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1. Antituberculous Drugs

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1 1. Antituberculous Drugs

2 Antituberculous Drugs
First-line agents: Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin Second-line agents: Para-aminosalicylic Ethionamide Amikacin Capreomycin Fluoroquinolones

3 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 Aminosalicylic acid 8-12 g/d Capreomycin Ciprofloxacin 1500 mg/d, divided Clofazimine 200 mg/d Cycloserine mg/d, divided Ethionamide 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.

4 Isoniazid 1.Antituberculous activity
Bacteriostatic & bactericidal for tubercle bacilli Remarkably selective for mycobacteria Resistance 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 action Inhibiting synthesis of mycolic acids – the essential components of mycobacterial cell walls. The Bacterial Cell Wall Gram Positive Gram Negative Peptidoglycan Mycobacteria Mycolate Cytoplasmic membrane Porin Acyl lipids LAM Outer 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. Hepatotoxicity Peripheral neuritis (slow acetylators, the structure of isoniazid is similar to that of pyridoxine, Vit B6) CNS toxic effects GI effects 5.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 action Binding strongly to the b subunit of bacterial DNA-dependent RNA ploymerase Inhibiting RNA synthesis. DNA template 3.Mechanism of resistance Resistance 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 Rifampicin 4.ADME Absorbed 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 reactions GI effects Cholestatic jaundice or hepatitis Hypersensitive reaction Causing 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 Uses Treatment 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 reactions Retrobulbar 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

17 2. Antifungal agents

18 Antifungal agents Onychomycosis Fungal 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)

20 Classification of antifungal agents
Polyenes: Amphotercin B Azoles: Ketoconazole, Fluconazol Pyrimidine analogues: Flucytosine Echinocandins: Caspofungin, micafungin, anidulafungin Allylamine: Terbinafine

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

22 Amphotercin B Mechanism of action

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 reaction Prevention 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

24 New formulations of Amphotercin B :

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.

26 Mechanism of action

27 Azoles antifungal agents
Imidazoles ketoconazle miconazole clotrimazole Triazoles fluconazole Itraconazole voriconazole

28 Azoles antifungal agents
Mechanism of action: reduce ergosterol synthesis by inhibition of fungal cytochrome P450 enzyme Antifungal 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 P450 clinical 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 kotoconazole side effects (interact with hepatic microsomal enzymes): less than kotoconazole.

30 Azoles antifungal agents
Fluconazole good 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. Voriconazole The newest triazole to be licensed less mammalian P450 inhibition Visual disturbance are common (30%) (1) candidiasis (2) aspergillosis

31 Topical antifungal agents
Polyenes : Nystatin: (topically used) Griseofulvin (systemic treatment) - Nucleoside analogue Allylamines: Terbinafine: oral formulation - squalene epoxidase inhibitor

32 3. Antiviral Drugs

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 virus DNA virus RNA virus

34 The major sites of antiviral drug action

35 Four types of antiviral agents
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)

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 of patients and save the lives. (3) AZT+3TC+proteinase inhibitor efficacy,resistance, toxicity (4) Side effects: GI CNS Bone 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 AZT 3. HIV proteinase inhibitor saquinavir: (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 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-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 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 The 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.

41 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

42 Empiric Therapy Vast majority of all antimicrobial therapy
Should be approached rationally Syndrome Likely pathogens Known resistance patterns Host factors Unfortunately, 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 for laboratory testing e.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.

45 Gram Negative cultured

46 Identification of Infecting Organism
Antimicrobial Susceptibility Testing Further 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 infections Fever caused by unidentified reasons Topical applications Antimicrobial prophylaxis Antimicrobial 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 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 Site of the infection Effective 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 tracts Friedlander 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 mechanism Individual variation

53 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 Age All 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 prohibited at necessary time Penicillin G Cefazolin Cefazidime Vancomycin Aminoglycosides Polymixins ethambutol Erythromycin Flucytosine Piperacillin Mezocillin Cefalotin Ceftriaxone Lincomycin Clindamycin Fleroxacin Sulfonamides Tetracyclines Chloramphenicol Isoniazid Rifampicin Amphotercin B Ketoconazole Miconazole It 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 prohibited at necessary time Macrolides Chloramphenicol Isoniazid Rifampicin Doxycycline Penicillin G Carbenicillin Cefalotin Cefazolin Cefamandole cefuroxime Cefazidime ofloxacin Vancomycin Aminoglycosides Polymixins Flucytosine Sulfonamides Tetracyclines nitrofurantoin Poor 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
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 Pregnancy : 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 infections Fever caused by unidentified reasons Topical applications Antimicrobial prophylaxis Antimicrobial agents combinations

58 Prophylaxis use of Anti-infectives
Nonsurgical prophylaxis,e.g. , 1) Tuberculosis 2) Malaria 3) HIV infection 4) Meningococcal infection 5) Rheumatic fever 6) 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 pyrazinamide Malaria :Travelers to areas endemic for chloroquine-susceptible disease ;Chloroquine HIV 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:Zidovudine Urinary tract infections (UTI):Recurrent infection;Trimethoprim-sulfamethoxazole Rheumatic fever:History of rheumatic fever or known rheumatic heart disease;Benzathine penicillin Meningococcal infection :Close contacts of a case;Rifampin, ciprofaxacin, or ceftriaxone;

59 Prophylaxis use of Anti-infectives
Surgical prophylaxis National research council expected infection wound classification criteria rate Clean ≤2% Clean contaminated ≤10% Contaminated about 20% Dirty about 40%

60 Prophylaxis use of Anti-infectives
Surgical prophylaxis, e.g., 1) Cardiac operation 2) Noncardiac, thoracic operation 3) Vascular (abdominal and lower extremity) operation 4) Head and neck operation 5) Gastroduodenal or biliary operation 6) Orthopedic operation (with hardware insertion) 7) Penetrating trauma 8) Burn wound 9) Colorectal operation 10) Appendectomy

61 Usage of Antimicrobial Agents
Route of administration - orally or parenterally Duration of therapy - 3-5 days days for serious infection Dose

62 Antimicrobial agents combinations
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 It 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 sequence Inhibition of enzymatic inactivation Enhancement of antimicrobial agent uptake Inhibition of different resistant strain respectively Several 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.

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