- than gram+ o New resistance is emerging among gram- → extended spectrum beta-lactamases (ESBLs) 4th generation - true broad spectrum and even more resistant to beta-lactamases o Especially good at treating p. aeruginosa Later generation drugs are good but have many side effects (mostly because of their side groups)

Why should macrolides be avoided in people with cardiac rhythym disorders?

All macrolides have the potential to cause prolongation of the QT interval, they should not be given to patients with cardiac rhythm disorders and/or if the co-administered drug is also associated with this effect on cardiac muscle repolarization.

What is the only bactericidal protein synthesis inhibitor?

Aminoglycosides (Gentamicin)

Aminoglycosides are most effective against gram(+) or gram(-) bacteria?

Aminoglycosides enter *aerobic gram(-) bacteria* through porin channels. Transport across the peptidoglycan cell wall of gram(+) bacteria may be enhanced by cell wall inhibitors such as penicillin or vancomycin, which can produce a synergistic effect with aminoglycosides.

What is Vancomycin intermediate level of resistance in s. aureus (VISA)?

First identified in Japan - Resistance where prolonged use of vancomycin is prevalent - Associated with alteration in peptidoglycan cell wall composition (thickening of the wall)

What is the most important adverse effect and one of the most common drug allergies?

HYPERSENSITIVITY to Penicillin Patients can become allergic to components of the R group or the ß-lactam ring. Degradation products of penicillin combine with host proteins and become antigenic

Cephalosporins share the common ß-lactam ring with penicillin but what makes them different?

Have two R-groups • Like penicillins, changes in R1 group alters spectrum of activity + susceptibility to beta-lactamases • Changes in R2 group modify metabolism and pharmacokinetic properties

Mycobacterium (tuberculosis) is slow growing and mutates often. Because each mutation leads to resistance to a drug, what is the strategy of dealing with mycobacterium?

Hit Mycobacterium tuberculosis with a cocktail of drugs. If resistance to one drug occurs, the other drugs will hopefully eliminate mutant (resistant) bacteria.

Adverse Effects to Sulfonamides

Hypersensitivity reactions: rash, fever, and photosensitivity Severe hypersensitivity: *Steven-Johnson syndrome* - wide spread lesions over skin and mucous membranes accompanied by fever - 25% mortality. *Kernicterus (a toxic encephalopathy) in infants. Sulfonamides are contraindicated in newborns & during the last 2 months of pregnancy.*

What is the contraindication of tetracycline therapy?

In nursing or pregnant women as well as young children due to potential effects on bone development (by binding to Ca+2) as well as cosmetically undesirable tooth staining.

Fluoroquinilones (Cipro)

Inhibit DNA gyrase and topoisomerase IV, enzymes necessary for DNA replication and cell division (unwinding and unknotting DNA). *Broad spectrum, Bactericidal*

Penicillin & Cephalosporin work by inhibiting what part of the bacterial cell wall biosynthesis?

Inhibit transpeptidase

Rifampin

Inhibits RNA synthesis by inhibiting DNA dependent RNA polymerase - *Bactericidal*. Rifampin is considered one of the most important & potent anti TB drugs. It is administered along with isoniazid, pyrazinamide, ethambutol (e.g. RIPE drug combination) or another anti TB drug to prevent the emergence of drug resistant myocbacteria.

How does isoniazid combat tuberculosis?

Inhibits biosynthesis of mycolic acids which are important for mycobacterial cell wall synthesis Along with Rifampin, Isoniazid is considered one of the best anti TB drugs available. *Bacteriostatic*

Isoniazid side effects

Isoniazid induced *hepatic toxicity* is the most frequent major toxic effect *Peripheral neuropathy* can occur in 10-20% of patients, but this side effect is minimized by daily prophylactic administration of *vitamin B6 pyridoxine*

Which triazole drug shows the greatest CYP 3A4 inhibition?

Itraconazole (strongest) Voriconazole (moderate-strong)

In what case would a dose reduction of Fluconazole be needed?

Patients with Renal Impairment. This drug is cleared by renal excretion with up to 80% appearing in the urine uncharged.

Proteins that interact with penicillin are referred to as?

Penicillin Binding Proteins (PBPs) There are many PBPs that vary in their affinities for ß-lactam antibiotics - reduced affinity can be a mechanism of resistance.

What is the mechanism in which ß-lactam inhibits the peptidoglycan synthesis?

Penicillins bind to and *inactivate transpeptidase enzymes* which are responsible for cross‐linking peptidoglycan monomer subunits together for cell wall integrety. This increases lysis

Which antibiotics are safest during pregnancy?

Penicillins, cephalosporins

How do penicillins gain access through the gram (-) cell walls?

Porin channels

What does it mean when we say aminoglycosides exhibit a "post-antibiotic effect"?

Residual bactericidal activity persists after the serum concentration has fallen below the minimum inhibitory concentration

What is one *clear* association with birth control failure and an antiobiotic?

Rifampin definitely alters the metabolism of many oral contraceptives. If a woman is taking rifampin, she must use a second form of birth control - recall that rifampin induces cytochrome p450 enzymes

Overview of bacterial cell wall biosynthesis

Step 1: Peptidoglycan monomers are synthesized in the cytoplasm Step 2: The peptidoglycan monomer is linked to a membrane-anchored lipid carrier which transports the monomer across the cell membrane. Step 3: The existing peptidoglycan cell wall is selectively cleaved through the action of autolysins: • Break the glycosidic bond between NAG and NAM • Remove the peptide crosslink bridges that link the sugar strands together Step 4: transglycosylase and transpeptidase link the new sugar strands and peptide crosslinks

What are the two types of fungal infections?

Superficial (yeast/fungi) Mycoses Systemic Mycoses

How is combining Trimethoprim with a sulfonamide beneficial?

Synergistic - bacteria are less likely to develop resistance to both agents.

What drug is used to treat MRSA?

Vancomycin

What is the antibiotic of "last resort"?

Vancomycin bacterial cell wall synthesis inhibitor We use these as a last resort because we don't resistance forming against it.

What is the distribution of penicillin?

Wide distribution but *does not penetrate the CNS*

What is clidamycin best suited for?

excellent activity against many anaerobic organisms *Almost all absorbed following oral administration*

Penicillins penetrate gram (+) or gram (-) walls more easily?

gram (+) - Gram (-) LPS membrane is impermeable to natural penicillin

Organisms associated with superinfections

o Clostridium difficile o Multiple Drug Resistant (MDR) gram‐negative rods o MRSA o Candida or other fungi

What are some of the atypical cephalosporin side effects?

o Hypothrombocytopenia - inhibition of enzyme necessary for redox metabolism of vitamin K o Disulfiram-like effect - increase in acetaldehyde when taking alcohol - hungover effect.

Methicillin-resistant staphylococcus aureus (MRSA) is what?

resistance to many antibiotics, and resistant to all beta-lactams

What are the two forms of resistance to penicillins?

ß-lactamases (most common) Low affinity transpeptidase (least common) • The ability to enter through the Outer Membrane (via Porins) • The resistance of the Penicillin to degradation by ß-lactamases produced by the bacterium. • The affinity of the Penicillin for Penicillin-binding proteins.

How do ß-lactam destroy bacteria?

ß-lactams target enzymes needed for bacterial cell wall synthesis (N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) which make up peptidoglycan wall)

What are the two resistance mechanisms to fluoroquinolones?

• Active efflux of drug (efflux pump) • Decreased affinity of bacterial DNA Gyrase for drug due to mutation

Indications for fluoroquinolones

• Broad spectrum of activity against aerobic gram Negative bacteria and Gram positive organisms • Urinary tract infections, GI infections, respiratory infections • Bone, joint, and soft tissue infections • Prophylactic treatment for anthrax (Ciprofloxacin). • Poor activity against anaerobes

Bacteriostatic antibiotics

• Clindamycin • Macrolides • Sulfonamides • Tetracyclines • Trimethoprim Relies on an intact immune system to eliminate infection - inhibits bacterial cell growth in the absence of cytotoxicity.

What is the difference between "Community acquired MRSA" and "Hospital Acquired MRSA"?

• Community-acquired MRSA (CA-MRSA) - soft tissue infections and life-threatening invasive infections - typically not multi-drug resistant. • Hospital acquired MRSA (HA-MRSA) - resistant to many other antibioticvs (erythromycin, clindamycin) - vancomycin is standard tx but resistance is rising

What do we look for in true penicillin allergy?

• Immediate onset-release of histamine • Hives-itchy raised red patches of skin, also known as uticaria • Angioedema (swelling of the tissue under the skin, commonly around the face) - swollen lips, eyes, toungue • Throat tightness, wheezing, coughing, and trouble breathing from asthma-like reactions (narrowing of the airways into the lungs) • Anaphylaxis-can be fatal

Bactericidal antibiotics

• Pencillins & Cephalosporins • Isoniazid • Metronidazole • Rifampin • Vancomycin • Aminoglycosides • Fluoroquinolones Better choice for an immunocompromised patient - directly eliminates infection due to direct cytotoxicity.