1. Antituberculous Dr1. Antituberculous Drugsugs
Antituberculous DrugsAntituberculous Drugs
• First-line agentsFirst-line agents ::IsoniazidIsoniazid
RifampinRifampin
PyrazinamidePyrazinamide
EthambutolEthambutol
StreptomycinStreptomycin
• Second-line agentsSecond-line agents ::Para-aminosalicylicPara-aminosalicylic
EthionamideEthionamide
AmikacinAmikacin
CapreomycinCapreomycin
FluoroquinolonesFluoroquinolones
Drug Typical Adult Dosage1
First-line agents (in approximate order of preference)
Isoniazid 300 mg/d
Rifampin 600 mg/d
Pyrazinamide 25 mg/kg/d
Ethambutol 15-25 mg/kg/d
Streptomycin 15 mg/kg/d
Second-line agents
Amikacin 15 mg/kg/d
Aminosalicylic acid 8-12 g/d
Capreomycin 15 mg/kg/d
Ciprofloxacin 1500 mg/d, divided
Clofazimine 200 mg/d
Cycloserine 500-1000 mg/d, divided
Ethionamide 500-750 mg/d
Levofloxacin 500 mg/d
Rifabutin 300 mg/d2
Rifapentine 600 mg once or twice weekly
1Assuming normal renal function.
2150 mg/d if used concurrently with a protease inhibitor.
1 . Antituberculous activity
• Bacteriostatic & bactericidal for tubercle bacilli• Remarkably selective for mycobacteria• Resistance mutants occurs easily when given as t
he sole drug.• Be active against both extracelluar and intracellul
ar tubercle bacilli. • Penetrating into phagocytes, Diffusing readily int
o all body fluid and tissues, including caseous material.
Isoniazid Isoniazid
•The Bacterial Cell Wall
PorinCytoplasmic membrane
Outer membrane proteins
Peptidoglycan
Acyl lipids LAM
Mycolate
Gram PositiveGram Negative
Mycobacteria
2.Mechanism of action
• Inhibiting synthesis of mycolic acids – the essential components of mycobacterial cell walls.
3 . ADME• Absorbed from the gastrointestinal tract readily.
• Distributed widely in all body fluids and tissues.
• Metabolism, especially acetylation by liver N-acetyltransferas
e, is genetically determined (slow acetylators , rapid acetylat
ors, and middle acetylators).
• Excreted mainly in the urine.
IsoniazidIsoniazid
4 . Clinical Uses• 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.• Hepatotoxicity• Peripheral neuritis (slow acetylators, the structure of isoniazid is similar to that of pyridoxine, Vit B6)• CNS toxic effects• GI effects
IsoniazidIsoniazid
5 . Adverse reactions
RifampicinRifampicin 1. Antibacterial activity • Broad-spectrum • Resistance mutants occurs easily, if used alone.• Bactericidal for mycobacteria.• Penetrates most tissues and into phagocytes.
• Binding strongly to the subunit of bacterial DNA-dependent RNA ploymerase
• Inhibiting RNA synthesis.
2 . Mechanism of action
DNA templateDNA templateDNA templateDNA template
3 . Mechanism of resistance• Resistance results from one of several possible p
oints in the gene for subunit of RNA polymerase. These mutation prevent binding of rifampicin to RNA polymerase.
4.ADME• Absorbed well after oral administration. The absorption is attenuated by food and para-amino
salicylic (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.
RifampicinRifampicin
5. Clinical Uses• mycobacterial infections• other indications
RifampicinRifampicin
6. Adverse reactions • GI effects • Cholestatic jaundice or hepatitis • Hypersensitive reaction• Causing a harmless orange color in urine,
sweat, tear, and contact lenses.
• 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.
22..Clinical UsesClinical Uses
• Treatment for tuberculosis of various forms when given concurrently with isoniazid.
EthambutolEthambutol
11 .. Antimycobacterial actvity Antimycobacterial actvity
33 .. Adverse reactionsAdverse reactions• Retrobulbar neuritis.• Hypersensitive reactions. • GI upset, rash, fever, headache, etc.
PyrazinamidePyrazinamide• 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 antit
uberculous drugs.
• Adverse reactions hepatotoxicity, GI reactions, drug fever, and hyperuricemia (acute gouty arthritis).
StreptomycinStreptomycin• The first effective drug to treat tuberculosis.
• in treatment of life-threatening forms of tuberc
ulosis, eg, meningitis and disseminated disea
se, and in treatment of infections resistant to o
ther drugs.
• Resistance to Streptomycin developed easily
when it is used alone.
• Given simultaneously to prevent emergence of
resistance and toxic reaction.
The principle for using antituThe principle for using antituberculous drugs berculous drugs
• Treatment should be initiated with antiTreatment should be initiated with antituberculous drugs tuberculous drugs earlyearly..
• Be initiated with Be initiated with combinationcombination of antitu of antituberculous drugs .berculous drugs .
• be continued for a long time (be continued for a long time (6-9 months6-9 months).).
e.g. 2HRZ/4HR and 2SHRZ/4HREe.g. 2HRZ/4HR and 2SHRZ/4HRE
2. Antifungal agents2. Antifungal agents
Fungal infections traditionally have Fungal infections traditionally have been divided to been divided to two distinct classes: two distinct classes: systemic and superficial.systemic and superficial. So, the major So, the major antifungal agents are described with antifungal agents are described with “systemic” and “topical”“systemic” and “topical”..
Antifungal agentsAntifungal agents
OnychomycosisOnychomycosis
Oral infection with Candida (Thrush)
www.thachers.org/ internal_medicine.htm http://vasculitis.med.jhu.edu/treatments/cytoxan.html
• Polyenes: Amphotercin B
• Azoles: Ketoconazole, Fluconazol
• Pyrimidine analogues: Flucytosine
• Echinocandins: Caspofungin, micafungin, anid
ulafungin
• Allylamine: Terbinafine
Classification of Classification of antifungal agents
• Broad-spectrumBroad-spectrum• Amphotericin B remains the drug of choice for all life-thrAmphotericin B remains the drug of choice for all life-thr
eatening mycotic infections (It is often as the initial regieatening mycotic infections (It is often as the initial regimen). e.g. Cryptococcal meningitis; men). e.g. Cryptococcal meningitis;
• local administration: mycotic corneal ulcerslocal administration: mycotic corneal ulcers
Amphotercin BAmphotercin B
Polyenes
Mechanism of actionMechanism of action
Amphotercin BAmphotercin B
Adverse reactions:Adverse reactions:
(1) fever, chill, hyperpnea, (1) fever, chill, hyperpnea, myalgiamyalgia and hypotension, and hypotension, etcetc. (~75%). (~75%)
(2) nephrotoxicity: renal tubular acidosis and renal wasting K(2) nephrotoxicity: renal tubular acidosis and renal wasting K++ and Mg and Mg2+2+
(3) hematological Toxicity: hypochromic, normocytic anemia, (3) hematological Toxicity: hypochromic, normocytic anemia, etcetc..
(4) hepatotoxicity, (5) cardiac toxicity, (6) CNS side effects (4) hepatotoxicity, (5) cardiac toxicity, (6) CNS side effects
(7) hypersensitive reaction(7) hypersensitive reaction
Prevention of adverse reactionPrevention of adverse reaction::
(1) Pretreatment with oral (1) Pretreatment with oral acetaminophen acetaminophen or use of intravenous or use of intravenous hydrocohydroco
rtisone hemisuccinatertisone hemisuccinate..
(2) Supplemental K(2) Supplemental K++ is required. is required.
(3) Do physical examination termly. (3) Do physical examination termly.
(4) drug interactions(4) drug interactions
New formulations of Amphotercin B :New formulations of Amphotercin B :
• a a norrow-spectrumnorrow-spectrum antifungal drug. antifungal drug.
• drug resistance occurs rapidly when flucytosine is used drug resistance occurs rapidly when flucytosine is used
alone. alone.
• usedused predominantly predominantly in combination with amphotericin Bin combination with amphotericin B
for therapy of crypotococcal meningitis in AIDS patient, for therapy of crypotococcal meningitis in AIDS patient,
or with itraconazole for chromoblastomycosis.or with itraconazole for chromoblastomycosis.
Adverse reactionsAdverse reactions::• depressing the function of bone marrowdepressing the function of bone marrow (leading to leuk (leading to leuk
openia and thrombocytopenia, openia and thrombocytopenia, etc.)etc.). . • Plasma levels of hepatic enzymes are elevated (reversiblPlasma levels of hepatic enzymes are elevated (reversibl
e).e).• rash, nausea, vomiting, diarrhea.rash, nausea, vomiting, diarrhea.
Flucytosine (5-FFlucytosine (5-FC)C)
Mechanism of actionMechanism of action
Imidazoles• ketoconazle • miconazole • clotrimazole
Triazoles• fluconazole • Itraconazole• voriconazole
Azoles antifungal agentsAzoles antifungal agents
Mechanism of action:Mechanism of action:• reduce ergosterol synthesis by inhibition of fungal creduce ergosterol synthesis by inhibition of fungal c
ytochrome P450 enzymeytochrome P450 enzyme
Antifungal activity Antifungal activity ::• Systemically (kSystemically (ketoconazle, fluconazole, itraconazole,
voriconazole) or topically (miconazole, clotrimazole). or topically (miconazole, clotrimazole).
Azoles antifungal agentsAzoles antifungal agents
Ketoconazle :Ketoconazle :
• the first oral azoles introduced into clinical use (sthe first oral azoles introduced into clinical use (systemically or topicallystemically or topicall
y)y). .
• less selective for fungal P450 less selective for fungal P450
• clinical use has been limited by endocrine side effects, liver toxicity and clinical use has been limited by endocrine side effects, liver toxicity and
the drug interactions. the drug interactions.
• itraconazole itraconazole or or fluconazole fluconazole has replaced ketoconazle for patients who cahas replaced ketoconazle for patients who ca
n afford the more expensive, newer product.n afford the more expensive, newer product.
Itraconazole: Itraconazole:
• antifungal spectrum: broader than kotoconazoleantifungal spectrum: broader than kotoconazole
• side effects (interact with hepatic microsomal enzymes): less thaside effects (interact with hepatic microsomal enzymes): less tha
n kotoconazole.n kotoconazole.
Azoles antifungal agentsAzoles antifungal agents
Fluconazole Fluconazole • good water solubility and good CSF penetration (high bioavailgood water solubility and good CSF penetration (high bioavail
ability).ability).• drug interactions and side effects are also less because of its ldrug interactions and side effects are also less because of its l
east effect on hepatic enzyme of all the azoles. east effect on hepatic enzyme of all the azoles. • Be used in:Be used in: (1) Candidiasis, (1) Candidiasis, (2) Cryptococcosis. (2) Cryptococcosis. VoriconazoleVoriconazole• The newest triazole to be licensedThe newest triazole to be licensed• less mammalian P450 inhibitionless mammalian P450 inhibition• Visual disturbance are common (30%)Visual disturbance are common (30%)• Be used in:Be used in:(1) candidiasis(1) candidiasis(2) aspergillosis (2) aspergillosis
Azoles antifungal agentsAzoles antifungal agents
PolyenesPolyenes : :Nystatin: (topically used)Nystatin: (topically used)Griseofulvin (systemic treatment)Griseofulvin (systemic treatment) - - Nucleoside analogue
Allylamines:Allylamines:Terbinafine: oral formulationTerbinafine: oral formulation - - squalene epoxidase inhibitor
Topical antifungal agentsTopical antifungal agents
3. Antiviral Drugs3. Antiviral Drugs
Antiviral Drugs1. Characters of VirusViruses are obligate intracellular parasites their replication depend
s 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
The major sites of antiviral drug actionThe major sites of antiviral drug action
1. Agents to Treat Herpes Simplex Virus (HSV) & Varicella Zoster Virus (VZV) Infections
(1) Acyclovir HSV (renal function), HSV meningitis
(2) Ganciclovir HSV CMV (bone marrow suppression)
(3) Idoxuridine HSV (topical use)
(4) Vidarabine (Ara-A) HSV
Four types of antiviral agentsFour types of antiviral agents
2. Antiretroviral agents
Zidovudine( AZT):(1) First drug for HIV infection approved by FDA.
(2) Different stage of HIV infection, to improve the symptom of patients and save the lives.
(3) AZT+3TC+proteinase inhibitor efficacy, resistance, toxicity
(4) Side effects: GI CNS Bone marrow suppression
Lamivudine( 3TC):(1) Uncleosides as antiviral agents
(2) Effective on AZT-resistant HIV
(3) Lower toxicity than AZT
3. HIV proteinase inhibitorsaquinavir:(1) Selective inhibition of HIV proteinase
(2) Single use or alone
(3) Sensitive to AZT-resistant HIV
4. Other antiviral agents(1).ribavirin( virazole): Board antiviral spectrum Effective to DNA or RNA virus Type A, B Influ., HSV, adnoviral pneumonia.
(2) Amaantadine : specifical inhibition of influ. Prevention for Type 1 influ.
(3) Interferon-: Board antiviral spectrum Influ., HSV, viral hepatitis and cancer. fever and bone marrow suppression
Clinical Uses of Antimicrobial Agents
Identification of Infecting Organism
• Staining of clinical specimens– Gram stain, Acid-fast stain, silver stains…
• Antigen detection (e.g. ELISA, latex agglutination)
• Nucleic acid detection (e.g. PCR)
• Culture methods– Obtain culture material prior to antimicrobial therapy,
if possible
Antimicrobial Susceptibility Testing
• Minimum inhibitory concentration (MIC)
• Minimum bactericidal concentration (MBC) 99.9% decrease in growth over 24 hours
• Multiple techniques– Disk: semi-quantitative– Broth Dilution: quantitative
Empiric Therapy
• Vast majority of all antimicrobial therapy
• Should be approached rationally– Syndrome– Likely pathogens– Known resistance patterns– Host factors
Empiric Therapy for Peritoneal Dialysate Infection
Collect specimens for laboratory testing
Gram Positive cultured
Gram Negative cultured
Identification of Infecting Organism
Antimicrobial Susceptibility Testing
Further modify the empiric therapy
A. Formulate a clinical diagnosis of microbial infection.
B. Obtain specimens for laboratory examination, empirical therapy begins.
C. Formulate a microbiologic diagnosis.D. Determine the necessity for empirical
therapy.E. Institute treatment.
Therapeutic applications of Anti-infectives
1. Choiceness of antimicrobial agents depends on pharmacological factors and host factors.
2. The uses of antimicrobial agents is strictly controlled in some situations.A. Viral infectionsB. Fever caused by unidentified reasonsC. Topical applicationsD. Antimicrobial prophylaxisE. Antimicrobial agents combinations
Choice of antimicrobial agent
A. kinetics of absorption, distribution, and elimin
ation;B. Bacteriostatic vs bactericidal activity; concent
ration-dependent killing & time-dependent killing;
C. the potential toxicity of an agent;
D. pharmacodynamic or pharmacokinetic interac
tion with other drugs.
Pharmacological factors:
• Site of infection– Adequate concentrations of antimicrobials must be delivered to the site
of infection
– Local concentrations greater than MIC
– Subinhibitory concentrations may still alter bacterial adherence, morphology, aid in phagocytosis and killing
– Serum concentration easy to determine, tissue concentrations more difficult to assess
– Protein binding of drugs• Excretion
– Urine: Aminoglycosides, fluoroquinolones (Urinary tract infections ) – Bile: Ceftriaxone
• Penetration into various sites– Central nervous system– Lung– Bone– Foreign bodies
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
Example of anatomic location of infection affecting antimicrobial agent selection: Brain abscess
A. Age
B. Hepatic or renal function
C. Pregnancy status
D. The functional state of host defense
mechanism
E. Individual variation
Host factors:
• Age– Gastric acidity low in young children and
elderly– Renal, hepatic function vary with age
• Dose adjustment for creatinine clearance and hepatic dysfunction is critical to avoid toxicities
– Developing bone and teeth• Tetracyclines stain teeth• Quinolones may impair bone and cartilage
growth
normal dosage decreasing dose decreasing dose using prohibited at necessary time
Penicillin G CefazolinCefazidimeVancomycinAminoglycosidesPolymixinsethambutol
ErythromycinFlucytosine
PiperacillinMezocillinCefalotinCeftriaxoneLincomycinClindamycinFleroxacin
SulfonamidesTetracyclinesChloramphenicolIsoniazidRifampicinAmphotercin BKetoconazoleMiconazole
•Antimicrobial agents dosing in hepatic insufficiencyAntimicrobial agents dosing in hepatic insufficiency
• Antimicrobial agents dosing in renal insufficiency
normal dosage decreasing dose decreasing dose using prohibited at necessary time
Macrolides ChloramphenicolIsoniazidRifampicinDoxycycline
Penicillin G CarbenicillinCefalotinCefazolinCefamandolecefuroximeCefazidimeofloxacin
VancomycinAminoglycosidesPolymixinsFlucytosine
SulfonamidesTetracyclinesnitrofurantoin
• Pregnancy– Teratogenicity and other toxicity to the fetus– Other toxic reactions
• Excretion in breast milk• Immune system and host defense • Allergy history • Genetic and metabolic abnormalities
– Isoniazid acetylation varies greatly– G-6-PD deficiency and risk of hemolysis
• Sulfonamides, nitrofurantoin
1. Choiceness of antimicrobial agents depends on pharmacological factors and host factors.
2. The uses of antimicrobial agents is strictly controlled in some situations.A. Viral infectionsB. Fever caused by unidentified reasonsC. Topical applicationsD. Antimicrobial prophylaxisE. Antimicrobial agents combinations
Choice of antimicrobial agent
• Nonsurgical prophylaxis, e.g. ,
1) Tuberculosis
2) Malaria
3) HIV infection
4) Meningococcal infection
5) Rheumatic fever
6) Urinary tract infections (UTI)
Prophylaxis use of Anti-infectives
• Surgical prophylaxis National research council expected infection wound classification criteria rateClean ≤2%Clean contaminated ≤10%Contaminated about 20%Dirty about 40%
Prophylaxis use of Anti-infectives
• Surgical prophylaxis , e.g., 1) Cardiac operation2) Noncardiac, thoracic operation3) Vascular (abdominal and lower extremity) operation4) Head and neck operation 5) Gastroduodenal or biliary operation6) Orthopedic operation (with hardware insertion) 7) Penetrating trauma8) Burn wound9) Colorectal operation10) Appendectomy
Prophylaxis use of Anti-infectives
Usage of Antimicrobial Agents
• Route of administration - orally or parenterally• Duration of therapy - 3-5 days - 7-10 days for serious infection• Dose
• Two is better than one?– Empiric therapy– Polymicrobial infection– Increase efficacy--synergism– Prevent emergence of resistance
• Combination therapy– Mycobacterium tuberculosis– HIV– Pseudomonas aeruginosa– ? Invasive aspergillosis
Antimicrobial agents combinations
Mechanism of synergistic action:
1) Blockade of sequential steps in a
metabolic sequence
2) Inhibition of enzymatic inactivation
3) Enhancement of antimicrobial agent
uptake
4) Inhibition of different resistant strain
respectively
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