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Trimethoprim (TMP) and Sulfamethoxazole (SMX)
TMP and SMX act synergistically to kill many gram + and gram - bacteria. They both inhibit TH4 production, but at different steps. They only work on organisms that utilize PABA. (People don't need to use PABA to form dihydrofolate, he we dietary folate)
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How does resistance develop to resistance of the sulfa drugs?
- Reduced cellular uptake
- Alteration of dihydropteroate synthase (sulfonamides target)
- Overproduction of PABA (sulfonamide is a competative inhibitor)
- Development of an alternate pathway for folate synthesis.
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What is the oral sulfonamide of choice?
Sulfisoxazole (very soluble, causes little crystalluria, T1/2 is only 5 or 6 hours) Used for uncomplicated UTIs, does not cross BBB)
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Sulfamethoxazole
Longer half life than sulfisoxazole, but more likely to cause crystalluria
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What sulfonamide achieves the highest concentration in the CSF?
Sulfadiazine (limited use due to crystalluria, better if taken with bicarbonate)
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What sulfonamide is used of IBD because it is poorly absorbed from the GI?
Sulfasalazine (highest concentration in the colon)
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What is the sulfonamide of choice to prevent infection (prophylaxis) in 2nd and 3rd degree burns?
Silver Sulfadiazine (used topically)
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What sulfonamide is used for ophthalmic infections in eye drops?
Sulfacetamide sodium
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Absorption, distribution, metabolism and exrection of Sulfonamides
- Except for sulfasalazine, they are well and rapidly absorbed from the GI tract (70-95%) with peak blood levels after 2-3 hr.
- Most readily enter all body compartments (pleural, peritoneal, synovial, ocular, cerebrospinal, etc.). They cross the placenta and fetal concentrations may be antibacterial and/or toxic.
- Binding to serum proteins (mostly albumin) is highly variable (35-50% for sulfadiazine to 80-99% for sulfisoxazole).
- They are variably metabolized in the liver to acetylated derivatives that are inactive and less soluble which promotes crystalluria.
- Since both parent compounds and acetylated metabolites are primarily excreted by glomerular filtration, renal function is required. Variation in urine flow rate might account for differences in t1⁄2.
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Toxicity of Sulfonamides (overall--5%)
- Urinary Tract Disturbances (Most common with long-acting sulfa drugs such as sulfadoxine which is used for prophylaxis of malaria in conjunction with pyrimethamine)
- Renal damage is caused by the deposition of crystalline aggregates of sulfonamide and acetylated sulfonamide. (Remember fluids and sodium bicarbonate!)
- Hypersensitivity Reactions (drug fever, skin rashes, photosenitivity, Stevens Johnson syndrome--very serious rash)
- Hematopoietic Disorders (Blood dyscrasias are extremely serious but rare; drug must be withdrawn. Acute hemolytic and aplastic anemia, eosinophilia, thrombocytopenia(most likely), and agranulocytosis (0.1%) have been reported. Ideally, white blood cell count and hemoglobin should be monitored twice a week. Sulfa drugs are contraindicated in patients with porphyria.)
- Hepatotoxicity (0.1%) – 3-5 days after initiation of Rx
- Kernicterus: bilirubin is displaced from its binding sites on albumin by sulfa drugs increasing the free bilirubin concentration in blood; this is important in premies and neonates in which the blood-brain barrier is generally not well developed. As a result, bilirubin can potentially pass into the CNS, accumulate in select neurons, and cause permanent damage. Sulfas shouldn’t be given to near-term women; also, sulfas are secreted in milk.
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What is the target of tremethoprim?
dihydrofolate reductase -- SMX potentiates the action of the TMP because it reduces the concentration of DHFA available to compete with TMP for its binding site on the enzyme. The net result is that this combination is bactericidal rather than bacteriostatic. TMP is a highly selective inhibitor of bacterial but not mammalian dihydrofolate reductase; 100,000 times as much TMP would be needed to inhibit our enzyme.
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Pyrimethamine
Pyrimethamine (Daraprim) is similar to TMP in its chemical structure and in its pharmacological action: it is also a highly selective inhibitor of dihydrofolate reductase that is sometimes used with sulfonamides for Rx of specific parasitic infections (protazoa).
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Resistance of TMX
- Mutation or overproduction of dihydrofolate reductase.
- Reduced bacterial permeability to TMP.
- Conversion of the bacterium to thymidine dependence.
- The frequency of bacterial resistance to TMP-SMX is lower than with either agent alone because resistance would have to develop to both agents at the same time, likely plasmid mediated.
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Gram-negative bacilli (Yersinia enterocolitica, Aeromonas, Burkholderia cepacia, Calymmatobacterium granulomatis, Haemophilus influenzae (upper resp. tract & bronchitis), Stenotrophomonas maltophilia (formerly Pseudomonas maltophilia))
Actinomycetes (Nocardia, Tropheryma whippelii (agent of Whipple’s disease))
Three Parasites (especially in AIDS/immunocompromised patients): Cyclospora, Isospora belli and Toxoplasma gondii. (In toxoplasmosis, a combination that works identically [pyrimethamine + sulfadiazine + leucovorin] is used.)
One Fungus: (especially in AIDS/immunocompromised patients) Pneumocystis jiroveci pneumonia (PCP) (formerly called Pneumocystis carinii). [NOTE: This organism is often listed as a parasite but genetically is much more like a fungus.]
Organisms sensitive to TMP-SMX (Trimethoprim - Sulfamethoxazole)
TMP-SMX is also a backup drug in Rx of infections caused by 24 other bacteria including some gram (+) & gram (-) cocci, a gram (+) bacillus, many enteric & non-enteric gram (-) bacilli, and one mycobacterium.
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What are major therapeutic uses of TMP-SMX
- Oral Rx of UTIs
- Methicillin-resistant Staph aureus (MRSA) infections
- Pneumonia jiroveci (PCP) --Although this is an opportunistic organism, this pneumonia occurs frequently in untreated AIDS patients. TMP-SMX is the drug of choice in AIDS patients but emergence of resistance is a problem. Used for both Tx and prophylaxis.
- Bacterial respiratory infections -- Acute otitis media (children) or maxillary sinusitis (adults) due tosusceptible strains of H. influenzae or Streptococcus pneumonia. Acute chronic bronchitis.
- GI infections -- Shigellosis (Bactrim is an alternative to fluoroquinolones.) Travelers' diarrhea esp. in children or adults; a fluoroquinolone is analternative in adults. Salmonella typhi. Enterohemorrhagic E. coli O157:H7 – treatment might increase therisk of hemolytic-uremic syndrome
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a) Absorption, distribution, metabolism and excretion of Trimethoprim (TMP)
b) Toxicity of TMP alone
- a) Trimethoprim (Proloprim) is well absorbed orally with peak concentration reached in 2 hr and a t1⁄2 = 11 hr; an IV preparation is available for serious infections.
- TMP is very lipid soluble and enters all body compartments. As with most sulfonamides, TMP crosses the placenta and it achieves high urinary conc.
b) n/v, diarrhea
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Toxiciy of TMP-SMX
- A higher frequency of hypersensitivity reactions occurs, especially fever,rashes (incl. Stevens-Johnson), leukopenia, and diarrhea. (Especially in AIDS patients. It causes three times as frequent skin problems as sulfimethoxazoleor sulfisoxazole alone; these can be severe in older patients. Pronounced glossitis and/or stomatitis can occur)
- Possible CNS effects include headache, depression, & hallucinations.
- Crystalluria is rare in normal patient treated with this drug combinationbut the use of TMP-SMX is contraindicated in patients with renal diseaseas it can cause permanent kidney damage.
- In folate-deficient individuals, TMP-SMX occasionally produces side effects of anti-folate drugs (megaloblastic anemia, leukopenia & thrombocytopenia) which can be prevented by folinic acid without loss of antimicrobial activity
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What is the target of the flouroquinolones?
Topoisomerases (bactericidal)
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Spectrum of action of Flouroquinolones
- One specific gram-negative organism: Pseudomonas aeruginosa - Cipro has the greatest activity (only alt is levofloxacin) but resistance is increasing.
- Gram-positive organisms: 2nd Gen FQs or Cipro are effective against many but resistance is increasing in general in Staph. aureus and is frequent in its methicillin-resistant strains.
- One specific gram-positive organism: Streptococcus pneumonia - 2nd gen FQs are backups except in strains exhibiting a high level of resistance to penicillin. Nisseria is now resistant
- NOT EFFECTIVE AGAINST SPIROCHETES OR ANAEROBES
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Advantages of Fouroquinolones
- They have a very broad antimicrobial spectrum including gram- positive and gram-negative bacteria,
- They can usually be given orally even for serious infections,
- They are especially useful for some infections which had
- previously required parenteral antibiotics,
- They are useful for pathogens resistant to TMP-SMX
- They have a relatively low incidence of side effects.
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__________only achieves low serum levels and is therefore only available in the US for treatment of UTIs due to susceptible organisms (Enterobacteriaceae, Enterococcus). Since other FQs are generally preferred for UTIs, it is not clear when it should be used.
Name the Flouroquinolone
Norfloxacin [Noroxin]
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_________is racemic mix of active and inactive isomers; it is seeing decreased use because of the availability of levofloxacin [Levaquin], the more active optical isomer of ofloxacin, has at least twice the potency of ofloxacin.
Name the flouroquinolone
Ofloxacin [Floxin]
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_________is used primarily for UTIs and bronchitis because pneumococci and other streptococci are resistant.
Name the Flouroquinolone
Lomefloxacin [Maxaquin]
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_________ is most potent against P. aeruginosa and has good activity against many other organisms; it is the most commonly used FQ and, in some cases, is singled out as the FQ of choice against a specific pathogen.
Name the Flouroquinolone
Ciprofloxacin [Cipro]
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2nd Generation Fluorinated Agents generally have similar spectra and, with a few exceptions, can be treated as a group. They are more active against gram-positive cocci than Cipro and some have activity against anaerobes and atypical pathogens. They have less activity against Pseudomonas than cipro; levofloxacin is the best of the group in that regard. They still have nearly as good gram-negative activity as cipro. All of the 2nd gen FQs can be given orally once per day.
Name the 2nd generation Flouroquinolones.
Gemifloxacin, Levofloxacin, & Moxifloxacin
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What are the clinical uses of Quinolones?
- UTI's --Cipro or levofloxacin
- Prostatitis -- Cipro or levofloxacinSexually Transmitted Disease
- Gastrointestinal & Abdominal Infections: Traveler’s diarrhea caused by enterotoxigenic E. coli: Cipro or levofloxacin (However, azithromycin is the drug of choice in areas with a high prevalence of FQ-resistant Camplyobacter such as Thailand or India.) Shigellosis: Ciprofloxacin or levofloxacin are the drugs of choice with azithromycin as a backup. Enteric fever caused by S. typhi (typhoid fever): FQs are the drugs of choice with trimethoprim-sulfamethoxazole as a backup. The 2nd gen FQs are more active than Cipro against most strains of Strep. pneumoniae and Staph. aureus For prophylaxis after either contact with patients with meningococcal disease or exposure to Bacillus anthracis (Anthrax); ciprofloxacin is a drug of choice.
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Absorption, Distribution, Metabolism, and Excretion of flouroquinolones
- *Elimination of most FQs occurs primarily by renal excretion of unchanged drug. Therefore, most FQs accumulate in the plasma if creatinine clearance is <50 ml/min and dosage adjustment is needed.
- In contrast, moxifloxacin is primarily (52%) metabolized via glucuronide and sulfate conjugation with only 20% excreted unchanged in the urine; it might be preferred in patients with reduced renal function but has no value in treatment of UTIs and shouldn’t be used in pats with hepatic failure.
- Serum half-life of most FQs is 3-7 hr; however, that of moxifloxacin is 12 hr.
- FQs are widely distributed into most tissues but penetration into the
- cerebrospinal fluid may be insufficient for antimicrobial therapy.
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________ are generally well tolerated. Adverse reactions usually don’t require discontinuation of therapy.
Gastrointestinal effects (3-17%) – most common; n/v, abdominal pain but not diarrhea
*CNS agitation – Dizziness, headache, restlessness, depression, & insomnia in children (overall freq. = 1-10%); most occur more often in elderly patients. Seizures, delirium, and hallucinations rarely occur; such events occur primarily in patients also receiving theophylline or an NSAID (see below). The mechanism appears to involve blockade of GABA receptors in the CNS.
*Rashes, urticaria, pruritus, and photosensitivity reactions may occur. (Phototoxicity is most common with lomefloxacin; rashes are most common with gemifloxacin.)
*Prolongation of the QT interval has been observed with levofloxacin and moxifloxacin. ________ should be used with caution in patients receiving antiarrhythmics (amiodarone, quinidine, procainamide).
*________ are absolutely contraindicated in pregnancy, during nursing, and are not recommended in children (largely due to the possibility that it might damage cartilage). Recent studies suggest that the benefits might outweigh the risks in, for example, children with cystic fibrosis.
Flouroquinolones
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These are the drug interactions of what drug?
Antacids (calcium, magnesium), iron, multivitamins with minerals (esp. zinc & calcium), sucralfate (aluminum ions) and didanosine (aluminum, magnesium) can chelate ____ and decrease the oral bioavailability by up to 90%. As a result, _____ must be taken at staggered times by at least 2 hr with respect to agents containing di- or trivalent cations.
*Caution is called for in using ______ in patients with a prolonged QT interval. *Cipro (but not levofloxacin) inhibits metabolism of theophylline and increases plasma levels of theophylline which might result in serious CNS effects.
*NSAIDS and _______ augment one another to enhance displacement of gamma- aminobutyric acid (GABA) from its receptors causing serious CNS effects.
*Probenecid increases plasma ______ because tubular secretion is blocked.
Flouroquinolones
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Nitroimidazoles
- Metronidazole and Tinidazole (newer)
- Therapeutic Uses: Only Against Anaerobic Organisms
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_____________ is a nitroimidazole derivative that is a prodrug which must be activated by reduction of its nitro group. Some anaerobic and microaerophilic pathogens (e.g., T. vaginalis, E. histolytica, G. lamblia) and anaerobic bacteria have sufficiently negative redox potentials that they can donate electrons to –NO2 in MN (or TIN) (see circles above) forming a highly reactive nitro radical anion which damages DNA strands and kills the activating organisms. Electrons are donated to ______ by reduced ferredoxin which is created in susceptible organisms by pyruvate decarboxylation. Aerobic bacteria cannot activate ___________ because the presence of oxygen decreases activation of _________.Activated _________ can recycle by losing its activating electron and reverting to the parent compound; the presence of oxygen speeds up drug inactivation.
Metronidazole
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____________ is a newer drug that is similar to metronidazole in chemistry and mechanism of action. It is as effective as metronidazole in many/most cases, is less toxic, and will sometimes work for treatment of organisms such as T. vaginalis even if they are resistant to metronidazole. Notice that ______ can sometimes be used instead of MN in certain clinical situations (see Therapeutic Uses below). The half-life of _________ is longer than that of metronidazole (12-14 hr vs. 7.5 hr) with the result that dosing is easier. For mild to moderate amebiasis, once per day for 3 days works for tinidazole in comparison to 3 times per day for 10 days for metronidazole.
Tinidazole
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What are the therapeutic uses of the Nitroimidazoles?
- ONLY ANAEROBIC
- oral vancomycin is an alternate that might be better in serious cases) - gram-negative bacilli:
- - Bacteroides fragilis - Fusobacterium - Garderella vaginalis (bacterial vaginitis) - Helicobacter pylori (together with clarithromycin and a proton pump inhibitor)
- Treatment for protozoal parasites: (usually administered orally) - amebiasis (Entaemoba histolytica; MN or TIN) - balantidiasis - Dientamoeba fragilis
- - giardiasis (Giardia lamblia; MN or TIN; not FDA approved in US but can be effective) - trichomoniasis (Trichomonas vaginalis genital infections; MN or TIN)
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Pharmacokinetics of nitriomidazoles
- Doesn't cross placenta, does cross BBB
- Complete and prompt oral absorption
- Largely excreted by oxidation in liver.
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Adverse effects and drug interactions of Nitriomadizoles
- Side effects rarely necessitates discontinuation.
- GI disturbances can include nausea, anorexia, diarrhea, epigastric distress, abdominal cramping and metallic taste.
- *Neurotoxicity may cause dizziness,vertigo, numbness, sensory neuropathies (only slowly and/or incompletely reversible), or paresthesias and might require drug discontinuation. Use by patients with an active CNS disease should be undertaken cautiously because of the drug’s potential neurotoxity.
- *Toxic epidermal necrolysis (rare) only occurs with high drug doses and with mebendazole. Use of MN in patients in the first trimester of pregnancy is not advised because of MN’s carcinogenicity in rodents and mutagenicity in bacteria although data on teratogenicity in humans is mixed.
- *Causes a disulfiram (Antabuse)-like reaction typically resulting in abdominal distress vomiting, flushing, and headache if a patient consumes alcohol within 3 days of therapy!
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What are the 2 major goals of anti-tubercular treatment?
- Interrupt tuberculosis transmission by rendering Pt's noninfectious
- Prevent morbidity and death my curing Pt's with TB
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What are these drugs used for?
Isoniazid
Rifampin
Pyrazinamide
Ethambutol
They are the first-line essential antituberculosis agents
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What effect does rifampin have on body fluids?
How could this effect be used to monitor patient compliance with drug therapy?
Rifampin turns body fluids (urine, saliva, sputum, tears) a red-orange color. This makes it simple and inexpensive to check on patients’ compliance with therapy.
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What effect does rifampin have on hepatic microsomal enzymes?
- Rifampin is a potent inducer of the hepatic microsomal enzymes and thereby decreases the half-life of a number of drugs, including digoxin, warfarin, prednisone, cyclosporine, methadone,
- oral contraceptives, clarithromycin, the HIV protease inhibitors, the HIV nonnucleoside reverse transcriptase inhibitors, and quinidine.
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How might this affect antiretroviral therapy in patients also being treated for HIV infection?
- Rifampin would affect the half life of the HIV drugs listed above, so they would essentially be less effective. Their doses/dosing frequencies would need to be altered to maintain serum drug
- levels.
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What are the two most important adverse effects of isoniazid?
- Hepatotoxicity and
- peripheral neuropathy.
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How should patients be monitored and counseled about potential isoniazid hepatotoxicity?
Patients should be asked monthly about hepatitis-related symptoms and filling of prescriptions for no more than 1 month’s worth of medication. Patients need to be made aware of what hepatic toxicity symptoms to look for (dark urine, fever, loss of appetite, nausea, vomiting and/or flu-like syndrome including myalgias) and to discontinue treatment promptly and seek medical care.
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In at risk patients, how could isoniazid neurotoxicity be potentially prevented?
- The risk for neurotoxicity is greatest for patients with preexisting disorders that also pose a risk of neuropathy, such as diabetes, alcohol abuse, or malnutrition. In these patients,
- the prophylactic administration of 25-50 mg of pyridoxine daily should be considered.
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What is the most notable and serious potential adverse effect of ethambutol therapy?
How should patients be monitored and counseled about this potential adverse effect?
- Retrobulbar optic neuritis is the most serious adverse affect. Axial or central neuritis-the only form reported in patients taking <30 mg/kg (adult dose is 15-25mg/kg)- involves the papillomacular bundles of fibers and results in reduced in reduced visual acuity, central scotoma, and loss of ability to see green.
- Patients taking the lower dose should be tested for visual acuity and red-green color discrimination at baseline and whenever there is a subjective change in vision. Patients taking the higher dose should be checked at baseline, monthly thereafter, and whenever there is a
- subjective change in vision.
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How should pyrazinamide associated polyarthralgia be managed?
Take asprin also
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How should pyrazinamide associated gout be managed?
Stop treatment if arthralgia turns to gouty arthritis.
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