3 DrugTypical Adult Dosage1First-line agents (in approximate order of preference)Isoniazid300 mg/dRifampin600 mg/dPyrazinamide25 mg/kg/dEthambutol15-25 mg/kg/dStreptomycin15 mg/kg/dSecond-line agentsAmikacinAminosalicylic acid8-12 g/dCapreomycinCiprofloxacin1500 mg/d, dividedClofazimine200 mg/dCycloserinemg/d, dividedEthionamidemg/dLevofloxacin500 mg/dRifabutin300 mg/d2Rifapentine600 mg once or twice weekly1Assuming normal renal function.2150 mg/d if used concurrently with a protease inhibitor.
4 Isoniazid 1．Antituberculous activity Bacteriostatic & bactericidal for tubercle bacilliRemarkably selective for mycobacteriaResistance mutants occurs easily when given as the sole drug.Be active against both extracelluar and intracellular tubercle bacilli.Penetrating into phagocytes, Diffusing readily into all body fluid and tissues, including caseous material.
5 The Bacterial Cell Wall 2．Mechanism of actionInhibiting synthesis of mycolic acids – the essential components of mycobacterial cell walls.The Bacterial Cell WallGram PositiveGram NegativePeptidoglycanMycobacteriaMycolateCytoplasmic membranePorinAcyl lipidsLAMOuter membrane proteins
6 Isoniazid 3．ADME Absorbed from the gastrointestinal tract readily. Distributed widely in all body fluids and tissues.Metabolism, especially acetylation by liver N-acetyltransferase, is genetically determined (slow acetylators，rapid acetylators, and middle acetylators).Excreted mainly in the urine.
8 Isoniazid 4．Clinical Uses 5．Adverse reactions Combination with rifampicin or second-line agents, used for severe infections with M tuberculosis.As a single agent, indicated for prevent and treatment of active tuberculosis of early stage.Allergic reactions: rashes, systemic lupus erythematosus, etc.HepatotoxicityPeripheral neuritis (slow acetylators, the structure of isoniazid is similar to that of pyridoxine, Vit B6)CNS toxic effectsGI effects5．Adverse reactions
9 Rifampicin 1. Antibacterial activity Broad-spectrum Resistance mutants occurs easily, if used alone.Bactericidal for mycobacteria.Penetrates most tissues and into phagocytes.
10 3．Mechanism of resistance 2．Mechanism of actionBinding strongly to the b subunit of bacterial DNA-dependent RNA ploymeraseInhibiting RNA synthesis.DNA template3．Mechanism of resistanceResistance results from one of several possible points in the gene for b subunit of RNA polymerase. These mutation prevent binding of rifampicin to RNA polymerase.
11 Rifampicin4．ADMEAbsorbed well after oral administration. The absorption is attenuated by food and para-aminosalicylic (PAS).Distributed widely, even in CSF when meninges is infectious.Metabolized in liver by deactylation, and rifampicin is a enzyme inducer.Excreted mainly through the liver into bile, then undergoes enterohepatic recirculation.
12 Rifampicin 5. Clinical Uses mycobacterial infections other indications 6. Adverse reactionsGI effectsCholestatic jaundice or hepatitisHypersensitive reactionCausing a harmless orange color in urine, sweat, tear, and contact lenses.
13 Ethambutol 1．Antimycobacterial actvity Nearly all strain of M. tuberculosis are sensitive.Be bactericidal to intercellular and extrecellular M. tuberculosis.Ethambutol inhibits mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall.Resistance to ethambutol is due to mutations resulting in overexpression of mycobacterial arabinosyl transferases.2．Clinical UsesTreatment for tuberculosis of various forms when given concurrently with isoniazid.Optic neuritis, induced decrease of visual acuity and loss of ability to differentiate red from green, etc.This dose-related side effect is more likely to occur at doses of 25 mg/kg/d continued for several months. At 15 mg/kg/d or less, visual disturbances are very rare.3．Adverse reactionsRetrobulbar neuritis.Hypersensitive reactions.GI upset, rash, fever, headache, etc.
14 Pyrazinamide Bactericidal (in vitro a slightly acidic pH). Well absorbed (p.o.), widely distributed.Resistance for Pyrazinamide develops fairly readily, but there is no cross-resistance with other antituberculous drugs.Adverse reactions hepatotoxicity, GI reactions, drug fever, and hyperuricemia (acute gouty arthritis).
15 Streptomycin The first effective drug to treat tuberculosis. in treatment of life-threatening forms of tuberculosis, eg, meningitis and disseminated disease, and in treatment of infections resistant to other drugs.Resistance to Streptomycin developed easily when it is used alone.Given simultaneously to prevent emergence of resistance and toxic reaction.
16 The principle for using antituberculous drugs Treatment should be initiated with antituberculous drugs early.Be initiated with combination of antituberculous drugs .be continued for a long time (6-9 months).e.g. 2HRZ/4HR and 2SHRZ/4HRE
18 Antifungal agentsOnychomycosisFungal infections traditionally have been divided to two distinct classes: systemic and superficial. So, the major antifungal agents are described with “systemic” and “topical”.
19 Oral infection with Candida (Thrush) internal_medicine.htm
21 Polyenes Amphotercin B Broad-spectrum Amphotericin B remains the drug of choice for all life-threatening mycotic infections (It is often as the initial regimen). e.g. Cryptococcal meningitis;local administration: mycotic corneal ulcers
23 Adverse reactions:(1) fever, chill, hyperpnea, myalgia and hypotension, etc. (~75%)(2) nephrotoxicity: renal tubular acidosis and renal wasting K+ and Mg2+(3) hematological Toxicity: hypochromic, normocytic anemia, etc.(4) hepatotoxicity, (5) cardiac toxicity, (6) CNS side effects(7) hypersensitive reactionPrevention of adverse reaction:(1) Pretreatment with oral acetaminophen or use of intravenous hydrocortisone hemisuccinate.(2) Supplemental K+ is required.(3) Do physical examination termly.(4) drug interactions
25 Flucytosine (5-FC) a norrow-spectrum antifungal drug. drug resistance occurs rapidly when flucytosine is used alone.used predominantly in combination with amphotericin B for therapy of crypotococcal meningitis in AIDS patient, or with itraconazole for chromoblastomycosis.Adverse reactions:depressing the function of bone marrow (leading to leukopenia and thrombocytopenia, etc.).Plasma levels of hepatic enzymes are elevated (reversible).rash, nausea, vomiting, diarrhea.
28 Azoles antifungal agents Mechanism of action:reduce ergosterol synthesis by inhibition of fungal cytochrome P450 enzymeAntifungal activity :Systemically (ketoconazle, fluconazole, itraconazole, voriconazole) or topically (miconazole, clotrimazole).
29 Azoles antifungal agents Ketoconazle :the first oral azoles introduced into clinical use (systemically or topically).less selective for fungal P450clinical use has been limited by endocrine side effects, liver toxicity and the drug interactions.itraconazole or fluconazole has replaced ketoconazle for patients who can afford the more expensive, newer product.Itraconazole:antifungal spectrum: broader than kotoconazoleside effects (interact with hepatic microsomal enzymes): less than kotoconazole.
30 Azoles antifungal agents Fluconazolegood water solubility and good CSF penetration (high bioavailability).drug interactions and side effects are also less because of its least effect on hepatic enzyme of all the azoles.Be used in:(1) Candidiasis,(2) Cryptococcosis.VoriconazoleThe newest triazole to be licensedless mammalian P450 inhibitionVisual disturbance are common (30%)(1) candidiasis(2) aspergillosis
33 Antiviral Drugs 1. Characters of Virus 2.Classification of virus Viruses are obligate intracellular parasites their replication depends primarily on synthetic processes of the host cell. Consequently, to be effective, antiviral agents must either block viralentry into or exit from the cell or be active inside the host cell. As a corollary, nonselective inhibitors of virus replication may interfere with host cell function and produce toxicity.2.Classification of virusDNA virusRNA virus
36 2. Antiretroviral agents Zidovudine（AZT）：(1) First drug for HIV infection approved by FDA.(2) Different stage of HIV infection, to improve the symptom ofpatients and save the lives.(3) AZT+3TC+proteinase inhibitorefficacy，resistance, toxicity(4) Side effects:GICNSBone marrow suppression
37 3. HIV proteinase inhibitor saquinavir： Lamivudine（3TC）：(1) Uncleosides as antiviral agents(2) Effective on AZT-resistant HIV(3) Lower toxicity than AZT3. HIV proteinase inhibitorsaquinavir：(1) Selective inhibition of HIV proteinase(2) Single use or alone(3) Sensitive to AZT-resistant HIV
38 4. Other antiviral agents (1).ribavirin（virazole）：Board antiviral spectrumEffective to DNA or RNA virusType A, B Influ., HSV, adnoviral pneumonia.(2) Amaantadine ：specifical inhibition of influ. Prevention for Type 1 influ.(3) Interferon-g：Influ., HSV, viral hepatitis and cancer.fever and bone marrow suppression
39 Clinical Uses of Antimicrobial Agents Thus, the good clinical uses of Antimicrobial Agents is very important.
40 Identification of Infecting Organism Staining of clinical specimensGram stain, Acid-fast stain, silver stains…Antigen detection (e.g. ELISA, latex agglutination)Nucleic acid detection (e.g. PCR)Culture methodsObtain culture material prior to antimicrobial therapy, if possibleThe simple way, to use the Antimicrobial Agents rationally and to reduce the incidence of resistance, is to identify the infecting organism and to do the Antimicrobial Susceptibility Test, the result will be the guidance for selection of antibacterial agents.
42 Empiric Therapy Vast majority of all antimicrobial therapy Should be approached rationallySyndromeLikely pathogensKnown resistance patternsHost factorsUnfortunately, it is not often possible or practical to wait until the microorganism has been identified. It is therefore necessary to begin with empirical initial therapy and then modify the therapy. Acutely ill patients usually require immediate treatment that is initiated after collecting specimens for laboratory testing but before the results of the cultures become available. The choice of drug in the absence of sensitivity data is influenced by patient history (e.g. recent travel, age), location of infection, and results of the Gram stain.
43 Empiric Therapy for Peritoneal Dialysate Infection Collect specimens forlaboratory testinge.g., the Empiric Therapy for Peritoneal Dialysate Infection.One may initiate therapy with a combination of antimicrobial drugs that cover infections by both gram-positive and gram-negative microorganisms. Ceftazidime is a 3rd generation cephalosporin, it is more active than 1st and 2nd generation cephalosporin against gram negative bacteria and has extended spectrum against pseudomonas.
44 Gram Positive cultured The Gram stain is the fastest and simplest procedure to identify bacteria. Although the use of dyes to stain bacteria sounds anachronistic, this time-honored approach provides rapid information about the ultrastructure of bacteria. Since ceftazidime is a kind of broad spectrum antimicrobial agent. it maybe will cause super-infection, it is better to choose narrow spectrum agent when the lab show the pathogen is gram positive organism. Ampicillin is a narrow spectrum drug. Vancomycin is active only against gram positive bacteria.
46 Identification of Infecting Organism Antimicrobial Susceptibility TestingFurther modify the empiric therapy
47 Therapeutic applications of Anti-infectives Formulate a clinical diagnosis of microbial infection.Obtain specimens for laboratory examination, empirical therapy begins.Formulate a microbiologic diagnosis.Determine the necessity for empirical therapy.Institute treatment.
48 Choice of antimicrobial agent 1. Choiceness of antimicrobial agents depends on pharmacological factors and host factors.2. The uses of antimicrobial agents is strictly controlled in some situations.Viral infectionsFever caused by unidentified reasonsTopical applicationsAntimicrobial prophylaxisAntimicrobial agents combinations
49 Pharmacological factors: kinetics of absorption, distribution, and elimination;Bacteriostatic vs bactericidal activity; concentration-dependent killing &time-dependent killing;C. the potential toxicity of an agent;D. pharmacodynamic or pharmacokinetic interaction with other drugs.One of the first considerations the activity of the drugs under consideration against the known or suspected pathogenic bacteria. In an immunocompetent patient with a minor infection, it may not be essential to use a bactericidal drug, because a bacteristatic drug will stop bacterial growth and the patient’s normal immune defense mechanisms will usually kill the remaining bacteria. What’s important here is to recognize the limitations of the bacteriostatic drugs. For example, endocarditis due to many bacteria responds poorly to bacteriostatic agents.Note that a drug may be bacteriostatic against one species of bacteria, yet bacteriocidal against another.
50 Site of infection Excretion Penetration into various sites Adequate concentrations of antimicrobials must be delivered to the site of infectionLocal concentrations greater than MICSubinhibitory concentrations may still alter bacterial adherence, morphology, aid in phagocytosis and killingSerum concentration easy to determine, tissue concentrations more difficult to assessProtein binding of drugsExcretionUrine: Aminoglycosides, fluoroquinolones (Urinary tract infections )Bile: CeftriaxonePenetration into various sitesCentral nervous systemLungBoneForeign bodiesSite of the infectionEffective levels of an antibacterial agent must reach the site of infection. Thus, factors that impair delivery of a drug to the infected site may alter the effectiveness of the treatment. For example, poor perfusion of an anatomic area (e.g. distal extremities in a diabetic with peripheral vascular disease), make infections in such areas notoriously difficult to treat.The blood brain barrier must be considered when trying to treat a CNS infection. Treatment of meningitis depends on the ability of the drug to penetrate into the cerebrospinal fluid. The blood brain barrier ordinarily excludes many antibiotics. However tissue inflammation often enhances drug penetrability and allows sufficient levels of many, but not all, antibiotics to enter the cerebrospinal fluid. The more lipid-soluble drugs will penetrate better then the more hydrophilic drugs. Examples of lipophilic drugs that stand a better chance of entering the CNS include: chloramphenicol, rifampin, and metronidazole. On the other hand, aminoglycosides will not penetrate well because they are highly polar. Penicillins, cephalosporins, aztreonam, imipenem and ciprofloxacin enter in variable amounts, and the delivery is enhanced when inflammation is present.
51 Example of anatomic location of infection affecting antimicrobial agent selection: Brain abscess The site of infection may alter the activity of the drug used. For example, penicillins are not as active in the acidic environement of an abscess.MRI Study of the Brain Showing a Heterogeneous Mass in the Right Frontal Lobe That Compresses the Right Lateral Ventricle.PANEL A: A T2-weighted image without contrast shows a mass (arrow) with high signal intensity centrally, a heterogeneous peripheral ring of signal intensity similar to that of the brain parenchyma, and a surrounding area of bright signal in the white-matter tracts.PANEL B:On the contrast-enhanced T1-weighted image (Panel B), the mass has low signal intensity in the central region, suggesting the presence of fluid, and is surrounded by a ring of enhancement. Beyond the ring of enhancement, a less well-defined area of abnormal low signal extends along the white-matter tractsFriedlander et al. NEJM 348 (21): 2125, May 22, 2003
52 Host factors: Age Hepatic or renal function Pregnancy status The functional state of host defense mechanismIndividual variation
53 Age Gastric acidity low in young children and elderly Renal, hepatic function vary with ageDose adjustment for creatinine clearance and hepatic dysfunction is critical to avoid toxicitiesDeveloping bone and teethTetracyclines stain teethQuinolones may impair bone and cartilage growthAgeAll drugs are more toxic at the extremes of age; both in the very young and in the elderly because of changes in hepatic metabolism, renal function, plasma protein binding etc. A common example is the “Grey Baby syndrome” seen when infants are administered chloramphenicol. Despite adjustment for weight, toxicity was seen because of limited metabolism and clearance of the drug in early infancy, leading to the accumulation of high drug levels.
54 Antimicrobial agents dosing in hepatic insufficiency normal dosage decreasing dose decreasing dose using prohibitedat necessary timePenicillin GCefazolinCefazidimeVancomycinAminoglycosidesPolymixinsethambutolErythromycinFlucytosinePiperacillinMezocillinCefalotinCeftriaxoneLincomycinClindamycinFleroxacinSulfonamidesTetracyclinesChloramphenicolIsoniazidRifampicinAmphotercin BKetoconazoleMiconazoleIt has no suitable markers of hepatic function. So, drug use in patients with liver disease must take into account 3 general principles:(1) Pharmacokinetics are modified.(2) Drugs may modify the functional status of the liver.(3) Pharmacodynamics may be modified.Some antimicrobial agents (e.g. tetracyclines) may worsen preexisting hepatic dysfunction. Antibiotics that are metabolized in the liver will require reduction in dosage.
55 Antimicrobial agents dosing in renal insufficiency normal dosage decreasing dose decreasing dose using prohibitedat necessary timeMacrolidesChloramphenicolIsoniazidRifampicinDoxycyclinePenicillin GCarbenicillinCefalotinCefazolinCefamandolecefuroximeCefazidimeofloxacinVancomycinAminoglycosidesPolymixinsFlucytosineSulfonamidesTetracyclinesnitrofurantoinPoor kidney function (about 10 – 15% or less of normal) causes accumulation of antimicrobial agents that are ordinarily eliminated by this route of excretion, e.g. Aminoglycosides. Some agents are nephrotoxic, and physicians will avoid their use if a patient already has renal dysfunction.
56 Excretion in breast milk Immune system and host defense PregnancyTeratogenicity and other toxicity to the fetusOther toxic reactionsExcretion in breast milkImmune system and host defenseAllergy historyGenetic and metabolic abnormalitiesIsoniazid acetylation varies greatlyG-6-PD deficiency and risk of hemolysisSulfonamides, nitrofurantoinPregnancy : All antibiotic drugs cross the placenta into the developing fetus. Adverse effects to the fetus, are rare. The notable exception is the tetracycline class, which causes tooth dysplasia and inhibition of bone growth. Streptomycin causes auditory toxicity in offspring of mothers who had taken the drug for tuberculosis during pregnancy. There is some concern that metronidazole, rifampin, trimethoprim may have teratogenic potential, based on laboratory animal studies.Excretion in breast milk :Most antibiotics are excreted in breast milk and can alter the newborn’s microflora or act as a sensitizing agent to cause future drug allergies to certain antibiotics.Immune system and host defense: Elimination of the infecting microorganisms from the body depends on a function intact immune system. Antibacterial drugs either reduce the total population of bacteria or inhibit further bacterial growth, but host defenses must ultimately eliminate the invading microorganisms.Allergy history : A history of any previous allergic reaction in selecting an antibacterial agent. Allergy to the penicillin group is the most frequent and important. Remember that cross sensitivity may exist among members of drug class.Genetic and metabolic abnormalities : Genetic variation in metabolism of drugs or susceptibility to toxicity. As an example, RBC hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency can be caused by sulfonamides, nitrofurantoin, pyrmethamine, sulfones, and chloramphenicol. G-6-PD：glucose-6-phosphate dehydrogenase.
57 Choice of antimicrobial agent 1. Choiceness of antimicrobial agents depends on pharmacological factors and host factors.2. The uses of antimicrobial agents is strictly controlled in some situations.Viral infectionsFever caused by unidentified reasonsTopical applicationsAntimicrobial prophylaxisAntimicrobial agents combinations
58 Prophylaxis use of Anti-infectives Nonsurgical prophylaxis，e.g. ,1) Tuberculosis2) Malaria3) HIV infection4) Meningococcal infection5) Rheumatic fever6) Urinary tract infections (UTI)Tuberculosis：Persons with positive tuberculin skin tests and one or more of the following: (a) HIV infection, (b) close contacts with newly diagnosed disease, (c) recent skin test conversion, (d) medical conditions that increase the risk of developing tuberculosis, (e) age < 35； Isoniazid, rifampin, or pyrazinamideMalaria ：Travelers to areas endemic for chloroquine-susceptible disease ；ChloroquineHIV infection：(Health care workers exposed to blood after needle-stick injury)：Zidovudine and lamivudine ± indinavir or nelfinavir； Pregnant HIV-infected women who are at ³ 14 weeks of gestation，Newborns of HIV-infected women for the first 6 weeks of life, beginning 8-12 hours after birth：ZidovudineUrinary tract infections (UTI)：Recurrent infection；Trimethoprim-sulfamethoxazoleRheumatic fever：History of rheumatic fever or known rheumatic heart disease；Benzathine penicillinMeningococcal infection ：Close contacts of a case；Rifampin, ciprofaxacin, or ceftriaxone；
59 Prophylaxis use of Anti-infectives Surgical prophylaxisNational research council expected infectionwound classification criteria rateClean ≤2%Clean contaminated ≤10%Contaminated about 20%Dirty about 40%
60 Prophylaxis use of Anti-infectives Surgical prophylaxis， e.g.,1) Cardiac operation2) Noncardiac, thoracic operation3) Vascular (abdominal and lower extremity)operation4) Head and neck operation5) Gastroduodenal or biliary operation6) Orthopedic operation (with hardware insertion)7) Penetrating trauma8) Burn wound9) Colorectal operation10) Appendectomy
61 Usage of Antimicrobial Agents Route of administration- orally or parenterallyDuration of therapy- 3-5 daysdays for serious infectionDose
62 Antimicrobial agents combinations Two is better than one?Empiric therapyPolymicrobial infectionIncrease efficacy--synergismPrevent emergence of resistanceCombination therapyMycobacterium tuberculosisHIVPseudomonas aeruginosa? Invasive aspergillosisIt is therapeutically advisable to treat an infected patient with a single antimicrobial drug that is most selective for the infecting microorganism rather than to use a broad spectrum antibiotic drug. That is, use a narrow or extended spectrum drug rather than a broad spectrum drug whenever possible.There are distinct advantages to the use of combination chemotherapy, however, where appropriate. Synergistic effects to treat severe infections with reduced host toxicity caused by the drugs can result from the use of lower than normal doses of 2 or more drugs that work by different mechanisms of action. This approach is particularly useful for treating a life-threatening infection. Bacteria resistant to one narrow spectrum drug may be present which would be killed by a second agent. Thus, the use of two drugs prevents the resistant organisms from surviving. Infections caused by several types of microorganisms would require combination chemotherapy.Examples:Brain abscesses: often caused by Bacteroides species plus anaerobic and microaerophilic streptococci; penicillin* is good for the streptococci, whereas metronidazole is good for the Bacteroides species.Pelvic inflammatory infections: chlamydial component is treated with one drug (e.g. tetracycline) and the aerobic or anaerobic gram-negative and gram-positive component(s) require another drug (e.g. ceftriaxone).
63 The responses of bacteria suspended in growth medium to exposure to drug A or B alone are represented by the solid lines. The dotted lines represent the responses to simultaneous administration of the two drugs. When the inhibitory or killing effects of two or more antimicrobials used together are significantly greater than expected from their effects when used individually, synergism is said to result. Antagonism occurs when the combined inhibitory or killing effects of two or more antimicrobials are significantly less than expected when the drugs are used individually.
64 Mechanism of synergistic action: Blockade of sequential steps in a metabolic sequenceInhibition of enzymatic inactivationEnhancement of antimicrobial agent uptakeInhibition of different resistant strain respectivelySeveral types of multidrug therapy are employed:Documented successful combination chemotherapeutic regimens:1.combination of drugs acting on sequential steps in a metabolic pathway (sulfonamide plus trimethoprim).2.Combination in which one drug (-lactamase inhibitor) prevents the bacterial-medicated inactivation of the antibiotic drug (penicillin).3.combination of an inhibitor of cell wall synthesis (penicillin) with an inhibitor of protein synthesis (aminoglycoside).Example: synergistic therapy for enterococcal infections:Penicillins are generally bactericidal, but are only bacteriostatic against enterococci. Aminoglycosides would kill these bacteria but these hydrophilic drugs cannot penetrate the cell wall of enterococci. Penicillin inhibits cell wall synthesis sufficiently to create holes in the cell wall to allow the passage of aminoglycoside drug into the interior of the bacteria. There, the aminoglycoside can go to work and kill the microorganisms.