Pharmacology – Antibiotics Lectures Combined

Make sure you know the learning objectives.
1. Learn mechanism of action, use and toxicity of trimethoprim/sulfamethoxazole.

2. Know mechanism of action, use, drug interactions and toxicity of fluoroquinolones.

3. Review use and toxicity of nitrofurantoin.

4. Be aware of use and toxicity of six TB drugs.

What can trimethoprim alone be used for?
Structurally similar to folic acid.

Selective inhibitor of dihydrofolate reductase.

Weak base which becomes trapped in acidic environments e.g. prostate/vagina. FOr this reason can be used alone for UTI prostatic infections.

How does trimethoprim/ sulfamethoxazole work?
Trimethoprim inhibits bacterial dihydrofolic acid reductase (which converts dihydrofolic acid to tetrahydrofolic acid) the pathway of purine synthesis and thus DNA synthesis.

TMP and SMX are synergistic, blocking sequential steps in folate synthesis increasing bacterial activity.

Antimetabolite-drug that through chemical similarity is able to interfere with endogenous compound in cellular metabolism.

Sequential blockade-combined action of two drugs that inhibit sequential steps in pathway of bacterial metabolism.

Combination is bactericidal!!! = TQ.

For TMP/SMX when do you need to do a dose reduction?
Comes in fixed 80:400 mg or 160:800 mg dose. So like high and low dose.

Acetylated or glucuronidated in the liver then excreted in urine.
–Dose reduction in significant renal failure.

What is the spectrum of activity for TMP/SMX?
Gram positive (MRSA, listeria- even though drug of choice of listeria is ampicillin).

Gram negative (Stenotrophomonas, Haemophilus influenzae, Moraxella catarrhalis).
~30% e. coli resistant to TMP/SMX
—Overproduction of PABA
—Dihydropteroate synthase with low affinity for drug
—Decreased bacterial permeability

Nocardia, pneumocystis (fungi), Toxoplasma (parasite).

What are the indications for TMP/SMX?
PCP (Pneumocystis carinii pneumonia)!!! = TQ
– Treatment and prophylaxis

MRSA

UTI/prostatitis
-Treatment and prophylaxis
-Avoid empiric in complicated UTI since 30% of E. coli is resistant to TMP/SMX.

Nocardia

Toxoplasmosis
-Treatment and prophylaxis

What is Sulfadiazine used for?
Sulfadiazine is used with pyrimethamine for treatment of toxoplasmosis; folinic acid/leucovorin rescue is given to prevent bone marrow suppression. This is since folate metabolism is needed to make WBC and RBC.

What is Sulfadoxine used for?
Sulfadoxine with pyrimethamine (Fansidar) for malaria.

What is Sulfasalazine used for?
Sulfasalazine (oral anti-inflammatory) for ulcerative colitis and RA.

What is Sodium sulfacetamide used for?
Sodium sulfacetamide ophthalmic for conjunctivitis.

What is Silver sulfadiazine used for?
Silver sulfadiazine topical for burns. This is then a topical antibiotic.

What are effects of sulfa toxicity?
1. Rash!!! = TQ (very common esp. in HIV)
-Assume cross-hypersensitivity among sulfa drugs
-Photosensitivity
-Stevens-Johnson: Rash all over body. Very severe, can be fatal.

2. Fever

3. Hepatitis

What toxicity does sulfa have on the blood?
Hematologic:
-Anemia, neutropenia, thrombocytopenia. This is due to interference with folate metabolism.

-Hemolysis in G6PD deficiency.

Why do you not give sulfa drugs to women in their third trimester of pregnancy?
-Sulfonamides displace bilirubin from plasma proteins risking kernicterus in neonate if used in third trimester of pregnancy
–Also displaces methotrexate and warfarin

What toxicity does sulfa have on the kidneys?
Hyperkalemia due to blockade of the collecting tubule sodium channel by trimethoprim.

Crystalluria with acid urine with SMX.

TMP decreases the tubular secretion of creatinine. So will have falsely elevated creatine.

What is Dapsone? What it is used for and what side effects does it have?
Similar to sulfa drugs. Inhibits folate synthesis.

Second line agent for PCP prophylaxis.

Used to treat leprosy.

Causes hemolysis in G6PD deficiency.

Methemoglobinemia.

Rash.

What is the mechanism of action for fluoroquinolones?
It prevents DNA uncoiling.

Synthetic fluorinated analogs of naldixic acid.

Block bacterial DNA synthesis by inhibiting DNA gyrase (gram negative)/topoisomerase IV (gram positive).

Bactericidal.

What post use effect is seen with fluoroquinolones?
Like aminoglycosides, has post antibiotic effect!!! = TQ.

Dose adjustment for decreased creatinine clearance (except moxifloxacin which is metabolized by liver).
-Have to dose adjust for renal dysfunction.

What is the spectrum of activity for fluoroquinolones?
Gram positive:
-MSSA sensitive but MRSA tends to be resistant
-Anthrax

Gram Negative:
-E Coli, Salmonella, Shigella, Campylobacter
-Pseudomonas
-Meningococcus
-Resistance issues: campylobacter, gonorrhea
–NB: there is cross resistance

Atypicals
-Mycoplasma
-Chlamydia
-Legionella
-Mycobacteria

Why are fluoroquinolones thought to be a very useful antibiotic?
You can use them for a wide variety of conditions:

-UTI/prostatitis
-Pneumonia
-Salmonella, shigella, toxigenic e. coli campylobacter
-Osteomyelitis
-Febrile neutropenia
-Mycobacteria
-Meningococcal carrier
-Anthrax

When would you want to use Levofloxacin?
Levofloxacin better against gram positives e.g. pneumococcus so more for Pneumonia.
-Conveniently also covers legionella.

Note this is a fluoroquinolone.

When would you want to use Moxifloxacin?
Moxifloxacin also used for Pneumonia but…
has anaerobic activity!!!! = TQ.

Not indicated for UTI.

When would you want to use Ciprofloxacin?
Ciprofloxacin better against gram negatives so more for UTI.

When would you want to use Ofloxacin or norfloxacin?
Ofloxacin and norfloxacin only for UTI

What is Fluoroquinolone Toxicity?
Headache, dizzy, insomnia.

Rash, photosensitivity.

Ciprofloxacin is most common cause of c. difficile. Also clindamycin.

QT prolongation

What are Fluoroquinolone drug interactions on PO?
Absorption inhibited by di/trivalent cation antacids (Calcium, Magnesium, Aluminum).

Also iron, zinc, milk.

Ciprofloxacin inhibits metabolism of theophylline.

What are consequences of Fluoroquinolone Toxicity?
Cartilage damage!!! = TQ.
Tendon rupture (risk factors age, renal insufficiency, corticosteroids).

Avoid in children and pregnant women to avoid damage of growing cartilage.

What is Nitrofurantoin used for and what type of killing does it perform?
Bacterostatic and cidal for many gram positive and negative bacteria but pseudomonas resistant as well as many proteus species.

No systemic levels. So will only have the drug in the urine!!! = TQ.

Drug concentrates in urine so can only use for simple UTI not in patients with pyelonephritis. Since the ABx doesn’t go into the blood.

Can use as treatment for cystitis since limited to the bladder.

Contraindicated in renal insufficiency.

What are the usages for nitrofurantoin and what are the adverse effects?
Usage: UTI or UTI prophylaxis.

Adverse effect: pulmonary hypersensitivity.

59 YOF presents to urgicare with 4 day history of frequent and painful urination. She has had fever chills and flank pain for 2 days but no vomiting. Urine dip positive leukocyte esterase. Urine culture pending. She has had three UTIs over the past year treated with TMP/SMX. She has osteoporosis and takes a calcium supplement daily. The decision is made to treat her with an oral antibiotic.

Questions:
Given her history what would be a reasonable empiric antibiotic choice?

Depending on the antibiotic choice are there potential drug interactions she should be counseled on?

Given her history what would be a reasonable empiric antibiotic choice?
-The question is ciprofloxacin vs. TMP/SMX.

Depending on the antibiotic choice are there potential drug interactions she should be counseled on?
-Want to use ciprofloxacin, but need to have patient stop taking calcium for the duration of the treatment since ciprofloxacin interacts with calcium.

What are the RIPE antimycobacterial drugs? Define if each is cidal or static.
Isoniazid (INH) (cidal)

Rifampin (cidal)

Pyrazinamide (PZA) (static)

Ethambutol (ETB) (static)

Note on anti-mycobacterial drugs.
Mycobacteria grow slowly and thus antibiotics that are most active against growing cells are ineffective.

The lipid-rich mycobacterial cell wall is impermeable to many agents.

Mycobacteria are intracellular pathogens.

Mycobacteria easily develop resistance.

For this reason usually give four drugs at the same time.

What is the pharmacology of isoniazid?
Inhibits synthesis of mycolic acids (essential component of mycobacterial cell wall).

More rapid clearance by rapid acetylators
-Proportion of fast acetylators higher among those of Asian origin including Native Americans.

INH inhibits metabolism of carbamazepine, phenytoin (both of these are seizure drugs) and warfarin.

What do you always give isoniazid with?
Always given with pyridoxine (vit. B6). Deficiency in vit. B6 can cause neuropathy.

Used to treat active TB (in combination with other drugs) or latent TB (as a solo agent for nine months).

What is toxicity associated with isoniazid?
Hepatoxicity!!!! = TQ.
-Mild increased asymptomatic transaminase increase in 10-20% of patient which does not require discontinuation of drug.
-Hepatitis in 1% with nausea, vomiting, jaundice; can be fatal.
-Risk greater in alocholics and possibly in pregancy/postparrtum.
–0.3% age 21-35
–1.2% of age 36-49
–2.3% of age >50

Peripheral neuropathy and CNS toxicity:
-More likely to occur in slow acetylators, malnourished, alcoholic, diabetes, AIDS, uremia.
-Neuropathy due to relative pyridoxine deficiency.

What is the toxicity associated with rifampin? When would you want to use it?
Toxicity:
-Turns urine, sweat, tears, contacts orange/Red.
-Jaundice/hepatitis
-Drug interactions!!!-induces CYP450 (Revs up)

Mnemonic: urine Red and Revs up.

Uses: Rifabutin similar but less drug interactions than rifampin so used as a substitute in HIV-infected.

What are the indications for use of rifampin?
Active against gram positive and gram negative cocci, mycobacteria.

Indications:
-TB
-Staphylococcus (eradication of carrier state or osteomyelitis)
-Meningococcal/Haemophilus influenzae carrier (like cipro)
-Leprosy

What are the Rifampin Drug Interactions?
Methadone

Anticoagulants: warfarin

Cyclosporine

Anticonvulsants

Protease inhibitors

Nonnucleoside reverse transcriptase inhibitors

Contraceptives

What toxicity is associated with Ethambutol?
Ethambutol causes retrobulbar neuritis with red-green color blindness.

Contraindicated in young children since they cannot tell you if they have had change in sight.

Mnemonic E is for eye…

What toxicity is associated with Pyrazinamide?
-Arthralgia
-Hyperuricemia
-Hepatitis

What aminoglycosides can be used for tx of TB?
Streptomycin is first line bactericidal IV treatment for tuberculosis. THis is the only IV tx for TB.

-Recall with streptomycin can get ototoxicity and renal toxicity.

Amikacin used more for MDR and atypical mycobacteria.

What are the drugs used to treat atypical mycobacteria?
10% of mycobacterial infections are caused by “atypical mycobacteria”
-M. avium complex (MAC)
-M. marinum
-M scrofulaceum

Clarithromycin often used. Recall this is also used for H. pylori.

MAC prophylaxis
-Azithromycin

A 45 year old homeless man presents to the ED with a two month history of weight loss, fever, night sweats and productive cough. He has lived in homeless shelters and prison. He drinks two pints of hard liquor daily and uses intravenous drugs. CXR shows right apical infiltrate. Patient is placed in respiratory isolation. Sputum shows acid fast bacilli and rapid HIV test is positive.

Questions:
What drugs should be started for presumptive treatment of pulmonary TB?

Does the patient have a heightened risk of medication toxicity?

How will HIV infection influence his treatment?

What drugs should be started for presumptive treatment of pulmonary TB?
-RIPE

Does the patient have a heightened risk of medication toxicity?
-Alcoholic -> liver disease.

How will HIV infection influence his treatment?
-Rifampin interacts with lots of medications, esp. those for HIV meds. So need to check. Could use Rifabutin.

Make sure you know the objectives.
1. Understand the mechanism of action, use, pharmacokinetics and toxicity of aminoglycosides.

2. Be aware of the use and toxicities of other protein synthesis inhibitors.

3. Recall that metronidazole and oral vancomycin treat C. difficile.

What do antibiotic protein synthesis inhibitors functionally do?
Target smaller bacterial ribosomes(70S made of 30S and 50S) leaving human ribosomes (80S) unaffected.

What two drugs are 30S inhibits?
1. Aminoglycosides.

2. Tetracyclines.

What drugs are 50S inhibitors?
Macrolides and clindamycin.

Chloramphenicol, Linezolid and quinupristin/dalfopristin.

What are examples of aminoglycosides?
Streptomycin, neomycin, amikacin, gentamicin, tobramycin, etc.

What bacteria are aminoglycosides used for? For what clinical conditions are aminoglycosides used for?
Active against gram negative enteric bacteria.

Usage:
-Gram negative bacteremia.
-In synergistic combination with vancomycin or a penicillin for endocarditis.
-Mycobacterial infections.

What is signature about the chemical structure of aminoglycosides?
A hexose ring. Recall this is a six-carbon ring.

What is the mechanism of action for aminoglycosides?
Passive diffusion via porin channels through outer membrane.

Active transport across cell membrane into cytoplasm by an oxygen dependent process
–low extracellular pH and anaerobic conditions may inhibit transport.
–Transport may be enhanced by cell well active drugs such as PCN or vancomycin.

Binds to 30S subunit ribosomal protein inside cell and irreversibly inhibits protein synthesis.

This aminoglycosides are bactericidal due to miscoding of the peptide chain. So miscoding, not just blocking.

Will aminoglycosides work for abscesses?
NO, since anaerobic conditions may inhibit transport of antibiotic.

How are aminoglycosides administered?
Minimal oral absorption so typically given IV (except neomycin, which cleanses bowel prior to surgery, not absorbed).

Dose based on weight and creatinine clearance. This makes the drug hard to dose, so people don’t use it often.

Traditionally aminoglycosides given 2-3 times daily in patients with normal renal function.

Partial removal by dialysis so given be given intermittently in dialysis patients for convenience.

Levels must be monitored in patients receiving higher doses for more than a few days or patients with rapidly changing renal function.

Intrathecal or intraventricular needed for high CNS penetration.

Why do we now do one daily aminoglycoside dosing?
Aminoglycosides have concentration dependent killing and a post-antibiotic effect. = TQ.

Increased concentration kill a greater proportion of bacteria and at a more rapid rate vs. PCN/cephalosporins which have time-dependent killing-efficacy is related to time above minimum inhibitory concentration (MIC).

Antibacterial activity persists beyond the time when measurable drug is present. = TQ.

What are the Adverse Effects of Aminoglycosides?
Ototoxic (may be irreversible). Hearing loss and balance problems.

Nephrotoxic.

What are the Clinical Uses of Aminoglycosides?
Typically used in combination with other antibiotics especially beta lactams (e.g. treatment of pseudomonas, listeria or enterococcus).

Gram negative (sepsis, antimicrobial resistance).

Endocarditis (streptococcal, enterococcal, staphylococcal).

What is gentamicin used for?
Covers staphylococcus and gram negatives (pseudomonas!!! = TQ, proteus, enterobacter, klebsiella, serratia, stenotrophomonas).

No anaerobic activity! = TQ.

Synergistic with beta lactams/vancomycin; usually used together with second agent.

Topical ophthalmic.

Note this an aminoglycoside. It is in fact the most widely prescribed.

What is Tobramycin used for?
Note this an aminoglycoside.

Better against pseudomonas!!! = TQ.

E. faecium is resistant to tobramycin.

Available as inhaled solution used for pseudomonas lung infections in cystic fibrosis patients.

What is Streptomycin used for?
Streptomycin is first line IV treatment for tuberculosis!!! = TQ.

15% of gentamicin resistant enterococcus will be sensitive to streptomycin.

Note this an aminoglycoside.

What is Amikacin used for?
Note this an aminoglycoside.

Used in gram negative infection resistant to gentamicin/tobramycin. = TQ.
–Amikacin often is resistant to plasmid-mediated inactivating enzymes (group transferases) that inactivate gentamicin/tobramycin.

Treats mycobacterial infections (atypical and multidrug resistant) = TQ. So it is like streptomycin.

Other aminoglycosides.
Neomycin used as topical and bowel prep & hepatic encephalopathy.

Paromomycin is anti-parasitic.

Spectinomycin (similar to aminoglycosides) used to treat GC in PCN allergic but not commercially available.

Major Pro Tip Note.
With respect to antibiotics that inhibit protein synthesis, only aminoglycosides are bactericidal. Any other antibiotic that inhibits protein synthesis is bacteriostatic.

What is Tetracycline Mechanism of Action?
Inhibit protein synthesis by binding to 30S ribosomal subunit.

What should you know about Tetracycline Pharmacokinetics?
Enterohepatic circulation results in high concentrations of tetracycline accumulating in the liver and bile.

Tetracycline is eliminated in the urine; others mostly biliary/fecal route.

What is the spectrum of use for tetracyclines?
Spectrum: gram positive, gram negative and rickettsia, chlamydia, mycoplasma.

Against what bacteria are tetracyclines used for?
Usage: MRSA, acne/rosacea, atypical pneumonia/community acquired pneumonia, chlamydia, Lyme disease and other borrelia, rickettsia, malaria prophylaxis, helicobacter pylori, vibrio. The point is that if you acquired it in the outdoors, you can treat it with tetracyclines.

-Demecyclocyline for SIADH (inhibits antidiuretic hormone in the renal tubule).

What is key to tell your patients when giving them tetracyclines about what not to eat or drink with it?
Do not administer orally with milk, antacids, iron because tetracyclines chelate cations.

What is Tigecycline used for?
-Large volume of distribution

-Broad spectrum (characteristic of tetracycline family).
-Covers MRSA, VRE, anaerobes
-excluding Pseudomonas, Proteus, Providencia and Morganella.

Approved for treatment of skin and abdominal infection.

Poor urinary concentration (not for UTI).

Low bloodstream concentration (not for bacteremia).

What are the Adverse Effects of Tetracycline?
Chelate with calcium and deposits in growing teeth and bone. Makes teeth yellow/grey. Thus, avoid in children and pregnancy.

Local irritation of gastrointestinal tract/esophageal irritation.

Sun sensitivity!

Dizzy, vertigo (with minocycline).

Nausea, vomiting (with tigecycline).

What are the three macrolides?
1. Erythromycin (derived from bacteria Streptomyces erythreus).

Semisynthetic derivatives of erythromycin:
2. Clarithromycin
3. Azithromycin

Macrocyclic lactone ring, thus the class name macrolide.

How does erythromycin work and what is it use against?
Binds to 50S ribosomal RNA.

Active against gram POSITIVE organisms (pneumococci, streptococci, staphylcoccus, corynebacteria), mycoplasma, legionella, chlamydia, bordatella pertussis.

What are Erythromycin Adverse Effects?
Gastrointestinal (nausea, vomit, diarrhea).
-Used to treat gastroparesis.

Hepatotoxicity (particularly estolate).

Drug interactions:
-Inhibits cytochrome p450 increases theophylline, anticoagulants, cyclosporine.
-Increases digoxin level by increasing bioavailabilty.

How does Clarithromycin work and what is it use against?
Similar to erythromycin except more active against mycobacterium avium complex (MAC).

H. pylori!!!! = TQ.

How does Azithromycin work and what is it use against?
Similar to erythromycin and clarithromycin but less GI upset and drug interactions.

Given this it is the most commonly used.

Slightly less active against gram positives and slight more active against haemophilus influenzae.

Active against chlamydia!!!!! = TQ, MAC, toxoplasma. These are the atypicals.

What is the dosing for Azithromycin?
Half life is 3 days!

1 gm dose for chlamydia!!! = TQ

1200mg once weekly MAC prophylaxis

Zpak for community acquired pneumonia = TQ

19YOF presents to student health with 2 weeks of foul smelling vaginal discharge. No fever or abdominal pain but reports vaginal bleeding after intercourse. Unprotected vaginal intercourse with two men over past 6 months. Patient missed her last period. Pelvic exam positive for mucopurulent cervical discharge. No cervical motion tenderness. NAAT test sent for GC/CT. Urine pregnancy test sent. Pending results, decision made to treat for GC/CT.

Questions:
What are the potential treatment options?

How does her potential pregnancy affect treatment decision?

What are the potential treatment options?
-Ceftriaxone for gonorrhea and doxycycline or Azithromycin.

How does her potential pregnancy affect treatment decision?
-No doxycycline to pregnant women due to cation chelating effect.

What is clindamycin and how does it work?
NOTE: this is NOT a macrolide. It just has a similar name.

A chlorine substituted derivation of lincomycin an antibiotic elaborated by streptomyces lincolnensis.

Binding site on 50s ribosome is identical to that of erythromycin.
-Prevents production of bacterial toxins. Such as in group A step.

Good bone penetration

What is the spectrum of use for Clindamycin?
Spectrum: gram positive (streptococci, pneumococci and staphylococci) and anaerobes (bacteroides and other gram positive and gram negative anaerobes).

What is unique about resistant to clindamycin?
Resistance to clindamycin generally confers cross resistance to macrolides. Oddly enough.

What are Clindamycin Indications for us?
Skin and soft tissue infections (streptococcus and MRSA)

Anaerobic infections
-Aspiration PNA
-Abdominal wounds
-Gynecologic (pelvic abscess, septic abortion, bacterial vaginosis)

Endocarditis prophylaxis

Second line for PCP or toxoplasmosis Rx

What are Clindamycin Adverse Effects?
Diarrhea
Rash

Predisposes to getting C. difficile.

Can get pseudomembranous colitis!!! = TQ.

What is the mechanism of chloramphenicol?

What is the spectrum of use?

Binds to 50S ribosomal subunit.

Used (cheap, OTC) in the developing world.

Broad spectrum, used for typhoid fever and meningitis.

What is the toxicity and concern about using chloramphenicol?
Toxicity of idiosyncratic, irreversible and possibly fatal aplastic anemia!!! = TQ.

Gray baby syndrome (when higher doses of drug accumulates infants with vomiting, flaccidity, hypothermia and shock).

What type of drug is Linezolid?
Linezolid is an oxazolidinone, new class of synthetic antimicrobials.

How does Linezolid work?
Inhibits protein synthesis, unique, binds to 23S ribosomal RNA of 50S subunit.

No cross resistance with other drug classes!!!! = TQ.

What is Linezolid used for?
Active against gram positive organisms including staphylococci, streptococci, enterococci, gram positive anaerobic cocci and gram positive rods and MTB.

Used for vancomycin resistant e. faecium and MRSA.

PNA or skin infections.

Key point: it is used for resistant bacteria.

What are adverse effects with Linezolid?
Thrombocytopenia, especially after two weeks administration (also anemia, neutropenia). It is then pancytopenia.

Serotonin syndrome with SSRI. Will cause more serotonin.

Optic neuritis, neuropathy.

What two drugs do you want to use for MSSA?
Nafcillin/Dicloxacillin

Cefazolin/Cephalexin

What six drugs do you want to use for MRSA?
Vancomycin
Daptomycin
Linezolid
TMP/SMX
Doxycycline/tigecycline
Clindamycin

What is Quinupristin-dalfopristin?
Combination of two streptogramins-quinupristin (a streptogramin B) and dalfopristin (a streptogramin A) in a 30:70 ratio.

What is Quinupristin-dalfopristin used for?
Active against gram positive cocci including resistant streptococcus, pneumococcus, MSSA/MRSA and e. faecium. So used for resistant bacteria.

Same ribosomal binding site as macrolides and clindamycin (50S).

E. fecalis is intrinsically resistant probably because of an efflux pump.

Used for Rx of vancomycin resistant e. faecium (VRE) (bacteriostatic).

Infusion related toxicity- need central line.

What three drugs do you use for enterococcus?
Penicillin
Ampicillin
Vancomycin

What two drugs do you use for VRE?
Linezolid
Quinupristin-dalfopristin

What is the mechanism for Metronidazole? How is it metabolized?
Nitroimidazole.

Mechanism of action: disruption of electron transport chain.

Bactericidal.

Metabolized in liver.

What are Adverse Effects of Metronidazole?
Nausea/vomiting.

Metallic taste!!!

Peripheral neuropathy/seizures.

Disulfiram/antabuse effect. -Can’t drink alcohol with it.

Drug interactions:
-Warfarin

What are Metronidazole clinical Indications?
Antiprotozoal and antibacterial/anerobic activity.

Examples:
-Bacteroides
-Clostridium
-Trichomonas
-Giardia
-Entameba

Clostridium difficile!!!! = TQ

Brain abscess (in combination with ceftriaxone, which has good CNS penetration).

Bacterial vaginosis

Trichomonas

Giardia

Amebasis

Rosacea

Note.
C. difficile can induce pseudomembranous colitis.

Make sure you know the learning objectives.
1. Understand beta-lactams and vancomycin are bactericidal by disrupting bacterial cell wall synthesis.

2. Know beta-lactams are a group of antibiotics with similar chemistry and side effects.

3. Recognize penicillins, cephalosporins, carbapenems and aztreonam as beta-lactams.

4. Distinguish among beta-lactams on the basis of antimicrobial activity, pharmacokinetics and adverse effects.

What are the four categories of drugs for beta-lactams?
1. Penicillins
2. Cephalosporins
3. Carbapenems
4. Aztreonam

Beta-lactam family shares:
-Chemistry
-Mechanism of action
-Pharmacologic characteristics. e.g. most excreted in urine.
-Immunologic characteristics. If allergic to one, are allergic to all of them.

What are the different types of penicillins?
-Natural Penicillins

-Anti-staphylococcal penicillins

-Extended spectrum penicillins
–Aminopenicillins
–Antipseudomonal penicillins

What did Alexander Fleming discover?
Growth of the bacteria Staphylococcus aureus is inhibited in the area surrounding the invading penicillin-secreting Penicillium mold colony.

What is the mechanism of action for beta-lactam antibiotics?
All beta lactam antibiotics inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis.

Beta lactam antibiotics bind to penicillin binding proteins.

Penicillin-binding protein (PBP) is an enzyme needed for cell wall synthesis located in the bacterial cytoplasmic membrane.

How do antibiotics go through gram negative bacteria?
They go through porins in the outer membrane.

What is the method of killing of beta-lactam antibiotics?
All Beta Lactams are Bactericidal.

Mnemonic: If it rhymes with ‘cillin, I know it’s killing.

Beta lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall.

Recall: Bacteriostatic inhibits bacterial multiplication, resumes upon removal of the agent.

Bactericidal kills bacteria, effect is irreversible; the killed organism can no longer reproduce even upon removal of the agent.

What are the four mechanisms of resistance used by bacteria against beta-lactams?
1. Inactivation of antibiotic by beta lactamases.

2. Modification of target PBP.

3. Impaired penetration of drug to PBP.

4. Efflux.

Mechanisms of Resistance: Inactivation of Antibiotic by Beta Lactamases .
Many hundreds of different beta lactamases.

Some, e.g. those produced by staphylococcus aureus prefer penicillin to cephalosporins (penicillinases) and thus maintain sensitivity to cephalosporins.

Others e.g. extended spectrum beta lactamases (ESBL) hydrolyze both PCN and cephalosporins.

Carbapenems are resistant to hydrolysis by penicillinases and cephalosporinases. So these are broad spectrum.

Four Mechanisms of Resistance: Altered Penicillin Binding Proteins.
Altered PBP are basis of methicillin resistance in staphylococcus and penicillin resistance in pneumococci and enterococci.

Resistant organisms produce PBPs that have low affinity of binding beta lactam antibiotics.

Mechanisms of Resistance in Gram Negative Organisms.
Gram negative bacteria have outer cell wall membrane.

Beta lactam antibiotics cross outer membrane and enter gram negative organisms via outer membrane channels (porins).

Absence/decrease of proper channel impairs drug entry (e.g. pseudomonas).

Gram negatives may also produce efflux pump.

What are the natural penicillins? What are they susceptible to?
Penicillin G and Penicillin V are called natural penicillins because they can be purified directly from cultures of Penicillium mold.

They are susceptible to hydrolysis by beta lactamases.

What is the spectrum of natural penicillins?
Spectrum: gram positive organisms, gram negative cocci, and non beta lactamase producing anaerobes.

Ex: Streptococci (pyogenes, viridans).
Ex: Treponema pallidum (syphilis).

What do you use Penicillin V for? How do you use it?
Penicillin V is oral:
-Group A Streptococcal pharyngitis – strep throat.
-Dental infections.

What do you use Penicillin G for? How do you use it?
Penicillin G is intravenous:

-Pneumococcal pneumonia
-Streptococcal Endocarditis
-Neurosyphilis
-Actinomyces; Clostridium perfringens, tetani; meningococcus; Pasteurella etc.

What is Benzathine penicillin used for?
Benzathine penicillin is intramuscular
-Syphilis
-Group A Streptococcal pharyngitis
-Erysipelas/Cellulitis

Benzathine penicillin IM yields prolonged blood levels.

What is the treatment of neurosyphilis?
-Daily IM Benzathine penicillin plus probenecid is an alternative treatment for neurosyphilis.

-Blood levels of penicillins can be raised by probenecid which impairs renal tubular secretion of penicillin.
–Probenecid is a uricosuric drugs used in gout.
–Promotes renal clearance of uric acid by inhibiting urate-anion exchangers in the proximal tubule that mediates urate reabsorption.

What are Penicillins are Resistant to Staphylococcal Beta Lactamase? What mnemonic can you use to remember this?
Nafcillin is the classic example of a semi-synthetic anti-staphylococcal, penicilllinase resistant PCN.

Oxacillin alternative.

Mnemonic: Use Naf for staph!

Dicloxacillin is oral version of nafcillin.

Methicillin=older version of same type. This drug causes renal toxicity.

Metabolized by the liver and thus do not need to adjust for renal disease!

What do you use the drug spectrum for?
Drug of choice to treat Staphylococcus that is sensitive to methicillin (MSSA-methicillin sensitive staphylococcus aureus).

-75% of Staph epidermidis are methicillin resistant.
-covers streptococcus but not as good as natural PCN.

What do you use Nafcillin for?
Use decreasing due to MRSA (MSSA-methicillin resistant staphylococcus aureus).

Indications: MSSA endocarditis or streptococcal cellulitis.

MRSA=Nafcillin resistant staphylococcus.

What are examples and what is the purpose of extended spectrum penicillins?
-Better activity against gram negatives because enhanced ability to penetrate gram negative outer membrane.

-Inactivated by many beta lactamases. So usually give with sulbactam or clavulanic acid. Or tazobactam for piperacillin.

Aminopenicillins:
-Ampicillin
-AmOxicillin give oral/PO better absorbed than ampicillin

Ureidopenicillins:
-Piperacillin

What are the indications for using aminopenicillins? What bug should you use this on?
Indications: urinary tract infection, otitis, sinusitis, bites.

Make sure to use for Listeria monocytogenes.

What is another name for ureidopenicillins?
Ureidopenicillins AKA Antipseudomonal Penicillins. So want to use these ureidopenicillins for Pseudomonas infections.

Piperacillin-tazobactam commonly used.

Indication: Hospital-acquired infections.

Mnemonic (P is for pip & pseudomonas)!

What percent of people have allergies to penicillins? What type of reactions can occur?
5-8% of patents state they have an allergy to penicillin.

1. Have have anaphylaxis (IgE, type 1 hypersensitivity reaction). This includes hives.

2. Can have rash.
-Ampicillin causes rash with patients that have EBV. EBV causes mono.

3. Diarrhea
-Amoxicillin/clavulanic acid.
-Antibiotic associated diarrhea vs. clostridium difficile.

4. Seizure especially with decreased creatinine clearance. All beta-lactam antibiotics can produce seizure.

5. Interstitial nephritis (classically associated with methicillin).

6. Neutropenia (with nafcillin)/hemolytic anemia/thrombocytopenia.

What is the drug of choice for syphilis?
Penicillin.

What is the drug of choice for MSSA?
Nafcillin.

What is the drug of choice for Listeria?
Ampicillin.

What is the drug of choice for pseudomonas?
Piperacillin.

What are two first generation cephalosporins? What are indications for use of these drugs?
Intravenous (IV) Cefazolin.

Oral (PO) Cephalexin.

Indication: skin infection, surgical prophylaxis (IV)

What is the spectrum of use for first generation cephalosporins?
Spectrum:
Streptococcus pyogenes (not enterococcus),
Staphylococcus (not MRSA),
some GNR (some e. coli, klebsiella and proteus mirabilis).

Pro Tip: In general, cephalosporins have increasing gram negative activity as generation # increases.

What are four second generation cephalosporins? What are indications for use of these drugs?
Intravenous (IV) Cefoxitin, Cefotetan, Cefuroxime.

Oral (PO) Cefaclor.

Indications:
IV surgical/gynecological infections
PO Otitis media

What is the spectrum of use for second generation cephalosporins?
Spectrum:
some gram positive cocci, s
ome gram negative rods (e. coli, klebsiella, proteus, haemophilus influenzae)

Cefoxitin and cefotetan active against anaerobes e.g. Bacteroides fragilis.

What are six third generation cephalosporins? What are indications for use of these drugs?
IV Ceftriaxone/Cefotaxime/Ceftazadine

PO Cefdinir/Cepodoxime/Cefixime

Indication: bacterial meningitis (ceftriaxone/cefotaxime since ceftriaxone has good CSF penetration), gonorrhea.

What is the spectrum of use for third generation cephalosporins?
Spectrum:
gram positive cocci (e.g. penicillin-resistant pneumococcus, streptococcus viridans)

haemophilus influenzae,

meningococci, gram negative rods (no anaerobes, enterococcus, listeria)

Avoid use with enterobacter due to development of resistance.

What is a fourth generation cephalosporin? What are indications for use of this drug?
Cefepime.

More resistant to hydrolysis by chromosomal beta lactamases produced by enterobacter.

Usage: Hospital acquired infections, neutropenic fever.

What is the spectrum of use for fourth generation cephalosporins?
Staphylococcus aureus, pneumococcus, pseudomonas.

What are two 5th generation cephalosporins?
Ceftaroline for MRSA.
Ceftobiprole.

What is the concern of giving cephalosporins to a patient with penicillin resistance.
Cross reactivity 5-10% so need to avoid in patients with a history of anaphylaxis to penicillin.

Cephalosporins that contain a methylthiotetrazole group (cefmandole, cefmetazole, cefotetan, cefoperazone) cause hypoprothrombinemia and bleeding as well as disulfiram/antiabuse effect (this is that you will feel sick when take with alcohol).

What are four examples of Carbapenems? How are they administered?
Imipenem, meropenem, doripenem, ertapenem.

All intravenous.

Why is Imipenem called Gorillapenem?
Imipenem aka “Gorillapenem” because of WIDE spectrum pseudomonas, gram positives, anaerobes (not enterococcus faecium, MRSA/SE, C. diff, Burkholderia, Stenotrophomonas)

Key here is wide spectrum.

What does it mean that “the kill is lastin’ with cilistatin?”
Imipenem packaged with cilistatin an inhibitor of renal dehydropeptidase because otherwise it would be inactivated in renal tubules.

How are carbapenems cleared? What is it the treatment for? What is the indication for using carbapenems?
All carbapenems are cleared renally.

Treatment of choice for enterobacter.

Indication: febrile neutropenia.

What are the side effects to know for carbapenems?
Side effects similar to penicillin:
-May cross react with penicillin allergic (10%).

-Imipenem may causes seizures especially in patients with renal failure.

What kind of antibiotic is Aztreonam?
A monobactam.

What is the spectrum and indications for aztreonam?
Spectrum: Gram negative rods ONLY (klebsiella, serratia, pseudomonas)

Indication: urinary tract infection.

What is the safety benefit of using aztreonam?
No cross reactivity with other Beta-lactams

Safe in penicillin allergic = TQ.

How does vancomycin work?
Vancomycin is a glycopeptide.

Inhibits cell wall synthesis by binding to D-Alanyl-D-Alanine portion of peptidoglycan precursor.
-Vancomycin resistant enterococcus and Staphylococcus aureus have modified D-Ala-D binding site of the peptidoglycan

Bactericidal but less efficient killer than penicillins.

What is the spectrum and indications for vancomycin?
Spectrum: gram POSITIVE cocci. You should think of it as a specialist.
-Staphylococcus aureus, staphylococcus epidermidis, streptococcus (pyogenes, viridans, pneumococcus), clostridium, some enterococcus)

Indication: MRSA/E (Staphylococcus aureus or epidermidis), (catheter-related infection), clostridium difficile, meningitis due to highly PCN resistant pneumococci, enterococcus (in synergy with an aminoglycoside).

What is the only indication for oral vancomycin?
Clostridium difficile is the only indication for oral vancomycin; otherwise IV is used.

Note: Vancomycin is renally cleared.

What are the adverse effects of vancomycin?
1. Red neck syndrome/red man syndrome!!!
-Itching, flushing
-Caused by release of histamine
-Prevented by prolonging infusion time
-Can give antihistamines

2. Can cause ototoxicity and nephrotoxicity esp. with aminoglycosides.

What does daptomycin do?
-Active against vancomycin-resistant enterococci and staphylococcus aureus

-Can cause myopathy; monitor creatinine phosphokinase

-Inactivated by lung surfactant. So it won’t work in the lung.

What is a good drug for meningitis?
Ceftriaxone.

What is a good drug for gonorrhea?
Ceftriaxone.

To Know.
-which drugs are B lactams
-cross-reactivity among them
-that they are bactericidal cell wall agents
-Know that penicillin treats syphilis
-Know that piperacillin covers pseudomonas
-Know ceftriaxone is the core empiric treatment of meningitis and gonorrhea
-Recognize “red man” syndrome

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