Unit 3 Ch 44: Pharmacotherapy of Bacterial Infections

Penicillins

kill bacteria by disrupting the cell wall

Penicillin-binding protein

substance in bacteria cell wall that serves as a receptor for penicillin

Beta-lactam ring

chemical structure of penicillin that is responsible for its antibacterial activity

Beta-lactamase/penicillinase

enzyme secreted by bacteria that splits the beta-lactam ring leading to resistance

Types of penicillins

- natural

- penicillinase-resistant (antistaphylococcals)

- broad-spectrums (aminopenicillins)

- extended-spectrums (antipseudomonals)

Generalizations about penicillins

- most are effective against gram-pos, a few against gram-neg

- narrow spectrum of antimicrobial activity

- only small amounts reach CSF

- rapidly excreted by kidneys

- short half-lives

What to monitor on penicillin therapy

- vital signs

- electrolytes

- renal function

- response to therapy

Effects of penicillin on electrolytes

hypernatremia and hyperkalemia > monitor cardiac status for worsening HF

- due to high sodium and potassium salts

Antibiotic-associated pseudomembranous colitis (AAPMC)

superinfection caused by antibiotics; C. diff secretes a toxin that inflames + necroses the bowel wall

Treatment of AAPMC

- no antidiarrheals; causes toxin to be retained in the bowel

- fluid + electrolyte replacement

Penicillin G

prototype drug of penicillin

Broad-spectrum penicillins (aminopenicillins)

- effective against gram-pos and certain gram-neg

- rapidly inactivated by penicillinase, ineffective against S. aureus

- widely prescribed for sinus and upper respiratory genitourinary tract infections > resistance

Types of aminopenicillins

ampicillin + amoxicillin

Augmentin

fixed-dose combination of amoxicillin + clavulanate (beta-lactamase inhibitor)

Unasyn

fixed-dose combination of ampicillin + sulbactam (beta-lactamase inhibitor)

Extended-spectrum (antipseudomonal) penicillins

- broad spectrum of antimicrobial activity + additional activity against Pseudomonas aeruginosa

Pseudomonas aeruginosa

opportunistic pathogen in air, soil, water

- infects immunocompromised + burn victims

- rapidly pumps out antibiotic molecules from its cells

Types of antipseudomonal penicillins

piperacillin + ticarcillin

Mechanism of action of antipseudomonals

also inhibit bacterial wall synthesis by binding PBPs, but have greater penetration through gram-neg outer membrane + higher affinity for PBPs

Zosyn

fixed-dose combination of piperacillin + tazobactam (beta-lactamase inhibitor)

Timentin

fixed-dose combination of ticarcillin + clavulanate (beta-lactamase inhibitor)

Piperacillin

extended-spectrum/antipseudomonal penicllin

- IM and IV routes

- effective against most gram-neg and many gram-pos aerobes + anaerobes

- can lead to hypokalemia + hyperkalemia

Ticarcillin

extended-spectrum penicillin w/ beta-lactamase inhibitor

- gram-neg infections

- IV route

- can lead to hypernatremia, hypokalemia, platelet dysfuntion

Penicillinase-resistant (antistaphylococcal) penicillins

- less effective than penicillin G against non-penicillinase-producing strains, ineffective against gram-negative > used against penicillinase-producing Staphylococcus aureus

- rapidly excreted by kidneys

- half-life of 30-60 mins

Types of antistaphylococcal penicillins

- dicloxacillin

- nafcillin

- oxacillin

Dicolaxacillin

penicillinase-resistant, PO route

- treats staph infections, ineffective against MRSA

- nausea + vomiting; eat on empty stomach to increase absorption

Nafcillin

penicillinase-resistant, parenteral (or PO)

- treats infections of blood, skin, respiratory, bone, joints

- excreted in BILE

- monitor CBC

Oxacillin

penicillinase-resistant, parenteral

- treats staph infections of blood, skin, respiratory, bone, joints, URINARY TRACT; ineffective against MRSA

Cephalosporins

similar to penicillins, also contain a beta-lactam ring; inhibit cell wall synthesis by binding to PBPs

- mostly excreted by kidneys

- cross-sensitivity with penicillin may occur; monitor

Common adverse effects of cephalosporins

rash, allergy, GI complaints

Therapeutic use of cephalosporins

treat gram-negative infections + for clients allergic to penicillin or have pencillin-resistant infections

First-generation cephalosporins

most effective gen against gram-positive staphylococci and streptococci; moderate activity against gram-negative

- unable to enter CSF sufficiently

Second-generation cephalosporins

broader spectrum against gram-negative than first gen; less sensitive to beta-lactamase

- unable to enter CSF sufficiently

Third-generation cephalosporins

even broader spectrum against gram-negative than second gen; longer duration of action, resistant to beta-lactamase

- able to enter CSF

Fourth-generation cephalosporins

more effective against organisms with resistance to earlier gens

- can enter CSF in sufficiently high conc.

Fifth-generation cephalosporins

extended gram positive effectiveness and effective against MRSA infections

- include ceftaroline and ceftolozane

Ceftolozane

5th generation cephalosporin, available as combo with tazobactam (Zerbaxa)

- enhanced against P. aeruginosa, can treat complicated intra-abdominal infections and UTIs

Cefotaxime (Claforan)

prototype drug, 3rd-gen cephalosporin

- broad spectrum against gram-negative + bacteria resistant to earlier-gen

- IM or IV, not absorbed from GI tract

- serious infections of lower resp tract, CNS, genitourinary system

What to monitor on cephalosporin therapy

- bleeding disorders

- hepatic function

- renal function

- blood coagulation

- pseudomembranous colitis

Why to monitor for bleeding disorders on cephalosporins

because they may reduce prothrombin levels through interference with vit. K metabolism

Why to monitor hepatic function on cephalosporins

because it is essential in vit. K production and cephalosporins interfere with vit. K metabolism

Carbapenems

bactericidal, one of broadest spectrum antibiotic classes, resistant to beta lactamase

- have a beta-lactam ring but different structure

- inhibit bacterial cell wall synthesis

Enterobactale infections

resistant to carbapenems, usually HAI, lethal

Imipenem

prototype carbapenem; inhibits bacterial wall synthesis by binding to PBPs

- rapidly destroyed by dipeptidase in kidney tubules, so in combo with cilastatin

- not PO; widely distributed

Cilastatin

renal dipeptidase inhibitor, combined with imipenem to prevent destruction of imipenem and allows for higher serum levels

Primaxin

imipenem & cilastatin (IV)

Tetracyclines

bacteriostatic, inhibit protein synthesis

- broad-spectrum, effective against gram-neg and gram-pos

- PO on empty stomach

What do tetracyclines treat

treat Rocky Mountain spotted fever, typhus, cholera, Lyme, H. pylori ulcers, chlamydia

Bacterial ribosomes

consist of two subunits; 30S and 50S (referring to size) = 70S

- antibiotics targeting protein synthesis affect 70S

Macrolides

bactericidal or (usually) bacteriostatic, inhibit bacterial protein synthesis by binding to 50S

- treat whooping cough, Legionnaire's, Strep, H. influenzae, M. pneumoniae, chlamydia

- some w/ enteric coating

- excreted in bile

Enteric coated macrolides

- allows the drug to dissolve in small intestine, causing less gastric irritation

- allows it to avoid destruction in gastric acid and reach alkaline small intestine

Erythromycin (Eryc)

macrolide prototype drug; inactivated by stomach acid thus administered as coated tablets > empty stomach

- mainly excreted in bile

- interacts with cyclosporine, warfarin, etc

Aminoglycosides

bactericidal, inhibit protein synthesis + cause abnormal protein synthesis

- treats TB, serious infections caused by aerobic gram-neg

- parenteral

- polar, poorly absorbed

- serious adverse effects, ex. ototoxicity

- post-antibiotic effect

How to increase effectiveness of aminoglycosides

- adminster one large dose per day > greater bactericidal effect, fewer resistants

- adminster with penicillin > weakens the cell wall, greater amount can enter

Post-antibiotic effect

antibacterial activity persists even once serum drug levels fall below minimally effective concentration

- certain tissues bind the drugs very tightly, renal excretion prolonged

Adverse effects of aminoglycosides

- ototoxicity

- nephrotoxicity

- neuromuscular blockade; ACh release inhibited

Gentamicin (Garamycin)

Prototype aminoglycoside; broad-spectrum, bactericidal for serious urinary, respiratory, neurological, GI infections when less toxic antibiotics are contraindicated

- IM

Fluoroquinolones

bactericidal, affect DNA synthesis by inhibition DNA gyrase + topoisomerase IV

- well-absorbed PO

- post-antibiotic effect

Bacterial DNA replication

Unwind: DNA helicase unwinds the 2 strands

Relax: DNA gyrase relaxes the supercoils

Replicate: DNA polymerase replicates original DNA

Migrate: topoisomerase IV frees the 2 new strands > migrate to opposite cell sides > 2 daughter cells

Fluoriquinolone binding to DNA gyrase

inhibits its ability to relax the supercoiling of the DNA

Fluoriquinone binding to topoisomerase IV

inhibits the freeing of the DNA strands and their migration to opposite side = division cannot be completed

Ciprofloxacin (Cipro)

Prototype fluoriquinone, second-gen; affects bacterial replication and DNA repair, more effective against gram-neg

Sulphonamides

bacteriostatic, inhibit folic acid synthesis by binding to enzyme, essential for synthesis of purine and nucleic acid

Trimethoprim-Sulfamethoxazole

prototype sulphonamide fixed combination

- treats UTIs

- inhibit bacterial metabolism of folic acid

- PO

Clindamycin

- for abdominal infections

- used when safer alternatives ineffective

Linezolid

- treats MRSA infections, vancomycin-resistant enterococci infections

- can cause hypertensive crisis and thrombocytopenia

Metronidazole

- treats abscesses, gangrene, diabetic skin ulcers, deep wound infections, H. pylori

- high doses of > neurotoxicity

Quinupristin/dalfopristin

- treats complicated MRSA, vancomycin-resistant Enterococcus faecium

- can cause hepatotoxicity and nephrotoxicity

Vancomycin

- severe infections, treats MRSA

- can cause ototoxicity, nephrotoxicity

- trough levels should be drawn after 3 doses

- rapid IV > red man syndrome

Red man syndrome

caused by rapid infusion of vancomycin; red rash, hypotension, flushing

Urinary antiseptics

anti-infective drugs used exclusively for urinary tract infections

- PO, reach therapeutic levels in renal tubules, not systemically

- monitor for renal impairment, hemolytic anemia

Nitrofurantoin

prototype urinary antiseptic; broad-based mechanism of action

- prophylaxis of recurrent UTI

Tuberculosis

caused by M. tuberculosis; mycobacteria dormant inside tubercles

- cell wall resistant to penetration, multidrug therapy must continue for 6-12 months

First-line antitubercular agents

safer, generally more effective against TB

Second-line antitubercular agents

more toxic, less effective, used when resistance develops

Tuberculosis transmission

airborne, thru droplets

Factors influencing transmission likelihood

- number of organisms expelled in air

- concentration of organisms

- length of time of exposure

- immune system of exposed

TB disease process

- healing of primary lesion > collagenous tubercle

- latent period

- clinical disease if organisms begin to multiply

Systemic TB manifestations

fatigue, malaise, anorexia, weight loss, low-grade fevers, night sweats

Pulmonary TB manifestations

frequent cough, produces mucus or mucopurulent sputum

Diagnosis of TB

- hypersensitivity to TB skin test

- chest x-ray

- culture (6-8 weeks)

Directly observed therapy (DOT)

requires that a health care provider directly observe the patient swallowing the pills

Leprosy

caused by M. leprae

- infectious or not, airborne

- macular skin lesions, can grow large

- rare in canada

Leprosy method of action

- invades peripheral nerves, causing thickening

- loss of sensation/paresthesia

- can cause bone resorption

Leprosy treatment

- prolonged drug therapy (similar to TB)

Lepromatous leprosy

occurs in clients with defective cell-mediated immunity; slow, progressive development of nodular skin lesions

Treatment of lepromatous leprosy

3 drugs; dapsone, clofzamine, rafampin for 2-5 yrs

Tuberculoid leprosy

less progressive, long periods of remission followed by reactivation

Treatment of tuberculoid leprosy

2 drugs; dapsone, rifampin for 6-12 months, dapsone for 2-3 yrs

Dapsone

prototype drug of choice for M. leprae

- inhibits folic acid metabolism

- PO