Sulfonamides, Trimethoprim, Macrodantion, and Methenamine PDF

SULFONAMIDES, TRIMETHOPRIM, MACRODANTIN, and METHENAMINE Jamie Allman, Pharm.D., BCPS Simplified Microbiology Gram Positive (3) Gram Negative (3 CATEGORIES) Weak/ Piddly FENCE BUGS SPACE Atypicals (3) Anaerobes (3) Terminology Broad/Narrow Spectrum Syner...

SULFONAMIDES, TRIMETHOPRIM, MACRODANTIN, and METHENAMINE Jamie Allman, Pharm.D., BCPS Simplified Microbiology Gram Positive (3) Gram Negative (3 CATEGORIES) Weak/ Piddly FENCE BUGS SPACE Atypicals (3) Anaerobes (3) Terminology Broad/Narrow Spectrum Synergy Time Dependent Kill/Concentration Dependent Kill Post Antibiotic Effect Bacteriostatic/Bacteriocidal Mechanisms of Action (Cell wall inhib, Protein Synthesis (50 S or 30S), DNA gyrase, Folic acid metabolism, Cell Membrane) Mechanisms of Resistance {Decreased Permeability into cell, Inactivating enzymes (b-lactamases, AG modifying enzymes), Altered target sites (PBP, DNA gyrase), Active Efflux} SPACE Bug Coverage Which ABX cover SPACE bugs? Pick one of the Cell Wall Inhibitors PCN, Cephalosporin, Carbapenem Anaphylaxis PCN allergy = Aztreonam Combine with one of the two below for different MOA DNA gyrase = FQN (Cipro, Levaquin) 30 S = Aminoglycosides (Gent, Tobra, Amikacin) Classes Covered PCN class Pen V and Pen G Antistaphlococcal (Methacillin, Naf, Ox, Clox, Diclox) AminoPCN (Amp, Amox) CarobxyPCN (Ticarcillin) UreidoPCN (Piperacillin) Beta-lactamase Inhibitors (Clauvulanate, Sulbactam, Tazobactam) Unasyn, Augmentin, Timentin, Zosyn Classes Covered Cephalosporins 1st Generation 2nd Generation (True and Cephamycins) 3rd Generation (True and Antipseuomonal) 4th Generation Aminoglycosides Vancomycin Linezolid/ Quinupristin/Dalfopristin Mupirocin Tigecycline, Daptomycin, Telavancin, Colisitin, Fosfomycin Maculopapular Rash  Sulfonamides Structure and Chemistry All sulfonamides are similar in structure to para-aminobenzoic acid (PABA). PABA is a precursor required by bacteria for folic acid synthesis. H2N COOH H2N SO2NHR PABA SULFONAMIDE NUCLEUS Sulfonamides Mechanism of Action Bacteria require tetrahydrofolic acid (derivative of folic acid) Cofactor in the synthesis of thymidine, purines, and ultimately DNA. Bacterial cell walls are impermeable to folic acid Bacteria must synthesize it from PABA Sulfonamides compete with PABA for the enzyme dihydropteroate synthetase (See Second Figure in Handout) Sulfonamides may have an increased affinity for the enzyme than the natural substrate, PABA. Host cells are not affected due to the fact that they require preformed folic acid; they cannot synthesize folic acid. Bacteriostatic Folic Acid Pathway Dihydropteroate Dihydrofolate Synthetase Reductase PABA Folic Acid Tetrahydrofolic Acid AA Sulfonamides Trimethoprim Sulfonamides Pharmacokinetics Excretion Excreted via glomerular filtration Extent of glomerular filtration varies with each agent Commonly used for UTI’s Sulfonamides Adverse Reactions Anaphylaxis Nephrotoxicity Crystalluria with less soluble compounds (Sulfadiazine and Cutaneous Reactions Sulfathiazole) Morbilliform Rash Administer with fluids- check hydration status of patients Steven Johnson Syndrome prior to use Erythema Multiforme Kernicterus Photosensitivity Rash When given in last months of pregnancy Compete for bilirubin binding Hematologic Rxns sites on plasma albumin Results in increased fetal Hypersensitivity Rxns blood levels of unconjugated bilirubin Drug Fever, Rash Sulfonamides Spectrum of Activity GRAM POSITIVE GRAM NEGATIVE OTHER Staphlococcus Haemophilus Chlamydia trachomatis (MRSA) influenza Streptococcus Salmonella Shigella Providencia Bacillus anthracis Proteus Toxoplasma gondii mirabilis/vulgaris (protozoa) E. coli Plasmodium falciparum (protozoa-malaria) K. pneumonia Nocardia Citrobacter Enterobacter *Resistance varies among organisms listed. Sulfonamides Mechanism of Resistance Overproduction of PABA (Neisseria, Staph) Structural change in dihydropteroate synthetase resulting in decreased affinity of dihydropteroate synthetase for the sulfonamide. (E. coli) Decreased permeability of the bacteria to the drug. Sulfonamides Indications Acute Uncomplicated UTI Pneumocystis carinii (tx and prophylaxis) Nocardosis Toxoplasmosis Malaria (Chloroquine-resistant) Rheumatic fever prophylaxis (PCN allergic)  Trimethoprim Mechanism of Action Trimethoprim Non-sulfonamide pyrimidine analogue Inhibits dihydrofolate reductase which prevents the formation of tetrahydrofolic acid ~ 50,000 times more active against bacterial dihydrofolate reductase than the human enzyme Bacteriostatic or bactericidal depending on the growth conditions Folic Acid Pathway Dihydropteroate Dihydrofolate Synthetase Reductase PABA Folic Acid Tetrahydrofolic Acid AA Sulfonamides Trimethoprim Trimethoprim Pharmacokinetics Excretion Excreted 80% unchanged via glomerular filtration and tubular secretion. Trimethoprim Adverse Effects Cutaneous Reactions Hematologic Reactions Pruritis Rash Caution in patients with Gastrointestinal possible folate Reactions deficiency! Alcoholics N/V/D Pregnant women Elevated serum transaminases, bilirubin Debilitated ptns Malabsorptive syndromes Trimethoprim Spectrum of Activity Gram Positive Gram Negative Other Staph spp. Salmonella Pneumocystis carinii*** Strep spp. Shigella Providencia spp. Haemophilus influenza Proteus mirabilis/vulgaris Bacillus E.coli anthracis Klebsiella pneumonia Citrobacter spp. Enterobacter spp. ***To be used in conjunction with dapsone (intolerant to sulfa/tmp.) Trimethoprim Indications Acute Uncomplicated UTI Recurrent UTI prophylaxis Traveler’s diarrhea (Treatment and Prophylaxis) TRIMETHOPRIM/SULFAMETHOXAZOLE (Bactrim) Mechanism of Action Combined mechanisms of both agents (Synergistic). Combination is usually bactericidal Goal is to reduce the rate of emergence of resistance Pharmacokinetics, Adverse Effects, and Resistance are the same as with each component  SMZ/TMP (Bactrim) Spectrum of Activity Gram Positive Gram Negative Other Staph. spp. Haemophilus influ Nocardia asteroides Streptococcus spp. Neisseria gonorrhoeae Chlamydia trachomatis Bacillus anthracis Salmonella Toxoplasma gondii (protozoa) Shigella Plasmodium falciparum (protozoa- malaria) Providencia spp. Pneumocystis carinii (fungus, formerly thought to be protozoa) Protues mirabilis/vulgaris E.coli Klebsiella pneumo Citrobacter spp. Enterobacter spp. SMZ/TMP (Bactrim) Indications UTI GI Infections Uncomplicated UTI Salmonella/Shigella Prophylaxis of UTI Traveler’s Diarrhea Acute and Chronic Prostatitis Cholera RTI STDs COPD exacerbations Uncomplicated gonococcal Pneumonia infections Acute Otitis Media Chancroid Acute Sinusitis Bacterial Vaginosis PCP (Px & Tx) Other Infections Stenotrophomonas maltophilia (DOC) SMZ/TMP (Bactrim) Drug Interactions Warfarin Highly likely to potentiate anticoagulant effects Methotrexate Sulfonamides can displace MTX from protein binding sites Increase free methotrexate Nitrofurantoin Mechanism of Action Unclear MOA Possibly interferes with the early stages of bacterial carbohydrate metabolism by inhibiting acetyl coenzyme A Possibly due to production of reactive 5-nitro anion, free radicals Nitrofurantoin Pharmacokinetics Distribution Serum/tissue concentrations are insignificant Urine concentrations are very high Excretion Rate of excretion is linear, related to CrCl Patients with impaired GFR Decrease in efficacy Increase in systemic toxicity Do not use if CrCl 50mcg/ml Indications/Uses Bacterial meningitis Haemophilus influenza, Strep pneumo, Neisseria meningitidis Penicillin/Cephalosporin allergic Oral alternative when IV cannot be used Rickettsial infections Quinolones & Tetracyclines Jamie Allman, Pharm.D., BCPS Birth Control/ABX Question regarding co-administering Rifampin, Tetracyclines, Ampicillin Be very careful with counseling points and recommend an alternative source of birth control. Literature is limited– Medline search produces few results Utilizing Local Antibiograms for Resistance New Breakpoints and the Clinical Significance New Clinical and Laboratory Standards Institute (CLSI) Breakpoints as of June 2018 Meeting (prev. Jan 2018 M100) Specifically New Fluoroquinolone Breakpoints Quinolones Mechanism of Action Target: DNA gyrase (topoisomerase II) DNA gyrase is essential for Supercoiling of cellular DNA by a nicking, pass through, and resealing process. Quinolones inhibit bacterial DNA gyrase and topoisomerase IV Bactericidal Postantibiotic Effect After exposure to inhibitory concentrations of quinolones, continued killing occurs. The postantibiotic effect averages ~ 1-2 hrs. Tends to increase with increasing concentrations and length of exposure. New Fluoroquinolone Risks and Warnings Identified Dr. Angie Liappis, M.D. Infectious Disease Dr. Angie Liappis, M.D. Infectious Disease New Fluoroquinolone Warning from BMJ Study in Sweden https://www.bmj.com/content/bmj/360/bmj.k678.full.pdf Fluoroquinolones have non-antimicrobial properties that may compromise the integrity of the vascular wall. In a nationwide cohort study from Sweden, Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection events within 60 days from the start of treatment Compared FQN use with Amoxicillin use (1.2 versus 0.7 cases per 1000 person years; absolute difference 82 cases per 1 million treatment episodes), Consistent with findings in prior studies. “We believe that this new study will not lead to revision of a 2017 US Food and Drug Administration safety communication stating that review of available information did not support reports that fluoroquinolones cause aortic aneurysm or dissection. “ If an association exists, the absolute risk is small and may be limited to individuals with additional predisposing risk factors New FDA Drug Safety Announcement – July 10, 2018 https://www.fda.gov/Drugs/DrugSafety/ucm611032.htm Diabetic Coma (More education to watch for low sugars) Blood sugar disturbances: both significant high and lows Neuropsychiatric Warnings Significant changes including: mood/behavior, agitation, attention, disorientation, nervousness, memory impairment  New FDA Drug Safety Announcement – Dec 20, 2018 https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about- increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics Avoid in ptns with Aortic Aneurysm or at risk for AA Peripheral atherosclerotic vasc disease, HTN, elderly Prescribe these only when “no other options” New FDA Drug Safety Announcement – Dec 20, 2018 https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns- about-increased-risk-ruptures-or-tears-aorta-blood-vessel- fluoroquinolone-antibiotics FQN – restricted use No longer recommended as first line treatment options for certain disease states Uncomplicated UTIs Acute Exacerbation of COPD Sinusitis May justify their use based on: Allergies Recent Antibiotics Cultures (new or recent)  Quinolones Pharmacokinetics Generic Name Half-life (hour) Bioavailability Renal Excretion (%) % Ciprofloxacin 3.2 70 29 Ofloxacin 5.0 >95 73* Levofloxacin 6-7 Close to 100% 61-86* Moxifloxacin 9-16 ~90% 15-21 Gemifloxacin 7 ~70% 36 Quinolones Adverse Effects Hypersensitivity Reactions Nephrotoxicity (Rare) Photosensitivity Interstitial Nephritis Hematologic Reactions CNS*** Neutropenia Headache Eosinophilia Dizziness Mental Status Changes Cardiac Musculoskeletal QT prolongation Arthropathy Gastrointestinal Caution in < 18 years Diarrhea, N/V Tendon Rupture New FDA warning 2008 Co-admin with Steroids, Age >60 Quinolones Gatifloxacin (no longer produced) FDA pulled from market in 2006 secondary to severe hypoglycemia Kidney and Liver dysfunction Ofloxacin Same generation as Ciprofloxacin Not prescribed as often but literature for disease states like Spontaneous Bacterial Peritonitis (SBP) often mention Ofloxacin 79 Quinolones Drug Interactions Theophylline Ciprofloxacin can double theophylline levels. Levofloxacin –little to no effect Antacids/ Iron/ Sucralfate/ Multivitamins Do not give within 2-4 hours of quinolone dose. Warfarin Increased anticoagulant effect possibly due to metabolism or protein binding changes. Levofloxacin - possibly no effect - still monitor Quinolones Spectrum of Activity- Overview Gram positive organisms Older agents– Cipro and Ofloxacin not good gm + coverage Newer agents appear to have better Staph/Strep coverage Levofloxacin, Moxifloxacin, Gemifloxacin Gram negative organisms Coverage varies among different agents (SACE vs SPACE) Cipro and Levofloxacin (SPACE) Moxifloxacin (SACE) Quinolones Spectrum of Activity- Overview Anaerobic coverage One agent onlyà Moxifloxacin Moxifloxacin has indication for complicated abdominal infections Atypicals Sensitivities Vary based on the agent Levofloxacin, Moxifloxacin, Cipro cover CML Watch Cipro resistance with Chlamydia (non-response) Quinolones Ciprofloxacin Generally considered very good coverage Wide range of FDA approved indications. Gram positive (generally considered poor)- Consider newer FQN for better coverage -or- Adding another agent with gm + coverage Gram negative Ciprofloxacin generally considered most potent of the quinolones against gram negative organisms Specifically most potent against Pseudomonas Excellent bioavailability – Use oral form if possible Functioning GI tract required (Do not use if Ileus or SBO) Quinolones Levofloxacin/Gemifloxacin/Moxifloxacin Gram positive coverage All three are good for Staph and Strep Excellent PCN Resistant Strep Pneumo (Common for CAP infections with previous ABX use, elderly or kids in day care) Gram negative coverage Levofloxacin (SPACE) potency is less than ciprofloxacin No Pseudomonas for Gemifloxacin or Moxifloxacin (SACE) All have Atypical (CML) Most common use for respiratory pathogens Mycoplasma – “Walking pneumonia” Excellent bioavailability – use oral agent ASAP Quinolones Levofloxacin/Gemifloxacin/Moxifloxacin Levofloxacin is a HYBRID Ciprofloxacin for Pseudomonas coverage Gemifloxacin & Moxifloxacin for Strep Pneumonia coverage (ever PCN-R version) Moxifloxacin Unique Characteristics Anaerobes (Complicated Intra-abdominal infections) Moxifloxacin dose NOT cover UTI’s Poor urinary concentrations, no indication Delafloxacin (Baxdela) Newest Fluoroquinolone: FDA approved June 2017 Approved for acute bacterial skin and skin structure infections Available IV 300mg BID or PO 450mg BID CrCl= 15-29ml/min 200mg IV BID or 450mg PO BID (Not recommend ESRD) Coverage: Staph/Strep/MRSA E.coli Enterobacter, Klebsiella, Pseudomonas Approval studies compared itself against Vanc/Aztreonam Pearls Differentiating from other FQNs Delafloxacin has not demonstrated QT prolongation Delafloxain has not demonstrated phototoxicity to date No markers of ADRs to liver, kidneys or glucose control *Retained warning for: Tendon ruptures/Neuropathy/CNS *All FQNs may exacerbate muscle weakness with myasthenia gravis Quinolones Mechanisms of Resistance Altered target enzyme (altered DNA gyrase) Reduction of Quinolone concentrations intracellularly Altered drug permeability across cell membrane due to changes in porin channels. Efflux of drug from bacterial cell Quinolones Place in Therapy Skin/Skin Structure Infections LRIs (good penetration) (Not Cipro/Ofloxacin if Gm + CAP and HAP (Pseudo Risk) cultured from tissue; good to Gonorrhea add ______ for gm + Chlamydia coverage) UTIs Bone and Joint Infections Pelvic Inflammatory Disease (Not Cipro/Oflox if coverage Prostatitis (28 days) for Gm +) Gastroenteritis/ Infectious Diarrhea Intra-abdominal Infections (Moxifloxacin or Cipro/Metronidazole or Levo/Metronidazole) TETRACYCLINES Jamie Allman, Pharm.D., BCPS Clinical Coordinator Residency Program Director Veterans Affairs Medical Center Huntington, West Virginia TETRACYCLINES Members Doxycycline (Vibramycin) Minocycline (Minocin, Vectrin) Demeclocycline (Declomycin) Oxytetracycline (Terramycin) Chlortetracycline (Aureomycin) Tetracycline (Achromycin, Panamycin) Tetracyclines Mechanism of Action Reversibly binds to 30S ribosomal subunit Decreases protein synthesis Bacteriostatic Absorption decreased by food Variable from 20-50% for various TCNs Characteristics of Tetracyclines Bioavailability varies dependent on products Doxy & Minocycline (~90-100%) Tetracycline, Demeclocycline, Oxytetracycline (~58-75%) Characteristics of Tetracyclines Primary Elimination Renally Tetracycline Oxytetracycline Demeclocycline Hepatobiliary Doxycycline Minocycline Tetracyclines Adverse Reactions Photosensitivity Discoloration of Developing Teeth Bones and teeth developing during pregnancy and in children thru ~8 years old Reversible diabetes insipidus associated with Demeclocycline Use this side effect to treat SIADH Tetracyclines Adverse Reactions Vestibular side effects associated with Minocycline Sxs: Dizziness, Ataxia, Vertigo Fanconi-like Syndrome Characterized by N/V, lethargy, polydipsia, polyuria, proteinuria, acidosis, hypokalemia Associated with use of outdated citric acid formulation of Tetracycline Tetracyclines Drug Interactions Decreased absorption of TCN agents when co-administer via chelation Di- and Trivalent cations (Ca, Mag, Zinc, Alum, Iron) Medications such as antacids Dairy products Potential antagonism effect since these agetns are static and many cidal agents require active growth Enhances anticoagulation of Warfarin -Increased PT/INR Tetracyclines Spectrum of Activity Broad Spectrum Coverage Gram Positive (Staph, Strep) Gram Negative (H.flu, Neisseria) Atypicals Rickettsia Tetracyclines Clinical Uses Rickettsia Infections (parasites) Rocky Mountain spotted fever Mycoplasma pneumonia Chlamydia infections Urogenital 7 days of Doxy Acne H. pylori in combination w/ other agents Bismuth, Metro, PPI QID dosing– less patient compliance  Tetracycines Clinical Uses Brucellosis (Tetracycline + Gentamicin) Unpasteurized cheeses, milk (not common in US) Humans become infected by coming in contact with animals or animal products that are contaminated with Brucella. In humans brucellosis can cause a range of symptoms that are similar to the flu and may include fever, sweats, headaches, back pains, and physical weakness. Severe infections of the central nervous systems or lining of the heart may occur. Brucellosis can also cause long-lasting or chronic symptoms that include recurrent fevers, joint pain, and fatigue. (CDC definition) Tetracycines Clinical Uses Vibrio cholera/vulnificus V. vibrio is an acute diarrheal disease endemic in India and Southeast Asia whose causative agent is Vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated (CDC definition) V. vulnificus can cause disease in those who eat contaminated seafood or have an open wound that is exposed to seawater  Tetracycines Clinical Uses Borrelia burgdorferi Better known as “Lyme disease” Lyme disease is a bacterial disease caused by Borrelia burgdorferi. Within 1 to 2 weeks of being infected, people may have a "bull's-eye" rash with fever, headache, and muscle or joint pain. SXS: Some people have Lyme disease and do not have any early symptoms while others have a fever and other "flu-like" symptoms without a rash. After several days or weeks, the bacteria may spread throughout the body of an infected person. These people can get symptoms such as rashes in other parts of the body, pain that seems to move from joint to joint, and signs of inflammation of the heart or nerves. If the disease is not treated, a few patients can get additional symptoms, such as swelling and pain in major joints or mental changes, months after getting infected. (CDC definition) Tetracycines AtypicalClinical Uses SIADH Demeclocycline only Tetracyclines Take Home Points Do not use in Pregnancy/kids