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ANTIBACTERIAL DRUGS PHARM 514 Douglas Black, Pharm.D. Associate Professor School of Pharmacy University of Washington [email protected] WE HAVE LOTS TO COVER IN TWO DAYS • Principles of antimicrobial chemotherapy • ß-lactams • Vancomycin • Aminoglycosides • Macrolides • Tetracyclines • TMP-SMX • Clindamycin • Linezolid • Fluoroquinolones • Nitrofurantoin • Rifampin • Metronidazole • Antifungal drugs THESE DEFINITIONS ARE IMPORTANT • Bacteriostatic antibiotic: a compound that only inhibits bacterial growth. • Bactericidal antibiotic: a compound that exerts an outright lethal effect. Some drugs are “rapidly” bactericidal, others are “slowly” bactericidal. • MIC (minimum inhibitory concentration): the minimum concentration of antibiotic required to inhibit growth of a specific organism. It is a reflection of the potency of the antibiotic; the lower the MIC, the more potent the antibiotic toward that organism. Only occasionally does the lab determine MICs for purposes of patient care. THERE ARE FIVE GENERAL WAYS A MICROBE CAN DEFEND ITSELF • Synthesize enzymes that alter the antibiotic (rendering it useless) – ß-lactamases – aminoglycoside-modifying enzymes • Alter the bacterial target of the antibiotic • Alter outer membrane permeability to the antibiotic (Gram-negative organisms only) • Pump (efflux) the antibiotic out of the bacterial cell • Bypass the biochemical blockade caused by an antibiotic (if that is its mechanism of action) A β-LACTAM IS JUST A CHEMICAL CLASS • Penicillins, cephalosporins, carbapenems, and aztreonam are all ß-lactam antibiotics • A ß-lactamase is a bacterial enzyme that destroys the activity of a ß-lactam antibiotic THERE ARE FOUR TYPES OF “PENICILLINS,” GROUPED HERE ACCORDING TO ANTIBACTERIAL SPECTRUM (*=oral) NATURAL PENICILLINS Penicillin G, penicillin V* AMINOPENICILLINS Ampicillin*, amoxicillin* ANTISTAPHYLOCOCCAL PENICILLINS (not MRSA) Nafcillin, dicloxacillin* ß-LACTAM/ß-LACTAMASE INHIBITOR COMBOS Amoxicillin/clavulanate* Ampicillin/sulbactam Piperacillin/tazobactam THE PENICILLINS STILL HAVE LOTS OF USES NATURAL PENICILLINS Pen VK: strep pharyngitis Pen G: serious streptococcal skin infection, syphilis AMINOPENICILLINS Amox: acute otitis media (AOM), acute bacterial sinusitis (ABS) Amp: Listeria meningitis, Enterococcus infection ANTISTAPHYLOCOCCAL PENICILLINS (not MRSA) Diclox: skin infection (staph or strep) Naf: more serious staphylococcal infection (e.g. endocarditis) ß-LACTAM/ß-LACTAMASE INHIBITOR COMBOS Amox/clav: refractory AOM or ABS, dog or cat or human bites Amp/sulb: community-acquired pneumonia, mild-moderate intraabdominal infection Pip/tazo: life-threatening infection PHARMACOKINETICS HELPS US TO MAKE PREDICTIONS ABOUT DRUG BEHAVIOR • Penicillins are bactericidal (targeting enzymes involved in cell wall synthesis) • Tend to have short half-lives and frequent dose intervals • Oral absorption isn't complete: Drug % absorbed penicillin V ampicillin amoxicillin dicloxacillin amox/clav 60-73 30-55 75-90 35-76 75-90 • Most common toxicities: GI, allergic • Rare side effects: drug fever, seizures, neutropenia, interstitial nephritis, liver toxicity BICILLIN IS AN ERROR WAITING TO HAPPEN • Bicillin L-A 2.4 million units = 2.4 million units of benzathine penicillin G • Bicillin C-R 2.4 million units = 1.2 million units of benzathine penicillin G + 1.2 million units of procaine penicillin G • 429 patients with documented syphilis treated at a large clinic in Los Angeles from 1999-2004 received the wrong product and were underdosed. 234 patients treated for sexual contact with someone known or suspected to have syphilis were also administered the wrong product. WE DO NOT NEED ALL 27 CEPHALOSPORINS THAT ARE CURRENTLY ON THE US MARKET • First generation (6) – Cefazolin – Cephalexin* (*=oral) • Second generation (10) – Cefotetan – Cefuroxime axetil* • Third generation (9) – Ceftriaxone – Ceftazidime – Cefpodoxime proxetil* – Cefdinir* – Cefixime* • Fourth generation (1) – Cefepime • Fifth generation (1) – for MRSA – Ceftaroline Sardinia: where cephalosporins were first discovered in 1945 1st generation 2nd generation G+ increasing ß-lactamase stability G3rd generation 4th generation CEPHALOSPORINS HAVE TYPICAL USES TOO 1st 2nd 3rd Cefazolin Surgical prophylaxis, skin infection Cephalexin (po) Skin infection Cefotetan GI surgery prophylaxis, mild-to-moderate intra-abdominal infection Cefuroxime (po) Refractory AOM, ABS Ceftriaxone Meningitis, endocarditis, skin infection, gonorrhea Ceftazidime Serious Pseudomonas infection Cefpodoxime (po) Refractory AOM, ABS Cefdinir Refractory AOM 4th Cefepime Life-threatening infection in the ICU CEPHALOSPORINS ARE SIMILAR TO PENICILLINS IN SOME RESPECTS BUT DIFFERENT IN OTHERS • Mechanism of action: fundamentally the same • Cephalosporins tend to have a bit longer half-lives than penicillins • Cephalosporins tend to be eliminated from the body by more mechanisms than simply the kidney • Side effects are generally the same; cephalosporins cause more diarrhea but less rashes than penicillins TWO TYPES OF PENICILLIN HYPERSENSITIVITY ARE IgE-MEDIATED, BUT ONE IS NOT Immediate Within 30-60 minutes of penicillin administration; IgE directed against minor (5%) determinants (benzylpenicillin, penicilloate, penilloate) Accelerated Within 1-72 hours of penicillin administration; IgE directed against major (95%) determinant (penicilloyl*) Delayed ≥ 72 hours after penicillin administration; type II-IV hypersensitivity (non-IgE) *Pre-Pen is the penicilloyl hapten conjugated to protein THIS IS A MACULOPAPULAR RASH (NON-IgE) 23S rRNA THIS IS AN URTICARIAL RASH (IgE) 23S rRNA HERE ARE SOME PENICILLIN CROSS-ALLERGY PERCENTAGES WITH OTHER BETA-LACTAMS (for IgE-mediated reactions) • Cephalosporins: probably 0.5% or less – We used to think it was much higher – Applies only to drugs with R-group similarity (cephalexin, cefadroxil, cefaclor) • Imipenem – Anaphylaxis: as high as 50% – Urticaria: probably under 10% – Not known for other carbapenems (might be less?) • Aztreonam – Almost zero Rashes are often thought of as benign drug hypersensitivity reactions that resolve merely by stopping the likely perpetrator. In most cases, this is true. However, there are some skin reactions that are dangerous and even fatal, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS ARE RARE BUT AWFUL • Horrendous drug reactions characterized by skin detachment – SJS: <10% BSA; TEN: >30% BSA • Common offenders: antibiotics, anticonvulsants, antinflammatory agents, allopurinol, even OTC meds like ibuprofen. • Generally appears 1-3 weeks after the drug is started • Course: prodrome → painful, burning rash → blistering → full thickness skin sloughing. Mucus membranes almost always involved. Complications likely. Patients are literally “burning” from the inside out. • Treatment (esp. TEN): fluid & electrolyte management, nutrition, antibiotics for secondary infections, analgesics. Corticosteroid use controversial. • Long term complications: blindness, scarring, internal organ damage, death (TEN: 25-44% mortality). 23S rRNA 23S rRNA 23S rRNA THE CLOCK IS PROBABLY TICKING FOR VENERABLE VANCOMYCIN • Our only glycopeptide and still drug of choice for MRSA (IV only, but patients drink the injection for C. difficile) • Slowly bactericidal • Strictly a Gram-positive spectrum • Predictable pharmacokinetics • Serum concentration monitoring is commonly done – Troughs 10-15 or 15-20 (µg/ml) depending on the infection • Toxicity – Histamine-release reaction – Ototoxicity (peaks >80, but we don't measure peaks anymore) – Nephrotoxicity (only in combination?) – Reversible neutropenia WE HAVEN’T HAD A NEW AMINOGLYCOSIDE SINCE GERALD FORD WAS PRESIDENT Drug Year Source organism Streptomycin 1944 Streptomyces griseus Neomycin 1949 Streptomyces fradiae Kanamycin 1957 Streptomyces kanamyceticus Paromomycin 1959 Streptomyces rimosus Spectinomycin 1962 Streptomyces spectabilis Gentamicin 1963 Micromonospora purpurea Tobramycin 1968 Streptomyces tenebrarius Sisomicin 1972 Micromonospora inyoensis Amikacin 1972 Semisynth deriv of kanamycin Netilmicin 1975 Semisynth deriv of sisomicin WE AVOID AMINOGLYCOSIDES BECAUSE THEY ARE TOXIC, NOT BECAUSE THEY DON’T WORK • Generally used only when necessary (less toxic drugs are preferred) • IV/IM only (poorly absorbed) • Bactericidal • These are powerful drugs, usually combined with a β-lactam for serious Gram-negative infections including Pseudomonas • Also used (in lower doses) to help drugs for Gram-positive infections work better • TOXIC!!! – nephrotoxic (probably due to drug abnormally accumulating in the renal cortex) – ototoxic • auditory (starting at high frequencies) • vestibular (can be extremely debilitating) – enhancement of neuromuscular blockade (rare) OTOTOXICITY FROM AMINOGLYCOSIDES IS WORSE THAN NEPHROTOXICITY, I THINK KIDNEY EAR Reversible Irreversible Well defined risk factors* Poorly defined risk factors Well defined time course (see next slide) Poorly defined time course Creatinine can be monitored No common labs to follow Serum concentrations correlate Poor correlation with serum concentrations *advanced age, duration of therapy, hypotension, concomitant liver disease, use of other nephrotoxins AMINOGLYCOSIDE DOSES ARE ADJUSTED ACCORDING TO BLOOD CONCENTRATIONS Infection Peak conc (μg/ml) Trough conc (μg/ml) Gram-positive 3 <1 Gram-negative (except pneumonia) 5-8 <1 Gram-negative pneumonia 10-12 <1 Critical: the peak is measured one hour after an infusion begins; the trough is measured immediately prior to the next dose (all done at steady state). The above numbers are for gentamicin and tobramycin. THE DRUGS IN YELLOW ARE THE ONLY MACROLIDES AVAILABLE IN THE US 12-membered ring (methymycin) 16-membered ring (spiramycin) 14-membered ring erythromycin 15-membered ring (azithromycin) clarithromycin dirithromycin flurithromycin roxithromycin telithromycin (the 1st ketolide) THIS IS ERYTHROMYCIN, THE PROTOTYPE “MACROLIDE.” THE CIRCLED –OH GROUP IS RESPONSIBLE FOR ITS NOTORIOUS GI TOXICITY. 6 1 THERE IS NOT MUCH TO LIKE ABOUT ERYTHROMYCIN LIKE DON’T LIKE Cheap Bacteriostatic Safe in pen allergy Short half-life (2 hours) Safe in pregnancy Doesn’t cover H. influenzae Poor for penicillin-resistant strains of S. pneumoniae Lots of confusing preparations Inhibits liver metabolic enzymes Causes nausea and vomiting Causes diarrhea May cause arrhythmias AZITHROMYCIN (The Z-PAK) IS VERY POPULAR FOR MANY REASONS ISSUE Less GI side effects than erythromycin AZ CL x New annoying toxicity: metallic taste x x Longer half-life than erythromycin x x Covers H. influenzae x x Inhibits hepatic drug metabolism x Less propensity to cause arrhythmias x Pregnancy category B like erythromycin x x SUMMARY: AZITHROMYCIN IS MORE GENERAL-PURPOSE THAN CLARITHROMYCIN • Oral erythromycin is still occasionally used, mainly for cost reasons. IV erythromycin is only rarely used. • Oral azithromycin (the Z-PAK) is HEAVILY used for communityacquired pneumonia. Zmax is a single-dose option for CAP. IV azithromycin is used in CAP patients who are admitted to the hospital. Oral azithromycin is also occasionally used for skin infections. • Single-dose azithromycin is the drug of choice for Chlamydia cervicitis/urethritis. • Azithromycin is popular for MAC (Mycobacterium avium complex) prophylaxis in AIDS patients (1200 mg every week). • Azithromycin is also approved for AOM, although some consider it a poor choice. • Clarithromycin is a key drug for treatment of peptic ulcer disease (H. pylori) in combination with other drugs. It finds occasional use in CAP and AOM. It is FDA-approved for sinusitis. It is only available as an oral formulation. THE TETRACYCLINES WERE RUINED PROBABLY BY OVERUSE, ALTHOUGH DOXYCYCLINE IS STILL HANDY TO HAVE AROUND • Tetracycline, doxycycline, minocycline (PO only) • Bacteriostatic • Particularly useful for Chlamydia, Mycoplasma. Resistance has limited their usefulness for Grampositive cocci (Staphylococcus, Streptococcus). • Toxicities are a serious issue – GI irritation (doxy → esophageal ulceration) – Phototoxicity – Brown discoloration of the teeth, retarded bone growth (avoid in patients <12) – Vestibular toxicity (minocycline) – Candidal superinfection • All tetracyclines are pregnancy category D • Avoid milk or dairy products, antacids, iron preparations (but doxycycline must be taken with food) NO ONE WANTS THIS WEIRD SIDE EFFECT • Black hairy tongue: Defective desquamation and reactive hypertrophy of the filiform papillae of the tongue (not a fungal infection, although candidal infection may be superimposed). Exact pathogenesis unclear. • Normal papillae: 1 mm in length; may reach >15 mm in this condition • Usually asymptomatic • Etiologic factors include poor oral hygiene, smoking, hyposalivation, broad spectrum antibiotics, head and neck radiation, illicit drug use, heavy coffee/tea drinking • Treatment options – increasing hydration and salivation – quitting smoking – brushing the tongue with a soft toothbrush – surgical excision as a last resort 23S rRNA STAPHYLOCOCCUS AUREUS CAN DEAL WITH ANYTHING WE THROW AGAINST IT EVENT YEAR COMMENT Penicillinase-producing S. aureus appears in an Oxfordshire constable 1942 Penicillin introduced into clinical practice in 1942 Emergence of MRSA (UK) 1961 Methicillin approved in 1961 Emergence of VISA (GISA) 1996 Vancomycin approved in 1958 4 deaths of children in rural ND and MN; no contact with the healthcare system 1999 The beginning of the CA-MRSA era Emergence of VRSA 2002 Reported 11 times so far TMP-SMX (BACTRIM): STILL GOOD FOR SKIN INFECTIONS, UTI, AND PCP • • • • • TMP=trimethoprim, SMX=sulfamethoxazole Potent combination working sequentially Inexpensive PO (SS and DS), also IV (inconvenient) Still useful for UTI and Pneumocystis pneumonia (PCP) in AIDS; not as useful anymore for otitis media (because of resistance) • Considered by many to be the drug of choice for skin infections caused by CA-MRSA • Toxicities – GI – dermatologic (including Stevens-Johnson Syndrome): 3-5% of patients – blood dyscrasias – hemolytic anemia in G6PD-deficient patients “SULFA” OR “SULFONAMIDE” ALLERGY MEANS WHAT, EXACTLY? THERE ARE A LOT OF NONANTIBIOTIC SULFONAMIDES, LIKE THESE. acetazolamide (Diamox) chlorpropamide (Diabinese) chlorthalidone (Hygroton) dapsone diazoxide (Hyperstat) furosemide (Lasix) glipizide (Glucotrol) glyburide (Micronase, Diabeta) hydrochlorothiazide metolazone (Zaroxolyn) probenecid tolazamide (Tolinase) tolbutamide (Orinase) torsemide (Demadex) QUALITY DATA SUGGEST IT IS SAFE TO GIVE NONANTIBIOTIC SULFONAMIDES TO PATIENTS WITH ALLERGIES TO SULFONAMIDE ANTIBIOTICS • Retrospective cohort study using the UK’s General Practice Research Database (over 8 million patients), established in 1987 (study period 1987-1999) • Of 969 patients who reacted to a sulfonamide antibiotic and were subsequently administered a sulfonamide nonantibiotic, 96 (9.9%) had an allergic reaction (odds ratio=2.8) • Of 5115 patients who reacted to a sulfonamide antibiotic and were subsequently administered a penicillin, 717 (14%) had an allergic reaction (odds ratio 3.9) • Among those with an allergic reaction to a sulfonamide antibiotic, the odds ratio for an allergic reaction to a subsequent sulfonamide antibiotic, compared to a subsequent penicillin, was 0.7 • An allergic reaction to a sulfonamide nonantibiotic occurred in 9.1% of patients with prior evidence of sulfonamide hypersensitivity, compared to 14.6% of patients with prior evidence of penicillin hypersensitivity Strom et al. NEJM 2003; 349: 1628-1635 CLINDAMYCIN HAS THE PERFECT SPECTRUM FOR MANY SKIN INFECTIONS • Good drug for anaerobic organisms; covers Grampositive aerobes also, plus a few protozoa • Bacteriostatic • Distributes widely throughout the body (except for the CSF); penetrates abscess cavities well • Uses: mixed aerobic-anaerobic infections, skin infections. Very handy drug. • Available PO and IV • Considered safe in pregnancy • Notorious toxicity: pseudomembranous colitis (PMC) caused by Clostridium difficile LINEZOLID (ZYVOX): A GOOD MRSA DRUG BUT RIDICULOUSLY EXPENSIVE • The first oxazolidinone antibiotic approved by the FDA • Useful for resistant Gram-positive infections • Recent data suggest superior clinical cure rates and survival vs vancomycin for MRSA nosocomial pneumonia, although vancomycin dosing may not have been optimal (Chest 2003;124:1789) • Synthetic drug with a unique mechanism of action • Larger dose in patients <12 years of age (10 mg/kg q8h) • Similar toxicities in adults and children (possibly less thrombocytopenia) • Available as injectable, tablets, and oral suspension • Expensive! • Becoming more and more useful as the prevalence of MRSA in the community increases THESE ARE THE FLUOROQUINOLONES. THERE ARE FEWER ON THE MARKET THAN HAVE BEEN REMOVED FROM THE MARKET! FIRST1 All obsolete 1nalidixic SECOND2 THIRD3 Ciprofloxacin Moxifloxacin FOURTH4 None Levofloxacin Gemifloxacin acid, cinoxacin, oxolinic acid 2obsolete: norfloxacin, enoxacin, lomefloxacin, ofloxacin 3gatifloxacin (Tequin) withdrawn from the market in 2006 4trovafloxacin hepatotoxicity (Trovan) withdrawn from the market because of BAD NEWS: MMWR 2007; 56(14): 325-360 (April 13, 2007) http://www.cdc.gov/mmwr FQs ARE GREAT. WE NEED TO GET THEIR USE UNDER CONTROL BEFORE THEY STOP WORKING FOREVER. 1. These are HEAVILY used drugs (usually PO, sometimes IV). There is great fear that overuse will lead to the demise of the entire class. Some evidence for this already exists. 2. FQs are popular because they are bactericidal against many important pathogens, and they are very well tolerated. 3. Levofloxacin is the workhorse. It is the drug of choice in a growing number of UTI patients. It is commonly used for communityacquired pneumonia and sinusitis. It has other uses as well, such as traveler’s diarrhea and STDs. 4. Ciprofloxacin is similar to levofloxacin except that it is less potent for Gram-positives, and its half-life is shorter. Moxifloxacin is theoretically the best FQ for Gram-positive organisms. 5. The most common side effect is GI. Photosensitivity can be a problem. FQs rarely have caused tendon rupture. They are probably not toxic to developing cartilage in humans. 6. Only ciprofloxacin precipitates metabolic drug interactions. The absorption of all FQs is affected by metal ions, however (e.g. aluminum, magnesium). NITROFURANTOIN (MACROBID,MACRODANTIN) CAN BE QUITE USEFUL NOW AND THEN • Only use: UTI (cystitis) due to susceptible strains of E. coli, Enterococcus, S. aureus (plus a few others) • Lower cure rates (85%) than firstline agents (90-95%) • Won’t work for pyelonephritis, won’t work in renal insufficiency (CrCl <50) • Treatment dose: Macrodantin 100 mg po QID, Macrobid 100 mg po BID • Prophylaxis dose: 50-100 mg po qhs • Duration of therapy: 5-7 days, not 3 days • Good choice in pregnancy (category B) • Side effects: – Significant GI toxicity – Peripheral neuropathy – Liver, lung toxicity with longterm use – Hemolytic anemia in G6PD-deficient patients RIFAMPIN‘S ABILITY TO INTERACT WITH OTHER DRUGS SHOULD ALWAYS GET YOUR ATTENTION • Rifampin inhibits bacterial DNA-dependent RNA polymerase • 3 major uses – first line drug for tuberculosis – combination therapy for Staphylococcus – meningitis prophylaxis (Neisseria meningitidis) • NEVER used alone (except for prophylaxis) because resistance will emerge quickly • Typical dose: 600-900 mg po qd (divided?) • Available PO and IV • Significant adverse effects – widespread discoloration of body fluids and tissues – nausea – flu-like symptoms – abnormalities in liver function tests • EXTREMELY potent inducer of liver metabolism METRONIDAZOLE IS A FREAK: AN ANTIPROTOZOAL DRUG THAT ALSO KILLS ANAEROBIC BACTERIA • Excellent for anaerobes and protozoa; no activity against aerobic bacteria • Bactericidal • Excellent tissue penetration; penetrates abscesses well; half-life 8 hours • Uses: to provide antianaerobic activity in a combination drug regimen; trichomoniasis; giardiasis; bacterial vaginosis (Gardnerella vaginalis); treatment of C. difficile colitis • Available PO and IV • May inhibit drug metabolism • Toxicities: GI discomfort, metallic taste, peripheral neuropathy, disulfiram-like effect, skin eruptions • Considered safe in all trimesters