Penicillin G

1) Mechanism of action

2) Metabolism

3) Spectrum

4) Mode of administration

5) Serious adverse effects

6) Unique indications (Pharmacokinetics)

1) Mech: Cell wall synthesis inhibitors, β-lactam

2) Metabolism: Not metabolized, excreted in urine unchanged

3) Spectrum:Narrow, Gram +

4) Mode of administration: Injection (oral absorption is poor)

5) Serious adverse effects: allergic reactions, and CNS problems (toxicity)

6) Unique indications: Short half-life

Oxacillin & Nafcillin

Class, group and mode of administration, excretion

Penicillins (Beta-lactamase-resistant= anti-staphylococcal penicillins)

Mode of administration: Parenterally (oral absorption is poor)

No dosage adjustment for renal impaired (renal impaired causes CNS toxicity > seizures)

Excretion is biliary for nafcillin

Excretion is via kidney and biliary for Oxacillin

Penicillin V

1) Mechanism of action

2) Metabolism

3) Spectrum

4) Mode of administration

5) Serious adverse effects

Penicillins

1) Mech: Cell wall synthesis inhibitors, β-lactam

2) Metabolism: Not metabolized, excreted in urine unchanged

3) Spectrum: Narrow, Gram +

4) Mode of administration: Oral

5) Serious adverse effects: allergic reactions, and CNS problems (toxicity)

Cloxacillin/Dicloxacillin

Class, group and mode of administration, excretion

Penicillins (Beta-lactamase-resistant= anti-staphylococcal penicillins)

Mode of administration: oral - chlorination increases absorption in GI.  Food interferes with absorption

No dosage adjustment for renal impaired (renal impaired causes CNS toxicity > seizures)

Excretion is via kidney and biliary

Ampicillin

Class, group, mode of administration, use, side effects

Extended Spectrum Penicillins (Activity Against + and -)

Mode of administration: Parenteral and oral (poor absorption

Use: prophylaxis against endocarditis

Can cause "Ampicillin rash" (Toxicity not reaction)

In patients with infectious mononucleosis and lymphatic leukemia. Or in patients taking allopurinol (gout, high levels of uric acid)

Amoxicillin

Class, group, mode of administration, clinical use

Penicillins

Extended Spectrum penicillins

Mode of Administration: Oral

Clinical use: acute otitis media/sinusistis; lower respiratory infections (bronchitis) OR prophylaxis for endocarditis

Ticarcillin

Class, group, mode of administration, side effects

Penicillins

Anti-pseudomonal penicillins

Mode:parenteral

Side effects: limited use (replaced by 3rd gen cephs, carbapenems, fluoroquinolones) because it can cause sodium overload (released in salt) and increased bleeding time

Piperacillin

Class, group, mode of administration, clinical use

Penicillins

anti-pseudomonal penicillin

Mode of admin: parenteral only

Broadest spectrum.  Best activity against pseudomonas and is combined with aminoglycoside often.

Cefazolin

1) Mechanism of action

2) Metabolism

3) Spectrum

4) Mode of administration

5) Serious adverse effects

6) Clinical use

Cephalosporins - 1st generation

1) Mech: Cell wall synthesis inhibitors, β-lactam

2) Metabolism: Not metabolized, excreted in urine unchanged

3) Spectrum: Mostly + (staphylococci, pneumococci, streptococci) and only some negative

4) Mode of administration: parenteral - good tissue penetration

5) Serious adverse effects: allergic reactions, and CNS problems (toxicity)

6) Unique indications:  used as prophylactic for surgery (cardiac, thoracic, vascular, craniotomy, orthopedic, head and neck, C-section, etc. , but can be used oral drug for basic bacterial infection

Cefoxitin

1) Mechanism of action

2) Metabolism

3) Spectrum

4) Mode of administration

5) Serious adverse effects

6) Clinical use

Cephalosporins

Cephalosporins - 2nd generation

1) Mech: Cell wall synthesis inhibitors, β-lactam

2) Metabolism: Not metabolized, excreted in urine unchanged

3) Spectrum: Mostly + (staphylococci, pneumococci, streptococci) and more neg. than 1st gen

4) Mode of administration: parenteral (prophylactic) or oral (basic infections)

5) Serious adverse effects: allergic reactions, and CNS problems (toxicity)

6) Unique indications:  widely used as prophylactic during abdominal surgery due to activity against anaerobes, but can be used oral drug for basic bacterial infection

Ceftriaxone & cefixime

1) Mechanism of action

2) Metabolism

3) Spectrum

4) Serious adverse effects

5) Clinical use

Cephalosporins - 3rd and 4th gen

1) Mech: Cell wall synthesis inhibitors, β-lactam

2) Metabolism: No dosage requirement for renally impaired patients for Ceftriaxone

3) Spectrum: Mostly + (staphylococci, pneumococci, streptococci) and many  negative

4) Serious adverse effects: allergic reactions, and CNS problems (toxicity), for Ceftriaxone DO NOT COADMINISTER WITH CALCIUM SALTS WITHIN 48 hours

contraindicated for all ages and is fatal in neonates

5) Unique indications:  GOOD at crossing CNS... first line of defense against gonorrhoeae.  Ceftriaxone used against meningitis (crosses inflamed meninges)

Erythromycin

1. Class

2. mechanism

3. spectrum

4. Use

5. Resistance

6. Metabolism

7. Adverse reactions

8. Adminstration

Macrolides (large ring)

2. Binds 50S

3. Similar to Pen G (mostly +)

4. For patients with pen. allergy, similar spec to pen G... esp. against staph, strep, or pneumoccocci

5. Wide spread, and cross resistance between all macrolides (mutant ribosomal proteins, RNA methylase, efflux pumps)

6. By P450 - dose reduction for hepatic problems; Also, can displace drugs from P450 enzymes

7. Toxicity if taken with oral anti-coags, benzodiazepenes, or statins; Otherwise safe but 20% have GI upset.  Can cause rare allergic rxn acute cholestatic hepatitis.  Crosses to placenta

8. Orally, in salts with enteric coating - estolate salt is best absorbed form, ethylsuccinate used for peds

9. Cross resistance between erythromycin and other macrolides

Clarithromycin

Class, and advantages/disadvantages

Macrolides

Similar CP450 metab. issues; Similar spectrum

Advantages: More potent, Acid stable, Better absorbed, less GI upset; longer half-life, so given every 12 hours vs every 6 (QID) for erythromycin

Azithromycin

Class, and advantages/disadvantages

Macrolides; Z pack

Long half life (administered QD vs BID and QID)

Not metabolized- no CP450 issues, no effect on other drugs

Tissue:blood ratios are incredible; very low plasma levels - use if someone on anticoagulant

Tetracyclines

Tetracyclines

Tetracycline: short acting, poorly absorbed, renal clearance

doxycycline is long acting, well absorbed, biliary

Tigecycline - tet resistant but contraindicated in pregnancy

Wide spectrum but lots of resistance

Tets form insoluble complexes with cations found in antacids, multivitamins, dairy products

Distributes with high conc. in skin, saliva, thus dermatological and dental use

Doxyclycline is tet of choic in renally impaired pts

Avoid use in pregnant women and children under 8

Renal toxicity happens with expired Tet

Doxycycline is drug of choice among the Tets

Used for STDS

Amikacin, Tobramycin, Streptomycin, Gentamicin

Protein synthesis inhibitors AND Bactericidal... extended spectrum

Binds 30s

Aminoglycosides work synergistically with beta-lactam antibiotics and the combinations are frequently used to treat severe infections.  However, they cannot be mixed up in the same injection solution >> chemically inactive one another

Sulfamethoxazole +- Trimethoprim

Sulfa drugs compete with PABA (para-aminobenzoic acid for the enzyme dihydropteroate synthase)

Trimethoprim - inhibits dihydrofolate reductase

these are broad spectrum; most are highly bound in protein and can displace other protein-bound drugs and proteins (can cause kernicterus in neonates -- displacement of bilirubin from albumin), limiting renal elmination

This can result in crystalluria

Can cause Stevens-Johnson syndrome (rare, skin and mucous membrane eruptions > detachment of epidermis)

Other Systemic Antibacterials - Carbapenem

Extremely broad spectrume > parenteral only > inactivate Beta-lactamases

Imipenem is metabolized by a renal enzyme called dehydropeptidase and must be administered with cilistatin  to block metabolism and nephrotoxicity

contraindicated in pregnancy

Drug of choice for enterobacter infections (nosocomial pathogens responsible for range of infections: lower resp tract, skin, soft tissue, UTI, opthalmic, etc)

Other Systemic Antibacterials/ Cell wall synth inhibitor (no beta lactam)

Narrow spectrum (Gram +)

Causes tissue necrosis if given IM

Must be given by slow IV infusion

Nephrotoxic and is excreted from the kidney... monitor kidney function

Main use is against bacteria that are resistant to safer drugs, such as MRSA

Also, Sepsis, endocarditis, severe skin and soft tissue inf caused by MRSA...

Is taken orally for antibiotic-associated colitis (if resistant to metronidazole; only metronidazole and vanco can treat this)

Clindamycin

Class and mechanism

Use

Distribution

Adverse effects

Other Systemic Antibacterials/ Lincosamide / binds 50S ribosome

Use: highly effective against anaerobic pathogens, including bacteroides fragilis

Distribution: Excellent penetration into bone

Adverse effects: Antibiotic-associated colitis is a concern > overgrowth of C. difficile; requires immediate treatment with metronidazole or vancomycin

Other Systemic Antibacterials

First broad spectrum antibiotic discovered; protein inhibtor... one of few for Salmonella; also effective against anaerobes

Excellent penetration into CSF, ocular and joint fluids

Aplastic anemia due to stem cell damage (lower RBC, WBC, platelets)

Metronidazole

Other Systemic Antibacterials - metabolized by microbes to products that damage their DNA; well tolerated;

effective against anaerobic bacteria (bacteroides and clostridium)

used for antibiotic-associated enterocolitis and drug of choice for E. histolytica infections

can cause furry tongue, and this is the disulfiram like effect, alcohol makes them vomit

Other Miscellaneous Agents; causes bacterial DNA strand breaks... use in UTIs or prophylaxis of UTI, patient with recurrent infections

In pts w/glucose-6-phosphate dehydrogenase deficiency, hemolytic anemia, peripheral neuropathy

Other Miscellaneous Agents; Drug of choice for prophylaxis and therapy; inhibits mycolic acid biosynthesis.. no dosage adjustment for pts with renal impariment

Given with pyridoxine (vit B6) to prevent peripheral neuritis and convulsions

ADR:Hepatitis - most frequent major toxicity 1%.. can be fatal

Other Miscellaneous Agents, a Rifamycin

Resistance develops readily, not used alone

Most commonly used in treatment of mycobacterial diseases...

combined with INH or other first line agent for TB..

ADR: Induces liver P450 enzymes, inhibits effectiveness of oral contraceptives...

Causes red-orange coloration of urine, tears, body fluids... can stain clothes and contact lenses

It is hepatotoxic and can cause cholestatic jaundice and hepatitis

You can use other rifamycins (rifabutin) for AIDS pts taking protease inhibitors or NNRTIs due to fewer drug interactions

Other Miscellaneous Agents - Inhibits mycobacterial cell wall synthesis by blocking arabinosyl transferase

retrobulbar neuritis > loss of visual acuity; red-green colorblindness - should have vision checks periodically... contraindicated in children too young to permit assessment of eyes

Other Miscellaneous Agents - highly effective as combo therapy with INH and rifampin for short term (6 month) regimens

But is liver toxic (1-5% of pts) must monitor pt liver function

Beta-lactams:

1) Mechanism of action

2) Metabolism

3) Spectrum

4) Mode of administration

5) Serious adverse effects

6) Unique indications (method of resistance)

7) Drugs in Class

1) Mech: Most important class of cell wall synthesis inhibitors, covalently bind to PBPs in the cell membrane that function in the building and remodeling of bac cell wall during cell division.. bacteriocidal

It is the most active against against growing bacteria, and Beta lactam ring must be intact for these agents to be effective

2) Metabolism: Most are not metabolized, most excreted in urine unchanged

3) Spectrum:Varies

4) Mode of administration: Varies

5) Serious adverse effects: High incidence of allergic reactions, and CNS problems (toxicity, carbapenems most problematic)

6) Unique indications (resistance): Hydrolysis of Beta-Lactam ring (via Beta-lactamases)

7) Drugs in Class:Penicillins, Cephalosporins, Carbapenems, Monobactams

Non-β-lactam cell wall synthesis inhibitors

(Class use and list drugs)

Use: Good against microbes that produce β-lactamase

List: Vancomycin, Bacitracin, Cycloserine, Novobiocin

Protein synthesis inhibitors

List: 1) classes & mechanisms and 2) resistance and 3) killing  mechanism

1) Active at 30s subunit: Tetracyclines, Aminoglycosides

    Active at 50s subunit: Macrolides, Lincosamides, Chloramphenicol, streptogramin, pleuromutilins

2) Resistance via altered ribosomal binding sites (50s), decreased drug entry through carrier systems, or active extrusion by bacteria (efflux pumps)

3) Bacteriostatic, except aminoglycosides

for 50S, gram + most significant with chloramphenicol being broad... and non-renal elimination is most important, with drug interaction

External Use Antiseptics and Germicides

List classes and properties

1) Anionic detergents - (salts of long-chain fatty acids, rapid onset)

2) Cationic detergents - (NH4CL derivatives) Form monolayer on skin under which micro-organisms live, do not kill spores

3) Phenols - Lysol (cresol + soapy water) caustic to tissues therefore limited use

4) Alcohols - 70% Ethanol (standard antimicrobial)

5) Iodine - usually dissolved in ethanol; some patients are allergic; kills bacteria, spores, protozoa, cysts, fungi, viruses

6) Metals (Hg,Ag) - Hg is bacteriostatic, Ag sulfadiazine is used commonly in burn treatment

1) Pen G and its congeners: Pen G (procaine Pen G, sodium Pen G, Benzathine Pen G) and Pen V

2) ß-lactamase-resistant penicillins: oxacillin, nafcillin, chloxacillin, dicloxacillin -- MRSA is resistant to these agents and is a growing problem,  no dosage adjustment for renal insufficient patients for this type

3) Extended spectrum penicillins: Ampicillin, Amoxicillin

- activity against gram pos and gram neg

4) Extended spectrum penicillins w/ß lactamase inhibitors: Ticarcillin or Amoxicillin + clavulanic acid, Ampicillin + sulbactam, Piperacillin + tazobactam

5) Anti-pseudomonal: Ticarcillin, piperacillin

Agent of choice for many organisms, especially gram positive bacteria

Overall pharmacokinetics: Absorption decreased by food, (except Amoxicillin) Take 1 hr before or 2 hrs after a meal

Most are rapidly excreted in urine as unchanged drug...

Can cause allergic reactions (most common is uticaria - hives, delayed allergy) or CNS toxicity in patients with renal insufficiency or high doses

1) Poor antimicrobial effects

2) Irreversibly inhibit bacterial lactamase

3) Used only in combination with penicillins

4) Mixed aerobic and anaerobic infections such as intra-abdominal infections (peritonitis)

Modes of Administration for:

Penicillin G congeners

Half lives?

Sodium Pen. G - IV

Procaine Pen. G - IM

Benzathine Pen. G - IM

Procaine and Benzathine are hydrolyzed to yield Pen G. Long half life because procaine is slowly dissolved (lasts two days) while Benzathine is even more slowly dissolved (lasts weeks).  Weekly injections for Benzathine (for syphillis).

Similar to penicillins, chemically, mechanism of action, toxicity profile

3rd and 4th gen. Cephalosporins are broader spectrum and more stable against beta lactamases.

3rd and 4th gen tend to cross into CSF better than other generations

Do not give cephs to patients who have undergone anaphylactic shock from penicillin... cross reactivity nevertheless of most 2nd, 3rd, 4th gen cephs with PCN is low

CNS excitation from high doses and bleeding abnormalities and alchol intolerance especially associated with NMTT side chain >> inhibits clotting factors

Bleeding abnormalities and alcohol intolerance!! Associated with NMTT side chain > inhibits clotting factors.

Can cause CNS excitation.  Also, cross-reaction is low but NEVER give if someone has had PCN anaphylactic shock.

Do not mix Ceftriaxone with Ca2+ solutions in IV - fatalities in neonates and contradicted for all ages. Do not coadminister within 48 hours.

Carbapenems (thienamycins)

1) Class & mechanism

2) List drugs in class

3) Properties

4) Uses

5) adverse reactions

6) administration

1) Beta-lactam, cell wall synthesis inhibitor, extremely broad spectrum, inactivates beta-lactamases

2) Imipenem, meropenem, ertapenem

3) Imipenem is metabolized by renal enzyme dehydropeptidase thus must be coadministered with cilistatin which blocks metabolism and nephrotoxicity

4)Used if microbes are resistant to other available drugs;  Drug of choice for enterobacter infections (nosocomial pathogens for a wide range of infections: UTI, lower resp. tract, skin, soft tissue, ophthalmic)

5) high incidence of CNS excitation; contraindicted in pregnancy... carbapenems highest CNS problems of beta lactams

6) parenteral only

Monobactams

1) Class & mechanism

2) List drugs in class

3) Properties

4) Uses

1) Beta-lactam, cell wall synthesis inhibitor, narrow spec.

2) Aztreonam (only one on market)

3)  beta lactam not fused to single ring > low degree of cross allergenicity; narrow spectrum, effective against Gram - bacilli only

4) Good against pseudomonas aeruginosa, used in combination with vancomycin or clindamycin for surgical prophylaxis

Bacitracin

Class, uses

Cell Wall synthesis inhibitor (non-beta lactam)

Used topically for surface lesions of skin, in wounds, on mucous membranes

Fosfomycin

Class, uses

cell wall synthesis inhibitors (non-beta lactam)

given orally, single dose, safe for pregnant women, used for uncomplicated UTI

inhibits pyruvyl transferase (cell wall synthesis enzyme)

Cycloserine

Class, Use

Non beta lactam cell wall synthesis inhibitor

Use: rarely, only for resistant Tb

Novobiocin

class, use

Non beta lactam cell wall synthesis inhibitor

Use: extremely toxic and as last resort desperation drug

Macrolides

1) Mechanism of action

2) Metabolism

3) Spectrum

4) Serious adverse effects

5) Distribution

6) Drugs in Class

1) Bind 50S ribosome

2) Metabolism - hepatic (except azithromycin), half life is azi. >> clari >> erythr

3) Extended spectrum

4) Serious adverse effects - Erythromycin can displace other drugs from CYP3A4

5) Distribution: Well distributed but does not enter CSF even if meninges inflamed

6) Erythromycin, clarithromycin, azithromycin.. telithromycin for macrolides resistance

Telithromycin

Class, Mechanism

Uses and warnings

Macrolide, 50S

Used for macrolide resistant microbes, QD dosing, contraindicted for myasthenia gravis and has caused serious hepatotoxicity - one death and one liver transplant

GI effects AND

Disturbance to normal flora causing overgrowth of non-susceptible organisms

New class of antibiotics

First one on market is Retapamulin... binds to 50S ribosome, active against MRSA and most anaerobes

Quinupristin, Dalfopristin

Infections from vanc-resistant strains of E. Faecium, and bacterial resistance to older drugs

An Oxazolidinone

ribosome binder... unique site.. reserved for treatment of inf caused by multiply drug-resist, Gram +

Aminoglycoside

Gram- infections

often used synergistically with beta lactams to treat severe infections (sepsis and pneumonia) resist to other antibiotics, which is often seen in immunocompromised pts

Bactericidal, orally effective, resistance develops at low frequency

Inhibit DNA gyrase

Highly active against gram - bacteria

4 generations... Gen 1 is some gram - coverage... Gen 2, ciprofloxacin, has excellent gram - activity.  It is the most effective quinolone for P. aeruginosa

Gen 3 adds + bacteria, levofloxacin, excellent for strep. pneumoniae

Gen 4 effective against anaerobes - moxifloxacin

Drug interactions with cations (antacids, vitamins); penetrates well into prostate and bone... thus good for soft tissue, bone, joint, intra-abdominal and respiratory infections except norfloxacin b/c of poor absorption from gut

Effects on cartilage development, thus not recommended for children < 18 and contraindicated for pregnancy

Can cause crystalluria so dripnk copius amounts of water; esp true with norfloxacin

Excellent pseudomonas activity

Last resort drugs, inhibitors of cell membrane function

Indicated for Gram + organisms that are resistant to other drugs (MRSA); used for skin and soft tissue infections

Long-term treatment with combination of drugs

Usually, Isoniazid (INH) and rifampin combo therapy for 9 months... can do standard 4 drug regimin, INF, rifampin, pyrazinamide, ethambutol

And if that fails, then use 2nd line drugs, like streptomycin (used when injectable drug needed)

Dapsone - drug of choice, onece a week dosing... this drug is similar to sulfonamides

Also give rifampin