Clinical Pharmacology Study Guide (Beta-lactam Antibiotics)

β-lactam Antibiotics Penicillins Natural penicillins penicillin G aqueous Inj penicillin G procaine and benzathine IM only penicillin V (PenVeeK, Vi-CillinK) PO Antistaphylococcal penicillins dicloxacillin (Dynapen) PO methicillin (Staphcillin) – not on market Inj nafcillin (Nafcil, Unipen) Inj oxacillin (Prostaphlin) Inj, PO Amino Penicillins amoxicillin (Amoxil) PO ampicillin (Omipen) Inj, PO Antipseudomonal penicillins piperacillin (Piperacil) Inj ticarcillin (Ticar) Inj β -lactamase inhibitor combos (Extended spectrum) ampicillin/sulbactam (Unasyn) Inj amoxicillin/clavulanate (Augmentin) PO piperacillin/tazobactam (Zosyn) Inj ticarcillin/clavulanate (Timentin) Inj Cephalosporins 1st generation cephalosporins cefadroxil (Duricef ) cefazolin (Ancef, Kefzol) cephalexin (Keflex) nd 2 generation cephalosporins cefaclor (Ceclor) cefoxitin (Mefoxin) cefuroxime (Zinacef) cefuroxime axetil (Ceftin) cefotetan (Cefotan) cefprozil (Cefzil) 3rd generation cephalosporins cefixime (Suprax) cefotaxime (Claforan) cefpodoxime (Vantin) ceftazidime (Fortaz) ceftriaxone (Rocephin) cefdinir (Omnicef) cefditoren (Spectracef) ceftibuten (Cedax) ceftizoxime (Cefizox) 4th generation cephalosporins cefepime (Maxipime) 5th generation cephalosporins ceftaroline (Teflaro®) Carbapenems imipenem/cilistatin (Primaxin) meropenem (Merrem) ertapenem (Invanz) doripenem (Doribax) pen a SIL in dye kloks a SIL in meth a SIL in naf SIL in oks a SIL in a moks a SIL in am pi SIL in pip er a SIL in tye kar SIL in SUL bak tam klav yoo LAN ate ta zoe BAK tam PO Inj PO sef a DROKS il sef A zoe lin sef a LEKS in PO Inj Inj PO IV PO SEF a klor se FOKS a tin sef yoor OKS eem PO Inj PO Inj Inj PO PO PO IM, IV Inj (or 3nd) Inj Inj Inj Inj Inj sef o TEE tan sef PROE zil sef IKS eem sef oh TAKS eem sef pode OKS eem SEF taz a deem sef trye AKS one SEF din eer sef di TOR en sef ti BEAUT en sef ti ZOX eem SEF e peem i mi PEN em / sye la STAT in mer oh PEN em ert a PEN em door I PEN em 109 Drugs that Weaken the Cell Wall (β β-lactam Antibiotics) (see previous page for list of specific antibiotics) Overview • All of the antibiotics in this next section selectively interfere with the synthesis of the bacterial cell wall • Mechanism of selective toxicity—mammalian cells lack cell wall, therefore no direct effect on host cells • • They are all in a group of agents commonly referred to as the “β-lactam” antibiotics • Discovered in 1929 when a mold called penicillium contaminated a bacterial culture and was noted to inhibit its growth • • Are among the least toxic drugs known The β-lactams are further divided into classes based on chemical structure and spectrum of activity Penicillins • Members of this family of drugs differ structurally from one another by only a single side chain This side chain is responsible for differences in pharmacokinetics and antimicrobial spectra Mechanism of Action • Interfere with bacterial cell wall synthesis • Penicillins bind to bacterial proteins (penicillin binding proteins, PBPs) which are necessary for the cross-linking of the peptidoglycan layer • Without this cross-linking, the cell wall is weak, will lyse, and cell death occurs (bacteridal) Mechanisms of Resistance • β -lactamase/penicillinase: some bacterial produce enzymes that can inactivate the drug’s β-lactam ring • Modified PBPs: some bacteria have modified PBPs that have decreased affinity for the penicillins • Decreased Permeability: some gram-negative bacteria have modified external surfaces that reduce drug permeability Adverse Drug Reactions • Allergic Reactions (0.4-7%): most common and most important ADR • Patients allergic to one penicillin should be considered allergic to all penicillins • Anaphylaxis (immediate hypersensitivity reactions) occur in 0.02% of patients • Mild reactions may occur within a few days to weeks • Medical alert bracelets are recommended for penicillin allergic patients • Common non-allergic reaction: diarrhea, GI intolerance • Penicillin aqueous may be administered IV. However, penicillin benzathine and penicillin procaine CANNOT be administered IV and are administered intramuscularly (IM) only • Considered safe in pregnancy and breast-feeding 110 Antibacterial Spectrum: • Natural Penicillins (narrow spectrum penicillin) – Mostly gram-positive cocci, strep species, neisseria species – Syphilis, strep throat, endocarditis, Streptococcus pneumoniae • Antistaphylococcal Penicillins – Staphylococcus aureus – Useful in soft tissue and bone infections • Amino Penicillins (broader spectrum penicillins) – Gram (+) and Gram (-) coverage – Otitis media & sinus infections (Haemophilus influenzae, Streptococcus pneumoniae) – Alternative to penicillin in strep throat – Amoxicillin is preferred to ampicillin orally; better absorption and less diarrhea • Antipseudomonal Penicillins – Nosocomial infections: Pseudomonas aeruginosa • β -lactamase inhibitor combinations – Adding a β-lactamase inhibitor broadens gram-negative and anaerobic coverage – Useful when resistant strains of β-lactamase producing pathogens are suspected such as sinusitis or otitis media that does not respond to amoxicillin – Useful in anaerobic infections or polymicrobial infections such as an abscess, diabetic foot, abdominal infections, animal bites, empiric therapy for immunocompromised patients – Increased incidence of causing diarrhea and superinfections Cephalosporins • • • Mechanism of action is the same as for the penicillins Cephalosporins are affected by the same mechanisms of resistance as the penicillins; however, they tend to be more resistant to β-lactamase Cephalosporins are divided into “generations” based upon their antimicrobial spectrum Adverse Drug Reactions • • • • Allergic Reactions: common – Cross sensitivity between the penicillins and cephalosporins: approximately 1% – Patients with mild reactions to penicillins can try a cephalosporin – Patients with anaphylactic reactions to penicillins should NOT TAKE cephalosporins. Common non-allergic reactions: diarrhea, GI intolerance Different individual agents have various infrequent side effects Ceftriaxone IV and calcium—potentially fatal precipitates—do not mix IV solutions! 111 Antibacterial Spectrum • 1st Generation Cephalosporins – Excellent gram-positive coverage. Streptococcus, staphylococcus – Limited gram-negative coverage. E.coli, Klebsiella species, Proteus species – Poor anaerobic coverage – Soft tissue and bone infections, surgical prophylaxis • 2nd Generations Cephalosporins – Adequate gram-positive coverage. Strep, staph, gram-positive cocci – Adequate gram-negative coverage. H. influenza. M. catarrhalis, Neisseria species – Excellent anaerobic coverage (Cefoxitin and Cefotetan) – Abdominal infections, abscess, pelvic infections – Pneumonias, otitis media, sinus infections, meningitis • 3rd Generation Cephalosporins – Adequate gram-positive coverage – Excellent gram-negative coverage – Limited anaerobic coverage. – Pneumonias, otitis media, sinus infections, meningitis, nosocomial infections • 4th Generation Cephalosporins – Excellent gram-positive coverage. – Excellent gram-negative coverage also covers Pseudomonas; – No anaerobic coverage – Respiratory infections, meningitis, • 5th Generation Cephalosporins Enhanced coverage of gram-positive including MRSA Similar gram negative coverage to 3rd and 4th generation but does not cover Pseudomonas. Limited anaerobic coverage MRSA and VRE infections This is a very general, graphical representation of the coverage of the various generations of ephalosporins. 112 Carbapenems Mechanism of Action: similar to the penicillins and cephalosporins except that these drugs bind to more than one type of penicillin binding protein. This causes rapid cell lysis and extended spectrum Adverse Drug Reactions • Allergic reactions: Cross sensitivity with penicillins is seen. Conflicting data, some data shows up to 50% and others show less than 1%. • N/V, diarrhea, superinfection (4%) • Rarely Seizure - can cause seizure in patients with or without a history of seizure. Seizure history and renal dysfunction will increase this risk Antibacterial Spectrum • Considered very broad-spectrum agents • Active against most gram-positive and gram-negative organisms, both aerobic and anaerobic • Serious polymicrobial infections such as sepsis, abdominal infections, diabetic foot, animal bites, 113 Vancomycin (van koe MYE sin) Mechanism of Action • Also affect cell wall permeability • Binding a membrane bound peptidoglycan precursor causes rapid inhibition of cross-linking and direct membrane permeability defects • Not absorbed orally. Used IV to treat most infections Mechanism of Resistance • Luckily, resistance to this drug is very low • Resistant strains of enterococcus and staphylococcus have been emerging and are of great concern • Avoiding overuse is important to reduce development of bacterial resistance Adverse Drug Reactions • No cross sensitivity with penicillins or cephalosporins • “Red-neck” or “red-man” syndrome: infusion related reaction with hypotension, flushing, and rash on face, neck, and upper body. This is not an allergic reaction and can be overcome by slowing the infusion (occurs in > 10% of patients) • Very, very rarely patients may be truly allergic to vancomycin • Drug fever (1-10%) • Ototoxicity (usually reversible) • Renal toxicity (5%) • Immune-mediated thrombocytopenia Antibacterial spectrum • Covers gram-positive organisms only! Especially effective against Staphylococcus aureus and Staphylococcus epidermidis • No gram-negative coverage • No anaerobic coverage except for Clostridium difficile CDC Guidelines for Appropriate Use • Should be reserved for documented or highly suspected cases of methicillin resistant staphylococcus aureus (MRSA) • Can be used in gm-pos infections in patients with anaphylactic reactions to penicillin • Orally, used to treat metronidazole resistant Clostridium difficile Drug Level Monitoring • Plasma concentrations are routinely monitored for this agent • Trough levels (lowest blood level) are associated with efficacy • Troughs are monitored to ensure adequate concentrations are present to avoid the development of resistant organisms and to ensure efficacy MIC 15-20 mcg/dL 114 Protein Synthesis Inhibitors 5 Classes of Protein Synthesis Inhibitors Tetracyclines Aminoglycosides Macrolides Clindamycin Linezolid Mechanism of selective toxicity • Fortunately, bacterial and human cells have different enough ribosomes that human cells are usually unaffected Mechanism of Action • • Inhibit protein synthesis. Target the bacterial ribosome Must enter the bacterial cell to be effective Tetracyclines *doxycycline (Vibramycin) po,IV (doks i SYE kleen) *minocycline (Minocin) po (mi noe SYE kleen) *tetracycline (Sumycin) po (tet ra SYE kleen) Pharmacokinetics / Drug Interactions • High concentrations are achieved in body organs, skin, bone, and teeth • Will cross the placenta and are excreted into breast milk • Will chelate with divalent and trivalent cations Al3+, Mg2+, Ca2+, Fe3+, antacids, multivitamins, milk, cheese, etc Separate doses by at least 2 hours from such products Adverse Drug Reactions • Photosensitivity - caution patients to avoid the sun or wear sunscreen/protective clothing • Discoloration of teeth – only a problem if given during time of tooth development May discolor deciduous (baby) teeth if given during pregnancy May discolor premature teeth if given to children 4mos – 8yrs old Causes a yellow or brown discoloration; may also weaken enamel • GI intolerance - caution against using antacids for this due to chelation drug interactions • Contraindications: pregnancy, breast feeding, children less than 8 years old Antibacterial Spectrum Effective against a variety of types of pathogens . Once considered broad spectrum but no longer due to bacterial resistance. Therapeutic Use • Uncomplicated respiratory tract infections • Community-Acquired Pneumonias caused by (Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumoniae) • Tick-borne diseases: Rocky Mountain Spotted Fever, Lyme disease, • Gastric infection with H. Pylori • Acne: Topically and orally • Bioterrorism: Used as an alternative to ciprofloxacin for anthrax and the plague • Periodontal disease 115 Aminoglycosides *gentamicin (jen ta MYE sin) tobramycin (toe bra MYE sin) amikacin (am i KAY sin) neomycin (nee oh MYE sin) most commonly used amioglycoside (IV, inhalation, ophthalmic) reserved for gent resistant strains (IV, inhalation, ophthalmic) reserved for tobramycin and gentamicin resistant strains (IV) po or topical form only Pharmacokinetics • Very water soluble but not very lipophillic. Does not distribute into adipose tissue • Not absorbed orally. Neomycin is used to reduce GI flora when given orally • High concentrations can accumulate in the kidneys and inner ear • Excreted totally unchanged in the urine (dose adjustment required in renal impairment) Adverse Drug Reactions • Nephrotoxicity - (2-10%) usually reversible. • Ototoxicity - usually irreversible hearing loss; begins as ringing in the ears. It may also cause vestibular toxicity (loss of balance). (Conflicting information regarding ototoxicity) • Nephrotoxicity is associated with trough levels, length of therapy greater than 10 days, and pre-existing renal dysfunction • Allergic reactions - contact dermatitis to topical neomycin is fairly common Antibacterial Spectrum • Used to treat serious, nosocomial, gram-negative infections and serious UTIs Klebsiella pneumoniae, Enterococcus, Pseudomonas aeruginosa • Hardly any gram-positive coverage • No anaerobic coverage • Often used in combination with β-lactams for empirical therapy in immunocompromized patients with “fever of unknown origin” • Commonly used in neonates along with ampicillin when sepsis is suspected • Synergy with the beta-lactam antibiotics Drug Level Monitoring • Plasma concentrations (blood levels) are routinely monitored for this antibiotic • Unlike the other antibiotics, this drug works the best with high peaks. Having very low troughs will actually protect the kidneys from renal damage. Peaks are monitored to make sure they are high enough to provide efficacy. Troughs are monitored to make sure they are low enough to avoid kidney toxicity. **How are Peaks and Troughs measured? – This applies to ANY drug • Because the peak represents the highest concentration the drug is expected to have in the • blood stream, it is most accurately measured about 30 mins to 60 mins after a dose. This allows a little bit of time for the drug to distribute before measuring. Because the trough represents the lowest concentration the drug is expected to have in the blood stream, it is most accurately measured about 5 to 15 mins before the next dose is due. 116 Macrolides *azithromycin (Z-pak, Zithromax) *clarithromycin (Biaxin) *erythromycin (multiple brands) (az ith roe MYE sin) (kla RITH roe mye sin) (er ith roe MYE sin) Pharmacokinetics / Drug Interactions • Erythromycin and clarithromycin are metabolized by cytochrome p450 system and have multiple drug interactions with drugs like theophylline, warfarin, and seizure drugs. • Azithromycin is less likely to have metabolism interactions. 48-hour half-life. • Use caution in patients with severe hepatic dysfunction. Adverse Drug Reactions • GI intolerance - Common and most troublesome side effect. Leads to patient non-compliance. • Clarithromycin can cause abnormal taste sensations. • Erythromycin and clarithromycin have been associated with prolongation of the QT interval. Antibacterial Spectrum • Broad spectrum; Usually bacteriostatic. • Excellent atypical coverage, some Gram (+), some Gram (-), some anaerobic coverage. Therapeutic Uses • Alternative treatment for strep throat in patients with PCN allergy • Upper respiratory tract infections: • Community-Acquired Pneumonias caused by (Strep. pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumoniae) • STDs: Chlamydia and gonorrhea • Drug of choice for Bordetella pertussis (Whooping cough) • Diphtheria • Uncomplicated skin infections including acne *Clindamycin (Cleocin) IV,po,topical (klin da MYE sin) Clindamycin is NOT a macrolide Antibacterial Spectrum • Covers anaerobic infections • Gram-positive cocci, streptococcus, staphylococcus • Has almost no gram -negative coverage • Used to treat diabetic foot ulcers, aspiration pneumonias, skin and soft tissue infections, pelvic infections and topically to treat acne Adverse Drug Reactions • Skin rashes • High incidence of causing Clostridium difficile About Clostridium difficile diarrhea • • • • • Also called pseudomembraneous colitis; it is a superinfection Many antibiotics, oral or IV, can cause it. Antibiotics can alter the normal GI flora, leading to an overgrowth of C. diff. Symptoms are caused by this anaerobic bacteria as it dies and releases toxins. C. diff diarrhea can occur anytime during antibiotic therapy or 4-6 weeks after a course of therapy. Symptoms of C. diff include severe diarrhea, watery stools up to 10 – 20 per day often with blood and mucous, fever, and abdominal paing Clostridium difficile is contagious! It can be transmitted person to person without antibiotic use Treatment: Stop the offending antibiotic and start metronidazole or oral vancomycin 117 Linezolid (Zyvox®) Antibacterial Spectrum • Covers gram-positive bacteria; streptococcus, staphylococcus, enterococcus • Has no gram-negative coverage • Primarily reserved for VRE (vancomycin resistant enterococcus) infections and MRSA • Adverse Drug Reactions: Diarrhea, nausea, and headache • Drug Interactions: Linezolid is a weak MOA inhibitor. Can increase the risk of serotonin syndrome if taken with an SSRI. Fluoroquinolones *Ciprofloxacin (Cipro®) *Levofloxacin (Levaquin) moxifloxacin (Avelox) gemifloxacin (Factive) (sip roe FLOKS a sin) (lee voe FLOKS a sin) (moxs i FLOKS a sin) (je mi FLOKS a sin) lomefloxacin (Maxaquin) ofloxacin (Floxin) norfloxacin (Noroxin) sparfloxacin (Zagam) (loe me FLOKS a sin) (oh FLOKS a sin) (nor FLOKS a sin) (spar FLOKS a sin) Mechanism of Action • Inhibit bacterial DNA replication by interfering with two enzymes--DNA gyrase and topoisomerase IV Pharmacokinetics • Oral absorption is excellent. Clinically, intravenous is equally effective to oral administration • Distributes into bone and prostate • Levels in the lungs and urine are usually much higher than in the blood • Excreted renally; some liver metabolism Drug Interactions • Chelation interactions with sucralfate, antacids, milk, vitamins, or anything containing polyvalent cations like Ca++, Mg++, Al++, and iron • Best oral absorption if taken on an empty stomach • Some have cytochrome p450 drug interactions with theophylline, cimetidine, warfarin, and others Adverse Drug Reactions • GI upset, diarrhea, nausea, abdominal pain • CNS: headache, dizziness, lightheadedness, confusion, and rarely seizure. CNS side effects can occur in any patient, but especially in the elderly and renally impaired • Phototoxicity • Some may cause prolongation of QT interval (heart arrhythmias) • Possible tendon ruptures, especially with long-term use • Contraindicated in pregnancy, breast-feeding, and children < 18y/o due to possible bone development abnormalities in beagle puppies (this has never been reported in humans) Therapeutic Indications • Coverage is difficult to categorize and varies somewhat per agent. In general, they have excellent gram negative coverage, some gram positive coverage and almost no anaerobic coverage • Emerging resistance and overuse is a concern • Urinary tract infections (UTI) and prostate infections • Respiratory tract infections (a drug of choice for community acquired pneumonias) • Anthrax; some skin/soft tissue infections; bone and joint infections; sexually transmitted disease, Chlamydia trachomatitis 118 Folate Antagonists (Sulfa Drugs/Sulfonamides) Mechanism of selective toxicity • Bacterial cells are impermeable to folic acid and must synthesize folic acid to survive • Human cells do not synthesize folic acid. We receive folic acid as a vitamin in our diet • Folate antagonists, therefore, are fairly specific to bacterial cells Mechanism of action • Sulfonamides are structurally similar to para-aminobenzoic acid (PABA) • Bacteria turn PABA into folic acid • Folic acid is essential for the synthesis of RNA and DNA precursors that these organisms need to grow and divide • Sulfonamides use up much of the enzyme needed to convert PABA to folic acid, thus decreasing folic acid production Sulfonamides are active against • Proteus mirabilis • Escherichia coli • Methicillin-resistant Staphylococcus Aureus (MRSA) • Pneumocystis Jiroveci (formerly identified as Pneumocystis carinii) Therapeutic Indications • Urinary tract infections Pharmacokinetics • Well absorbed orally. Distributes throughout body water, into CSF, pass the placental barrier and into breast milk. Highly protein bound. Metabolized in the liver. Excreted by the kidney; decreased renal function causes accumulation of the parent compound and metabolites Adverse Effects • Allergic Reactions - fairly common - rashes, photosensitivity, Stevens-Johnson syndrome • Nephrotoxicity - Crystalluria - adequate hydration - drink lots of water. Contraindicated in renal failure • Kernicterus - in newborns, sulfas displace bilirubin from protein binding sites • Drug interactions with other highly protein bound drugs  i.e. warfarin (Coumadin), phenytoin (Dilantin) Sulfa drugs include: • Sulfamethoxazole, Bactrim® component • mafenide • silver sulfadiazine, Silvadene® • sulfacetamide, Cetamide® • sulfadiazine, Microsulfon® • sulfisoxazole, Gantrisin® (sul fa meth OKS a zole) (oral,IV) (MA fe nide) (topical) (SIL ver sul fa DYE a zeen) (topical) (sul fa SEE ta mide) (ophthalmic) (sul fa DYE a zeen) (oral) (sul fi SOKS a zole) (oral) 119 Dihydropteroate synthetase Trimethoprim (trye METH oh prim) Dihydrofolate Reductase PABA → Folic →Tetrahydrofolic Acid Acid (active) Mechanism of Action • Dihydrofolate reductase inhibitor • Dihydrofolate reductase converts folic acid to its active form, tetrahydrofolic acid • Resistance in gm-negative organisms is due to the presence of an altered dihydrofolate reductase that has lower affinity for the drug Pharmacokinetics • Similar to sulfonamides Adverse Drug Reactions • Can produce effects of folate deficiency if given in very high doses Trimethoprim/Sulfamethoxazole (Bactrim, Septra) (oral, IV) **Sulfamethoxazole / Trimethoprim (sul fa meth OKS a zole and trye METH oh prim) This drug is a combination of two antibiotics: 1) a sulfa drug (sulfamethoxazole) plus 2) a folate antagonist (trimethoprim) Mechanism of Action • Inhibits two sequential steps in the synthesis of active folic acid Spectrum of Activity • Broader spectrum than the sulfonamides alone • Synergy - shows greater antimicrobial activity than equivalent quantities of either drug used alone • Resistance - much less frequent; resistance by an organism would require simultaneous resistance to both drugs Adverse Drug Reactions • Same as for the sulfonamide antibiotics and trimethoprim Therapeutic Indications • Urinary tract infections • Treatment and prophylaxis against Pneumocystis pneumonia Miscellaneous *Nitrofurantoin (Macrodantin, Macrobid) • • • po (nye troe fyoor AN toyn) Mechanism of action: inhibits various bacterial enzymes and damages bacterial DNA Therapeutic Uses Used to treat uncomplicated UTIs caused by E.coli and other common UTI pathogens Adverse Effects Turns urine brown/orange. GI disturbances are common. Take with food or milk *Metronidazole (Flagyl ) • • • • (me troe NI da zole) Mechanism of action: Damages bacterial DNA Therapeutic Uses: A drug of choice for Clostridium difficile diarrhea. Has excellent anaerobic coverage for abdominal infections. Also targets some protozoa Adverse Effects: N/V, headache, metallic taste, loss of appetite, vertigo, insomnia, CNS effects Interactions: NO alcohol. “Disulfuram reaction” with alcohol = severe N/V & abdominal cramps 120 Drugs to Treat Tuberculosis Overview of Tuberculosis • Mycobacterium tuberculosis - Slow growing microbe that requires lengthy treatment. - Acid fast bacteria • Disease of the lungs, transmitted by inhaling infected, aerosolized sputum. • Worldwide: 2 billion people harbor latent infection • Worldwide: 1.7 million people died from TB in 2009 • Globally of the disease is on the rise. • In the US the disease is declining • Mostly due to increasing numbers of HIV patients and emergence of multi-drug resistant mycobacterium. • Resistance is due to inadequate drug therapy. • The Prime Directive: Always treat TB with 2 or more drugs!! Primary Infection • Primary infection begins in the lungs. • Bacteria multiply freely until immunity develops and the infection is brought under control. - Colonization / Colonized • 90% of patients with primary infection never develop clinical evidence of the disease. • However, since they harbor the organism, the threat of reactivation is always present. Reactivation • If the immune system is unable to bring the infection under control or if reactivation of the primary infection occurs, progressive tissue destruction and patient death may occur. • Reactivation may occur in times of suppressed immune function • Times of severe physical/mental stress. • Immunosuppressive medications Screening • Tuberculin skin test (PPD) - Purified protein derivative. - Intradermal injection. - Read 48 - 72 hours later. - Looking for a local hypersensitivity reaction. • Interferon Gamma Release Assays - Blood test - White blood cells when exposed to an antigen that represents M. tuberculosis respond and release interferon then the test is considered positive for TB. - As sensitive as the TST - Results available sooner (24 hours) 121 *Isoniazid (INH) • • • (eye soe NYE a zid) Mechanism of Action: Targets enzymes responsible for assembly of the outer layer of the mycobacterium. Therapeutic Use: Treatment and prophylaxis of TB. Adverse Effects: Peripheral neuropathy due to pyridoxine (Vit B6) deficiency. Always add a vitamin B supplement! Liver failure *Rifampin • • • • (RIF am pin) Mechanism of Action: Blocks RNA synthesis by inhibiting a specific bacterial enzyme. Therapeutic Use - Treatment of TB - Sometimes used to treat Staphylococcus aureus (especially MRSA) - Prophylaxis against Neisseria meningitidis and Haemophilus influenzae meningitis. Adverse Effects - N/V, rash, fever. - Will turn all body fluids orange-red color. (urine, sweat, tears, will stain contacts) - Liver failure. Drug Interactions - Cytochrome p450 inducer. - It will decrease the half-lives of theophylline and seizure drugs. Rifapentine (Priftin®) Long acting analog of rifampin *Pyrazinamide • • • (peer a ZIN a mide) Mechanism of Action: Unknown. Therapeutic Use: Treatment of TB. Adverse Effects: Gouty attacks and Liver Failure. *Ethambutol • • (e THAM byoo tole) Therapeutic Use: Treatment of TB Adverse Effects: Optic nerve irritation causing reversible, red/green color blindness. Common TB Treatment Regimens • Initially: Isoniazid + Rifampin + Pyrazinamide + Ethambutol x 2 months • Then: Isoniazid + Rifampin x 4 months OR • Initially: Isoniazid + Rifampin x 1 month • Then: Isoniazid + Rifampin daily or biweekly x8 mos. • DOT = Directly Observed Therapy: administration of each dose in the presence of an observer, usually a representative of the health department. Treatment of Latent TB • • • Isoniazid daily x 6 - 9 months or twice weekly Isoniazid plus Rifapentine once weekly x 3 months Given to prevent development of active infection and to prevent transmission to others. Although combination therapy is necessary in the treatment of TB, liver toxicity from these drugs is additive. Monitor liver function tests monthly. Do not drink alcohol!! 122 Antifungal Drugs Overview of Fungal Infections • Most fungal infections are superficial and involve the skin or fingernails. • Systemic fungal infections are rare and usually life-threatening. • Systemic fungal infections usually occur in immunocompromised patients. E.g. Neutropenic cancer patients, transplant recipients, AIDS, severe physical stress / major trauma Fungi are Different than Bacteria • Fungi are slow growing organisms. • They possess a rigid cell wall and a cell membrane that contains sterols. • Many fungus infections take longer to treat due to their slow growth. • Several of the antifungals are more toxic than the antibacterials. • Bacterial cells do not contain sterols, but human cells do. Mechanism of Action of the Antifungals Either • Bind to sterols in fungal cell membranes to form pores or channels. This disrupts the membrane, allowing electrolytes and small molecules to leak from the cell which leads to cell death Or • Prevent the synthesis of sterols. This prevents cell wall synthesis and repair. There are 4 classes of antifungals used to treat systemic infections: 1) polyenes, 2) azoles, 3) pyrimidine analogs, & 4) echinocandins 1) Polyenes *Amphotericin B (Fungizone ) IV Liposomal Amphotericin (Abelcet ) IV (am foe TER i sin bee) (lye po SO mal am foe TER I sin) Therapeutic Uses • Serious, systemic fungal infections • Administered IV only • Partially metabolized by the liver and partially renally cleared Adverse Drug Reactions • Shake and Bake: fever and shaking chills, nausea, headache  Infusion related. Starts 1-3 hours after infusion begins.  Slowing rate of infusion may help or premedicate with acetaminophen (Tylenol) and diphenhydramine (Benadryl) • Renal damage: direct damage to kidney cells  Some degree of renal impairment occurs in all patients. Monitor renal function and adjust dose as necessary.  K+ and Mg++ wasting by the kidneys. Watch for hypokalemia • Hypotension (infusion related), anemia (impaired iron utilization), and thrombophlebitis 123 2) Azoles Ketoconazole (Nizoral ) po, shampoo (kee toe KOE na zole) Therapeutic Uses Treatment of lung, bone, and skin fungal infections Drug Interactions • Requires an acidic environment for adequate absorption  Food, antacids, acid blockers, and proton pump inhibitors will impair absorption  Coca-Cola, being acidic, will improve absorption • Cytochrome p450 interactions Adverse Drug Reactions • GI upset, nausea and vomiting • Endocrine effects - Can inhibit sex steroid synthesis in humans.  Gynecomastia, decreased libido, impotence, menstrual irregularities • Liver Failure - Monitor liver function tests periodically *fluconazole (Diflucan ) IV, po (floo KOE na zole) • Similar therapeutic uses to ketoconazole, esophageal candidiasis. A single oral dose is also effective for vaginal yeast infections. NO endocrine side effects. NO absorption interactions. itraconazole (Sporanox ) po (i tra KOE na zole) • Used for fungal nail infections. Also for systemic infections. NO endocrine side effects. Requires acidic environment for best oral absorption. posaconazole (Noxafil ) po(pose a CON a zole) • Used to prevent invasive Candida and Aspergillus infections in patients who are immunocompromised. Works better than fluconazole and itraconazole for this. voriconazole (Vfend ) po (vore a CON a zole) • Used to treat life-threatening fungal infections All “azoles” have Cytochrome p450 drug interactions (cyp3A4 inhibitors) and the potential to cause liver failure 3) Pyrimidine analog flucytosine (Ancobon ) po (floo SY toe seen) • Narrow antifungal spectrum of Candida species and Cryptocossus neoformans 124 4) Echinocandins caspofungin (Cancidas®) IV micafungin (Mycamine®) IV anidulafungin (Eraxis®) IV • • • • (cass pow FUN gin) (MY caa fun gin) (aneh DOO laa fun gin) Must be given IV; cannot be given PO Narrow spectrum (Aspergillus and Candida species) Fewer adverse effects than polyene class More expensive Griseofulvin (Fulvicin , Gris-PEG ) po • • • (gri see oh FUL vin) Therapeutic uses: tinea infections of skin, hair, and nails Adverse Effects: rash, itching, headache, GI upset, photosensitivity Cytochrome p450 drug interactions. Liver failure. Superficial Fungal Infections • • • • • • • Ring Worm of body (tinea corporis) Ring Worm of scalp (tinea capitis) Athlete’s foot (tinea pedis) Jock itch (tinea cruris) Oral Candida (thrush) Vaginal Candida (vaginal yeast infections) Onchomycosis (fungal nail infections) *Clotrimazole (Gyne-Lotrimin, Mycelex, Lotrimin AF®) (kloe TRIM a zole) • Superficial fungal infections and vaginal yeast infection • Clotrimazole troche (lozenge) for oral candidiasis Miconazole (some Absorbine, Lotrimin & Monistat products) (mi KON a zole) • Superficial fungal infections and vaginal yeast infections *Nystatin (Mycostatin) (nye STAT in) • superficial candidal infections • swish and swallow suspension - not absorbed orally Terbinafine (Lamisil) (TER bin a feen) • orally and topically for superficial and nail infections Terconazole (Terazol) (ter KONE a zole) Tioconazole (Vagistat) (tye oh KONE a zole) • vaginal yeast infections Tolnaftate (Tinactin, some Absorbine products) (tole NAF tate) • superficial fungal infections 125 Antiviral Drugs Overview • Viruses are very different than bacteria! • Viruses are intracellular parasites • They have no cell wall and no cell membrane and do not carry out metabolic processes • They live and replicate within the host’s cells • Some antivirals are selective enough to prevent viral replication without affecting host cells; many are not Mechanism of Action • Mechanism of action of most antivirals involves inhibition of viral replication. • Different antivirals act at different steps of viral replication and upon different enzymes necessary for that replication, but the bottom line is…Inhibition of viral replication. Non-HIV Antivirals Influenza Antivirals Neuraminidase Inhibitors: *Oseltamivir (Tamiflu®) po (oh sel TAM I veer) • Indication: treatment and prevention of Influenza A and B --also effective against H5N1 (avian flu) and H1N1 (“swine flu”) • Therapy must be started within 48 hours of onset of illness. • Problem: Many patients may not seek treatment in time. Once symptoms set in, most of the viral replication has already occurred. • Adverse Reactions: nausea and vomiting • Expensive; about $110 *Zanamivir (Relenza®) powder for inh (za NA mi veer) • Indication: treatment and prevention of Influenza A and B • Adverse Reactions: uncommon, occurring in less than 5% of patients: nausea, headache, cough, bronchospasm in asthma • Expensive; about $60. Can reduce transmission by 90% if started w/i 2 days of symptoms. Severity & duration of symptoms reduced by ~ 1.5 days Adamantanes: • • Indication: prophylaxis and treatment of Influenza A (flu) Most strains are resistant to adamantanes now: CDC currently does NOT recommend their use. Amantadine (Symmetrel®) (po) (a MAN ta deen) • Renally eliminated; crosses the blood brain barrier • CNS side effects (insomnia, anxiety, irritability, hallucinations, confusion) • Orthostatic hypotension, nausea Rimantadine (Flumadine®) (po) (ri MAN ta deen) • Liver metabolized; does not cross the BBB, less CNS side effects • Orthostatic hypotension, nausea 126 Is it a Cold or the Flu? Annual Influenza Vaccine • • Best protection against influenza Vaccinate in October / November Who should be vaccinated? All people age 6 months and older Common Symptom Fatigue Cold No Flu Yes Fever Muscle ache Joint pain Loss of appetite Headache Cough Stuffy nose Diarrhea/vomiting No No No No Yes Yes Yes No 100 – 104 F Yes Yes Yes Yes Yes No No Who should not be vaccinated? • People who have a severe allergy to chicken eggs* - FluBlock® does not use chicken eggs as the growth medium • People who have had a severe reaction to the influenza vaccine in the past • People who have experienced Guillain-Barre’ syndrome (GBS) • People with moderate or severe illness with fever (these individuals should wait until symptoms resolve) Herpes Antivirals *Acyclovir (Zovirax®) (ay SYE kloe veer) po Valacyclovir (Valtrex®) (val ay SYE kloe veer) po better absorbed prodrug of acyclovir Famciclovir (Famvir®) (fam SYE kloe veer) po • Indications – Herpes simplex virus (HSV-1): self-limiting “cold sores;” usually acquired in childhood – Herpes simples virus (HSV-2): genital herpes; present 25% of US adults; Up to 70% of genital herpes is transmitted when partner is asymptomatic (no visible lesions); some genital herpes infections are actually caused by HSV-1. Life-long, daily suppressive therapy with antivirals will reduce frequency and viral shedding by 85%-90%. – Varicella-zoster virus (Chicken pox): treatment can reduce severity by 30% if started early; Viravax® (chicken pox vaccine) + booster vaccination now required for all school age children – Varicella-zoster virus latent (shingles): latent virus; can flare-up later in life due to stress or immunocompromized conditions; treatment is important to prevent postherpetic neuralgia. Postherpetic neuralgia pain is extremely difficult to treat – occurs when the virus damages the nerves. Zostavax® – shingles vaccine ↓ shingles by 50%. • Antivirals reduce the frequency, duration, and severity of outbreaks. They are not a cure. • Adverse Reactions: dizziness, seizure, agitation, confusion, nausea 127