Week 3 Principles Of Antimicrobial Therapy PDF

PRINCIPLES OF ANTIMICROBIAL THERAPY Dr Tarza Jamal Thanoon 1 can't.fi ni nsE Tausewehaventcef Antimicrobial drugs...

PRINCIPLES OF ANTIMICROBIAL THERAPY Dr Tarza Jamal Thanoon 1 can't.fi ni nsE Tausewehaventcef Antimicrobial drugs wall ◦ Antimicrobial drugs are effective in the treatment of infections because of their selective toxicity ◦ Therefore, they have the ability to injure or kill an invading microorganism without harming the cells of the host. Identifythe suceptability of the site of Infection and patients factor cost and safety 2 allergy Identifythe susceptibility of site of Infection 1  it a_ SELECTION OF ANTIMICROBIAL AGENTS ◦ Selection of the most appropriate antimicrobial agent requires knowing 1) The organism’s identity 2) The organism’s susceptibility to a particular agent 3) The site of the infection 4) Patient factors 5) The safety of the agent 6) The cost of therapy co ◦ However, some patients require empiric therapy (immediate administration) Identify theantigen Ceo Identify the RNA andDNA 3 n i A. Identification of the infecting organism ◦ Characterizing the organism is central to selection of the proper drug. ◦ A rapid assessment of the nature of the pathogen can sometimes be made on the basis of the Gram stain ◦ However, it is generally necessary to culture the infective organism To arrive at a conclusive diagnosis and co Determine the susceptibility to antimicrobial agents. ate I winissIWI 4 2  or ◦ Definitive identification of the infecting organism may require other laboratory techniques:  Detection of microbial antigens  DNA, or RNA  Host immune response to the microorganism 5 B. Empiric therapy prior to identification of the organism i ◦ Ideally, the antimicrobial agent used to treat an infection is selected After the organism has been identified Its drug susceptibility established. ◦ However, in the critically ill patient, such a delay could prove fatal, immediate empiric therapy is indicated. 6 3 This slide discusses empiric therapy, which means starting treatment before knowing the exact organism causing an infection. Here’s a simpler explanation: 1. Ideal situation: Doctors prefer to: Identify the exact organism causing the infection. Determine which drug will work best (its susceptibility). 2. Critical patients: In very sick patients (critically ill), waiting to identify the organism could be dangerous or even fatal. In such cases, doctors quickly start empiric therapy using antibiotics that are likely to work based on the symptoms and the type of infection. This ensures the patient receives life-saving treatment without unnecessary delays. Later, therapy can be adjusted when lab results are available.  1. Timing: ◦ Acutely ill patients with infections of unknown origin, For example, 0326 ◦ A neutropenic patient (one who is predisposed to infections due to a reduction in neutrophils) ◦ A patient with meningitis (acute inflammation of the membranes covering the brain and spinal cord)  Require immediate treatment. ◦ If possible, therapy should be initiated after specimens for laboratory analysis have been obtained but before the results of the culture and sensitivity are available. 7 inactivebacteria kidthebacteria 2. Selecting a drug: 4612025 ◦ Drug choice in the absence of susceptibility data is influenced by  The site of infection  The patient’s history ◦ (for example, previous infections, age, recent travel history, recent antimicrobial therapy, immune status, and whether the infection was hospital- or community-acquired). ◦ Broad-spectrum therapy may be indicated initially when the organism is unknown or polymicrobial infections are likely. 8 4 C. Determining antimicrobial susceptibility of infective organisms ◦ After a pathogen is cultured, its susceptibility to specific antibiotics serves as a guide in choosing antimicrobial therapy. ◦ The minimum inhibitory and bactericidal concentrations of a drug can be experimentally determined 9 1. Bacteriostatic versus bactericidal drugs: ◦ Antimicrobial drugs are classified as either  Bacteriostatic  Bactericidal 1. Bacteriostatic drugs: arrest the growth and replication of bacteria thus limiting the spread of infection until the immune system attacks, immobilizes, and eliminate the pathogen. ◦ If the drug is removed before the immune system has scavenged the organisms, enough viable organisms may remain to begin a second cycle of infection. 2. Bactericidal drugs: kill bacteria at drug serum levels achievable in the patient. Because of their more aggressive antimicrobial action:  Bactericidal agents are often the drugs of choice in seriously ill and immunocompromised patients. 10 5 2. Minimum inhibitory concentration: inhibitory minimum ◦ The minimum inhibitory concentration (MIC): concentration ◦ Is the lowest antimicrobial concentration that prevents visible growth of an organism after 24 hours of incubation. ◦ This serves as a quantitative measure of in vitro susceptibility and is commonly used in or practice to streamline therapy. 11 12 6  3. Minimum bactericidal concentration: ◦ The minimum bactericidal concentration (MBC) : ◦ Is the lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubations. The The minimum bactericidal concentration (MBC) is a measure used to determine the effectiveness of an antimicrobial agent, like an antibiotic. It represents the lowest concentration of the drug that can kill 99.9% of the bacteria in a sample after an overnight incubation. In simpler terms, it tells us the minimum amount of the drug needed to effectively kill most of the bacteria, rather than just inhibiting their growth. 13 14 7  D. Effect of the site of infection on therapy: The blood–brain barrier ◦ Adequate levels of an antibiotic must reach the site of infection for the too invading microorganisms to be effectively eradicated. ◦ Capillaries with varying degrees of permeability carry drugs to the body tissues. ◦ The penetration and concentration of an antibacterial agent in the CSF are particularly influenced by the following: 15 chloramphenicol metronidazole chloramphenicol 1. Lipid solubility of the drug: metronidazole ◦ The lipid solubility of a drug is a major determinant of its ability to penetrate into the brain. ◦ Lipid soluble drugs, such as chloramphenicol and metronidazole have significant penetration into the CNS ◦ Whereas β-lactam antibiotics, such as penicillin, are ionized at physiologic pH and have low solubility in lipids. ◦ Therefore, they have limited penetration through the intact blood–brain barrier under normal circumstances. ◦ In infections such as meningitis in which the brain becomes inflamed, the barrier does not function as effectively and local permeability is increased. ◦ Some β-lactam antibiotic can enter the CSF 16 8 2. Molecular weight of the drug: ◦ A compound with a low molecular weight has an enhanced ability to cross the blood–brain barrier, or ◦ whereas compounds with a high molecular weight (for example: vancomycin) penetrate poorly, even in the presence of meningeal inflammation. 17 3. Protein binding of a drug: ◦ A high degree of protein binding of a drug restricts its entry into the CSF. ◦ Therefore, the amount of free (unbound) drug in serum, rather than the total amount of drug present, is important for CSF penetration. 18 Multidrug-resistant organisms (MDROs) are bacteria or other microorganisms that have developed resistance to multiple classes of antibiotics or antimicrobial agents. This resistance makes infections caused by these organisms more difficult to treat. 9  E. Patient factors ◦ In selecting an antibiotic, attention must be paid to the condition of the patient. 1.Immune system: ◦ Elimination of infecting organisms from the body depends on an intact immune system, and the host defense system must ultimately eliminate the invading organisms. ◦ Alcoholism, diabetes, HIV infection, malnutrition, autoimmune diseases, pregnancy, or advanced age can affect a patient’s immunocompetence, as can immunosuppressive drugs. ◦ High doses of bactericidal agents or longer courses of treatment may be required to eliminate these individuals' infective organisms. 19 2. Renal dysfunction:  Poor kidney function may cause accumulation of certain antibiotics.  Dosage adjustment prevents drug accumulation and therefore adverse effects.  Serum creatinine levels are frequently used as an index of renal function for adjustment of drug regimens. II 1,91 of serum levels of some antibiotics Serum creatinine levels are  However, direct monitoring often measured to assess how  (for example, vancomycin, aminoglycosides) is preferred to identify well the kidneys are working.  maximum and/or minimum values to prevent potential toxicities. These levels help doctors adjust medication dosages to ensure they are safe and effective for patients with varying kidney function. 20 10  3. Hepatic dysfunction: ◦ Antibiotics that are concentrated or eliminated by the liver (for example, erythromycin and 1751066 doxycycline) must be used with caution when treating patients with liver dysfunction. joy 4. Poor perfusion: ◦ Decreased circulation to an anatomic area, such as the lower limbs of a diabetic patient, reduces the amount of antibiotic that reaches that area, making these infections difficult to treat. 21 5. Age: ◦ Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides. ◦ Young children should not be treated with tetracyclines or quinolones, which affect bone growth and joints, respectively. ◦ Elderly patients may have decreased renal or liver function, which may alter the pharmacokinetics of certain antibiotics. 22 11  6. Pregnancy and lactation: ◦ Many antibiotics cross the placental barrier 8 D or enter the nursing infant via breast milk. 23 7. Risk factors for multidrug-resistant organisms: ◦ Infections with multidrug-resistant pathogens need broader antibiotic coverage when initiating empiric therapy. 24 12  F. Safety of the agent ◦ Antibiotics such as the penicillins are among the least toxic of all drugs because they interfere with a site or function unique to the growth of microorganisms. ◦ Other antimicrobial agents (for example, chloramphenicol) have less specificity and are reserved for life-threatening infections because of the potential for serious toxicity to the patient. ◦ [Note: Safety is related not only to the inherent nature of the of the drug but also to patient factors that can predispose to toxicity.] 25 G. Cost of therapy ◦ Often several drugs may show similar efficacy in treating an infection but vary widely in cost. For example, treatment of methicillin-resistant Staphylococcus aureus (MRSA) generally includes one of the following: ◦ vancomycin, clindamycin, daptomycin, or linezolid. ◦ Although choice of therapy usually centers on the  Site of infection  Severity of the illness  Ability to take oral medications  It is also important to consider the cost of the medication. 26 13 ROUTE OF ADMINISTRATION ◦ The oral route of administration is appropriate for mild infections that can be treated on an outpatient basis. ◦ In hospitalized patients requiring intravenous therapy initially, the switch to oral agents should occur as soon as possible. ◦ However, some antibiotics, such as vancomycin, the aminoglycosides, and amphotericin B are so poorly absorbed from the gastrointestinal (GI) tract that adequate serum levels cannot be obtained by oral administration. ◦ Parenteral administration is used for drugs that are poorly absorbed from the GI tract and for treatment of patients with serious infections. 35 IV. DETERMINANTS OF RATIONAL DOSING ◦ Rational dosing of antimicrobial agents is based on: 1. Their pharmacodynamics (the relationship of drug concentrations to antimicrobial effects) 2. Pharmacokinetic properties (the absorption, distribution, metabolism, and elimination of the drug). ◦ Three important properties that have a significant influence on the frequency of dosing are 1. Concentration dependent killing 2. Time-dependent killing 3. Post antibiotic effect (PAE) 36 18  A. Concentration-dependent killing ◦ Certain antimicrobial agents, including aminoglycosides and daptomycin, show a significant increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug for the infecting organism 37 B. Time-dependent (concentration-independent) killing ◦ In contrast, β-lactams, glycopeptides, macrolides, clindamycin, and linezolid do not exhibit concentration-dependent killing). ◦ The clinical efficacy of these antimicrobials is best predicted by the percentage of time that blood concentrations of a drug remain above the MIC. 38 19  C. Post antibiotic effect ◦ The PAE is a persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC. ◦ Antimicrobial drugs exhibiting a long PAE (for example, aminoglycosides and fluoroquinolones) often require only one dose per day, particularly against gram negative bacteria. 39 A. Narrow-spectrum antibiotics ◦ Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum. ◦ For example, isoniazid is active only against Mycobacterium tuberculosis 40 20  B. Extended-spectrum antibiotics ◦ Extended spectrum is the term applied to antibiotics that are modified to be effective against gram-positive organisms and fear also against a significant number of gram-negative bacteria. 41 C. Broad-spectrum antibiotics ◦ Drugs such as tetracycline, fluoroquinolones and carbapenems affect a wide variety of microbial species and are referred to as broad-spectrum antibiotics 42 21  VI. SINGLE VS COMBINATIONS OF ANTIMICROBIAL DRUGS ◦ It is therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism. ◦ This strategy  Reduces the possibility of superinfections  Decreases the emergence of resistant organisms  Minimizes toxicity. ◦ However, some situations require combinations of antimicrobial drugs ◦ For example, the treatment of tuberculosis benefits from drug combinations. 43 A. Advantages of drug combinations ooo ◦ Certain combinations of antibiotics, such as β-lactams and aminoglycosides, show synergism; that is, the combination is more effective than either of the drugs used separately. ◦ Addition effect: ◦ Drug A activity 30% + Drug B activity 20% = 50% ◦ Synergistic effect: ◦ Drug A activity 30% + Drug B activity 20% = 80% 44 22 B. Disadvantages of drug combinations ◦ A number of antibiotics act only when organisms are multiplying. ◦ Thus, coadministration of an agent that causes bacteriostasis plus a second agent that is bactericidal may result in the first drug interfering with the action of the second. ◦ For example, bacteriostatic tetracycline drugs may interfere with the bactericidal effects of penicillins and cephalosporins. 45 Us to aid fix w pig DRUG RESISTANCE ◦ Bacteria are considered resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth. ◦ Some organisms are inherently resistant to an antibiotic. ◦ For example, ◦ most gram-negative organisms are inherently resistant to vancomycin. 46 23 A. Genetic alterations leading to drug resistance ◦ Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic information. ◦ Resistance develops due to the ability of DNA to undergo spontaneous mutation or to the resistance moves from one organism to another 47 48 24  B. Altered expression of proteins in drug-resistant organisms ◦ Drug resistance is mediated by a variety of mechanisms, such as  Alteration in an antibiotic target site  Lowered penetrability of the drug due to decreased permeability  Increased efflux of the drug  Presence of antibiotic-inactivating enzymes 49 1. Modification of target sites: ◦ Alteration of an antibiotic’s target site through mutation can confer resistance to one or more related antibiotics. ◦ For example, S. pneumoniae resistance to β-lactam antibiotics involves alterations in one or more of the major bacterial penicillin-binding proteins, resulting in decreased binding of the antibiotic to its target. 50 25  2. Decreased accumulation: ◦ Decreased uptake or increased efflux of an antibiotic can confer resistance because the drug is unable to attain access to the site of its action in sufficient concentrations to injure or kill the organism. ◦ For example, gram-negative organisms can limit the penetration of certain agents, including β-lactam antibiotics, as a result of:  an alteration in the number and structure of porins (channels) in the outer membrane.  Also, the presence of an efflux pump can limit levels of a drug in an organism, as seen with tetracyclines. 51 3. Enzymatic inactivation: ◦ The ability to destroy or inactivate the antimicrobial agent can also confer resistance on microorganisms. ◦ Examples of antibiotic-inactivating enzymes include 1) β-lactamases (“penicillinases”) that hydrolytically inactivate the β-lactam ring of penicillins, cephalosporins, and related drugs 2) Acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides; 3) Esterases that hydrolyze the lactone ring of macrolides. 52 26 PROPHYLACTIC USE OF ANTIBIOTICS ◦ Certain clinical situations, such as dental procedures and surgeries, require the use of antibiotics for the prevention rather than for the treatment of infections ◦ The duration of prophylaxis should be closely observed to prevent the unnecessary development of antibiotic resistance. 53 COMPLICATIONS OF ANTIBIOTIC THERAPY ◦ Even though antibiotics are selectively toxic to an invading organism, it does not protect the host against adverse effects. For example, ◦ the drug may produce an allergic response or may be toxic in ways unrelated to the antimicrobial activity. 54 27  A. Hypersensitivity ◦ Hypersensitivity or immune reactions to antimicrobial drugs or their metabolic products frequently occur. ◦ For example, the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from urticaria (hives) to anaphylactic shock. Patients should never be rechallenged. 55 Direct toxicity ◦ High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. ◦ For example, aminoglycoside can cause ototoxicity by interfering with membrane function in the auditory hair cells. 56 28  C. Superinfections ◦ Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents, can lead to alterations of the normal microbial flora of the upper respiratory, oral, intestinal, and genitourinary tracts, ◦ Permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. ◦ These infections usually require secondary treatments using specific anti-infective agents. 57 X. SITES OF ANTIMICROBIAL ACTIONS ◦ Antimicrobial drugs can be classified in a number of ways: ◦ 1) Their chemical structure (for example, β-lactams or aminoglycosides), 58 29  ◦ 2) Their mechanism of action 59 3) Their activity against particular types of organisms ◦ for example, bacteria infection 60 30 Fungal infection 61 viral infection 62 31