Basic Pharmacology Mod 5: Introduction to Chemotherapy of Infectious Diseases PDF

BASIC PHARMACOLOGY 09/04/2024. MOD 5: INTRODUCTION TO CHEMOTHERAPY OF INFEC...

BASIC PHARMACOLOGY 09/04/2024. MOD 5: INTRODUCTION TO CHEMOTHERAPY OF INFECTIOUS DISEASES Deo L. Panganiban MD FPSECP Trans Group: 6A I. GENERAL CONCEPTS AND PRINCIPLES IN THE 1. TRANSMISSION CHEMOTHERAPY OF INFECTIOUS DISEASE The passing of a communicable disease pathogen Antimicrobial agents are among the most commonly from an infected individual or a group to another used and misused of all drugs. individual or groups regardless of a previous infection The inevitable consequence of the widespread use of antimicrobial agents has seen the emergence of 2. ACQUISITION antibiotic resistant pathogens, fueling an ever increasing need for new drugs. The communicable disease may be acquired through a However, the base of antimicrobial drug development portal of entry: has slowed down dramatically, with only a handful of ○ Contact new and novel agents being introduced into clinical ○ Inhalation practice each year. ○ Common vehicle — like shared fomites Reducing inappropriate antibiotic use is thought to be ○ Vector-borne the best way to control resistance. Although awareness of the consequences of antibiotic 3. PATIENT INFORMATION misuse is increasing, overprescribing remains widespread. Age, Gender, Place of residence ○ Driven largely by patient demand, time pressure on Family and personal contact clinicians, and diagnostic uncertainty. Occupation, hobbies If in the case of the treatment of infectious disease are Contact with animals to be preserved, clinicians must be wiser and more Travel history selective in the use of antimicrobial agents. Dietary habits II. DEFINITION AND CHARACTERISTICS 3.1 Age An important determinant of antimicrobial drug A. CHEMOTHERAPEUTIC AGENTS pharmacokinetics Chemical agents or drugs that are selectively toxic to Mechanisms of elimination, especially renal excretion the causative agent of the disease such as a virus, and hepatic biotransformation, are poorly developed in bacterium or other microorganisms. the newborn → especially the premature infant ○ Adjustments should be made in such patients B. ANTIBIOTICS Antimicrobials 3.1.1 Elderly patients Antibacterial substances produced by various species of microorganisms like bacteria, fungi, and actinomycetes Clear drugs eliminated by the kidneys are poor because that suppress the growth of other microorganisms. of reduced creatinine clearance. Common usage often extends the term antibiotics to May also metabolize drugs less rapidly, predisposing include synthetic antimicrobial agents (e.g., them to elevated and potentially toxic concentrations of sulfonamides and quinolones) drugs compared to younger patients. Antibiotics differ markedly in physical, chemical, and More likely to suffer toxicity of otherwise safe pharmacological properties in the antimicrobial spectrum concentrations of drugs, as is the case of and in mechanisms of action. aminoglycoside induced ototoxicity. Knowledge of molecular mechanisms of bacterial replication has greatly facilitated rational development of 3.1.2 Developmental factors compounds that can interfere with their replication. May also determine the type of untoward response to Includes antibacterials, antifungal, antiviral, and a drug antiparasitic drugs Tetracyclines bind avidly to developing teeth and bones ○ Antiparasitic drugs may be antimalarial, ○ Their use in young children can result in retardation anthelmintic, and amebicidal of bone growth and discoloration or hypoplasia of tooth enamel. C. ANTISEPTIC Kernicterus may follow the use of sulfonamides in newborn infants. D. DISINFECTANT 3.1.3 Genetic factors III. FACTORS INVOLVED IN AN INFECTIOUS PROCESS May influence the choice of drug, or drugs used to treat Must be considered when prescribing antibiotics a disease condition. A number of drugs (i.e. sulfonamides, nitrofurantoin, chloramphenicol and nalidixic acid) may produce acute A. EPIDEMIOLOGIC CONSIDERATIONS hemolysis with G6PD deficiency Patients who acetylate isoniazid rapidly may have sub-therapeutic concentration of the drug in the plasma Pharmacology - Mod 5 Introduction to Chemotherapy of Infectious Diseases 1 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Host defenses are Host defenses are 3.2 Gender INTACT & ACTIVE IMPAIRED Females: pregnancy may impose an increased risk of reactions to antimicrobial agents for both mother and A minimum inhibitory Antibiotic-mediated fetus effect such as that killing (e.g. bactericidal ○ Hearing loss in children has been associated with provided by bacteriostatic effect) may be required to administration of streptomycin to the mother agents may be sufficient. eradicate the infection. during pregnancy. ○ Tetracycline may affect the bones and teeth of the The concentration of drugs at the site of infection not fetus. only inhibit the organism, but also remain below the ○ Pregnant women receiving tetracycline may level that is toxic to human cells. develop fatal acute fatty block necrosis of the ○ If this can be achieved, the microorganism is liver resulting in pancreatitis and associated renal considered susceptible to the antibiotic. damage. If an inhibitory or bactericidal concentration exceeds ○ Pregnancy may also affect the pharmacokinetics that which can be achieved safely in vivo, then the of various antibiotics. microorganism is considered resistant to that drug. ○ Lactating females can pass antimicrobial agents through their milk to their lactating child. 1. HOST FACTORS 1.1 General Health 3.3 Drug Allergies Healthy vs. Immunocompromised Antibiotics, especially beta-lactams, are notorious in provoking allergic reactions. 1.2 Age Patients with a history of atopy are seen particularly susceptible to the development of these reactions. Young and Elderly Sulfonamides, Trimethoprim, Nitrofurantoin, and Erythromycin are also associated with hypersensitivity 1.3 Genetic reactions, especially rashes. A history of anaphylaxis or hives and laryngeal Hypogammaglobulinemia edema precludes the use of the drugs in all but extreme life threatening situations (especially penicillins may be 1.4 Concurrent Diseases of value in predicting life threatening reactions). Seizures Antimicrobial drugs can cause drug fevers which can ○ Patients predisposed to seizures are at risk for be mistaken for a sign of infection. local or major motor seizures while taking doses of Penicillin G. 3.4 Travel history ○ This neurotoxicity of Penicillin G and other Can determine whether the individual or groups came beta-lactam antibiotics correlates with high from a place where infection occurred concentration of the drug in the CSF. May reveal certain infections that are communicated ○ Typically occurs in patients with impaired renal through traveling in endemic areas function who are given large doses of the drugs. Diabetes: diabetics and HIV infected patients who are prone to neuropathy because of their underlying B. INFECTIVITY diseases Microorganism’s ability to cause an infection Alcoholics who are often malnourished are also predisposed C. VIRULENCE FACTORS Obstruction (e.g., stones) Toxins, adherence factors Foreign body (e.g., urinary catheter, prosthetic heart The relative capacity of a pathogen (i.e. bacteria or valves) virus) to overcome the host’s defenses to cause the infection or disease 1.5 Local Factors Degree of pathogenicity of a causative agent The cure of an infection with antibiotics depends on an D. HOST FACTORS understanding of how local factors at the site of Aspects that are inherent to the potential host that infection affect the antimicrobial activity of the drug. separates an individual apart from others in the context Antimicrobial activity may be significantly reduced in of contracting an infectious disease pus ○ Contains phagocytes, cellular debris, and proteins IV. FACTORS WHICH DETERMINE SUSCEPTIBILITY that can bind drugs or create conditions Successful antimicrobial therapy of an infection unfavorable to drug action ultimately depends on the concentration of antibiotic at Low pH characteristic of the fluid in abscesses and in the site of infection. other confined, affected or infected sites like pleural These concentrations must be sufficient to inhibit space, CSF, and urine, as well as anaerobic conditions growth of the offending microorganism. can reduce the antimicrobial activity of some agents ○ Abscess → acid pH → impaired circulation A. HOST B. INFECTING ORGANISM ACTIVE VS. IMPAIRED HOST DEFENSES SUSCEPTIBILITY FACTORS RELATING TO THE INFECTING ORGANISM Pharmacology - Mod 5 🏠 Introduction to Chemotherapy of Infectious Diseases 2 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Excretion: the process by which drugs are eliminated Is the infecting organism from the body, most commonly through the kidneys Location intracellular or extracellular? (other sites: lungs, skin, GIT) Bacterial Cell Is the bacterial cell permeable to 1.7.1 Location of Infection Permeability antibiotics? May dictate the choice of drug and the route of Ability to Produce Does the bacteria have the administration Inactivating ability to produce inactivating Enzymes enzymes? (e.g. β-lactamase) 1.7.2 Minimal Drug Concentration achieved at the Infected Site Is the antimicrobial highly bound Affinity to Binding Should be approximately equal to the MIC (minimum to binding sites or target cells Sites inhibitory concentration) for the infecting organism within the bacteria? It is advisable to achieve multiples of this concentration if possible in most instances C. ANTIMICROBIAL DRUG HIGH MIC: higher concentration of the drug is needed to inhibit the growth of a specific bacteria 1. FACTORS RELATING TO ANTIMICROBIAL DRUGS LOW MIC: better drug efficacy against a specific bacteria 1.1 Concentration at Site of Action 1.7.3 Aim of Antimicrobial therapy Success of the antimicrobial therapy of an infection Produce antibacterial concentration of drug at the site depends on the concentration at the site of infection of infection during the dosing interval Involves looking at the correct dose, correct frequency, Achieved ONLY if the pharmacokinetic and and appropriate route of administration pharmacodynamic principles presented are satisfied 1.2 Dosing Interval V. CLASSIFICATIONS OF ANTIMICROBIAL DRUG Time between administration of consecutive doses Ensures that the drug remains at therapeutic levels A. BASED ON MECHANISM OF ACTION without causing toxicity or reducing effectiveness Determined by the drugs pharmacokinetics and the 1. INHIBITION OF CELL WALL SYNTHESIS disease being treated ANTIMICROBIALS THAT INHIBIT CELL WALL 1.3 Dosing Frequency SYNTHESIS How often a drug is administered over a specific period of time LACTAM CLASS OTHER CELL WALL E.g., once a day, twice a day, every 8 hours (BETA-LACTAMS) AGENTS 1.4 Appropriate Duration of Treatment Penicillins Cycloserine Cephalosporins Vancomycin Usually 5 to 10 days Carbapenems Bacitracin 1.5 Culture and Sensitivity Test 2. INHIBITION OF RIBOSOMAL PROTEIN SYNTHESIS This should be done before giving treatment to see (30S OR 50S RIBOSOMAL SITES) and identify the infecting organism. ANTIMICROBIALS THAT INHIBIT RIBOSOMAL 1.6 Static vs. Cidal PROTEIN SYNTHESIS In vitro activity (although critical) is only a guide whether an antibiotic is likely to be effective for an DISRUPTS 30s and 50s BINDS TO 30s SUBUNIT infection. RIBOSOME SUBUNITS Successful therapy depends on achieving a drug concentration sufficient to inhibit or kill bacteria at Generally bacteriostatic Generally bactericidal the site of the infection without harming the patient ○ To accomplish this therapeutic goal, several Reversibly inhibits protein Alters protein synthesis pharmacokinetic and host factors must be synthesis evaluated. Examples: Examples: 1.7 Pharmacokinetic Chloramphenicol Aminoglycosides Tetracyclines Lincosamides Absorption: movement of the drug into the bloodstream Erythromycins Macrolides after administration (affects bioavailability) Clindamycin Fusidic acid Distribution → blood brain barrier, placental barrier Streptogramin ○ Efficacy and toxicity depends on distribution to Linezolid tissues ○ Protein binding Metabolism: transformation of a drug or any 3. INHIBITION OF NUCLEIC ACID SYNTHESIS pharmaceutical agent such that their elimination or excretion is improved There may be agents that affect bacterial nucleic acid metabolism such as Rifamycins Pharmacology - Mod 5 🏠 Introduction to Chemotherapy of Infectious Diseases 3 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Examples: ○ Rifampin and Rifabutin, which inhibit RNA Examples: Examples: polymerase Aminoglycosides Beta-lactams ○ Quinolones which inhibit topoisomerases Fluoroquinolones Vancomycin ○ Rifampicin ○ Fluoroquinolones VI. EMPIRIC THERAPY ○ Metronidazole Giving antimicrobial before actual identification or isolation of infecting microorganism. 4. INHIBITION OF CELL MEMBRANE FUNCTION Usually, the choice is based on epidemiologic data. Agents that act directly on the cell membrane of the E.g., community-acquired pneumonia, UTI microorganisms, increasing permeability and leading to The most common reason for using combination of leakage of intracellular compounds including detergents antimicrobials such as polymyxin and polyene antifungal agents Knowledge on the types of infections, microbiology, and Examples: spectrum of activity of several potentially useful ○ Nystatin and Amphotericin B, which bind to cell antimicrobial agents is very essential in the selection of wall sterols the rational and effective regimen ○ Daptomycin, a lipopeptide BROAD SPECTRUM antibiotics: drugs given initially ○ Polypeptides during severe illness and uncertain with the causative ○ Imidazoles agent. ○ Polyene Antibiotics More than one agent may be required to ensure that the regimen includes a drug that is active against the 5. ANTIMICROBIALS WITH ANTIMETABOLITE ACTIVITY potential pathogen PROLONGED administration of empirical broad There may be antimicrobials with antimetabolite activity spectrum antibiotics or multiple antibiotic therapy should Trimethoprim and sulfonamides block enzymes of be avoided. folate metabolites. ○ May result to toxicity, superinfection and production of multi-resistant pathogens B. BASED ON MODE OF ACTION Inappropriate broad coverage should be discontinued. They may be also classified according to mode of action whether they are bactericidal or bacteriostatic VII. SELECTIVE TOXICITY BacteriCIDAL: agents capable of KILLING the bacteria Ultimate goal when administering a drug. with a known mechanism of action As much as possible, avoid the side or adverse BacterioSTATIC: agents capable of INHIBITING the effects usually seen with antimicrobial treatment. further growth of the bacteria Ability of the drug to kill the invading microorganism without harming the host cells. Drugs are intended to selectively affect processes in CLASSIFICATIONS OF ANTIMICROBIAL DRUGS the microbial cells without affecting counterpart BASED ON MODE OF ACTION processes in mammalian cells. EXAMPLES: CIDAL PRIMARILY STATIC ○ Chloramphenicol – affects 70S ribosomes (Bactericidal) (Bacteriostatic) ○ Sulfonamides – inhibit bacterial FA synthesis Beta-Lactams Chloramphenicol VIII. POST ANTIBIOTIC EFFECT (PAE) Aminoglycosides Macrolides Vancomycin Sulfonamides Persistent suppression of bacterial growth even after Polypeptides Ethambutol limited exposure to the antimicrobial Metronidazole Lincosamides Mechanisms: Quinolones Tetracyclines ○ Post-antibiotic leukocyte enhancement Rifampicin Trimethoprim ○ Subinhibitory concentration may make bacteria Isoniazid more susceptible to phagocytic and bactericidal action of neutrophils 1. BACTERICIDAL DRUGS IX. PROPHYLAXIS The prophylaxis of infections with antimicrobial agents. 2 GROUPS OF BACTERICIDAL DRUGS A. CHEMOPROPHYLAXIS CONCENTRATION TIME DEPENDENT Giving of antimicrobial drug to a healthy person DEPENDENT KILLING KILLING exposed to an infectious agent to prevent that person from acquiring the infection Examples: Rate and extent of killing Increasing concentration ○ Rifampicin for Meningococcemia increases with increasing above MBC does NOT ○ Rifampicin + Isoniazid for Tuberculosis drug concentration. result in killing. Highly effective in some clinical setting ○ it may also account for some of the most flagrant Ratio of the AUC to the Killing continues as long as misuses of antimicrobials and is totally without MIC (AUC/MIC) correlates concentration is above value and may even be deleterious. best with efficacy. MBC. Recommended for patients with valvular or other structural lesions of the heart predisposing to NO post antibiotic effect. endocarditis who are undergoing gentle, surgical, or other procedures that produce a high incidence of bacteremia Pharmacology - Mod 5 🏠 Introduction to Chemotherapy of Infectious Diseases 4 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Use of antimicrobial compounds to prevent infections remains controversial in numerous situations: SYNERGY Enhanced effect. Shown to have better effects than single agent therapy in SUCCESSFUL FAILED relatively few infections for CHEMOPROPHYLAXIS CHEMOPROPHYLAXIS empirical therapy in which the cause is not known A single effective non-toxic if the aim of prophylaxis is Penicillin + aminoglycoside drug is used to: to prevent colonization or for Pseudomonas Prevent infection by infection by any or all a specific microorganisms present EXTENDED Trimethoprim + microorganism in the environment ANTIMICROBIAL sulfamethoxazole OR Eradicate an early SPECTRUM Amoxicillin + Clavulanic acid infection Intermittent use PREVENTS urinary tract infection caused by E. Coli B. PROPHYLAXIS May be used to protect healthy persons from PREVENTION OF Empirical therapy infection is acquisition or invasion by specific microorganisms RESISTANCE the most common reason for to which they are exposed the combination of antibiotics. Knowledge of the type of SUCCESSFUL EXAMPLES OF PROPHYLAXIS infection, microbiology, and spectrum of activity of the 1 Rifampin administration to prevent meningococcal several potentially useful meningitis in people who are in close contact with a antimicrobial agents is essential case. for the selection of rational and effective antimicrobials 2 Prevention of gonorrhea or syphilis after close Avoid prolonged administration contact with an infected person and intermittent use of of empirical broad spectrum trimethoprim-sulfamethoxazole to prevent recurrent coverage or multiple antibiotics urinary tract infections usually caused by E. coli. → often unnecessary and expensive 3 Antimicrobial prophylaxis often with oral Reluctance to change fluoroquinolone is used to prevent a variety of antimicrobial agents is infections in patients undergoing organ understandable when a transplantation or receiving cancer chemotherapy. favorable clinical response has occurred 1. SURGICAL PROPHYLAXIS ○ The goal should be to use the most selectively Prevent infectious complications in surgically active drug that produces traumatized areas such as bowel surgery, and the fewest adverse ruptured acute appendicitis. effects ○ Including adverse effects 2. IMMUNOPROPHYLAXIS on the hosts normal flora Use of vaccines E.g., Rifampicin + Isoniazid TREATMENT OF Treatment of polymicrobial PASSIVE Immediate protection MIXED infections INFECTION E.g., Intra-abdominal ACTIVE Long term protection infection Also for hepatic and brain X. ANTIMICROBIAL COMBINATION abscesses and some genital The simultaneous use of 2 or more antimicrobial tract infections agents is recommended in specifically defined May require the use of a drug situations based on pharmacological rationale. combination to eradicate this However, selection of an appropriate combination typically mixed aerobic and requires understanding the potential for interactions anaerobic infections between the antimicrobial agents. These and other mixed Interactions may affect either the microorganism or the infections may be caused by patient. two or more microorganisms Antimicrobial agents acting at different targets may that are sufficiently different in enhance or impair overall antimicrobial activity. antimicrobial susceptibility such A combination of drugs also may have additive or that no single agent can provide super additive toxicities. required coverage ○ Vancomycin (alone) → minimal nephrotoxicity ○ Vancomycin + aminoglycoside → toxicity of DECREASED E.g., Aminoglycosides + aminoglycoside increases DRUG TOXICITY Penicillin ANTIMICROBIAL COMBINATIONS Pharmacology - Mod 5 🏠 Introduction to Chemotherapy of Infectious Diseases 5 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  XI. MECHANISMS OF RESISTANCE 1.3 Bacitracin The recent emergence of antibiotic resistance in Disrupts movement of peptidoglycan precursors bacterial pathogens both commonly and in the (topical use) community is a very serious development that threatens Resistance: fails to penetrate into cell the end of the antibiotic era. The rampant spread of antibiotic resistance mandates a 1.4 Antimycobacterial Agents more responsible approach to antibiotic use. The Centers for Disease Control and Prevention has Disrupts mycolic acid or arabinoglycan synthesis outlined a series of steps to prevent or diminish Resistance antimicrobial resistance. Important components include: ○ Reduced uptake ○ Appropriate use of vaccination, judicious use, ○ Alteration of target sites and proper attention to indwelling catheters ○ Early involvement of infectious disease experts 2. ALTERATION OF CELL WALL SYNTHESIS ○ Choosing antibiotic therapy based on local patterns of susceptibility of organisms 2.1 Polymyxins (Topical) ○ Proper antiseptic techniques to ensure infection Cationic detergent-like activity (topical use) control rather than contamination Resistance: inability to penetrate outer membrane ○ Appropriate use of prophylactic antibiotics in surgical procedures 2.2 Bacitracin (Topical) ○ Infection control procedures to isolate the pathogen Disrupt cytoplasmic membranes ○ Strict compliance to hand hygiene Resistance: inability to penetrate outer membrane EXAMPLES OF MECHANISMS OF RESISTANCE 3. INHIBITION OF PROTEIN SYNTHESIS (TRANSLATION) 3.1 30s Ribosome Site Enzymatic inactivation Beta-lactams, or modification Aminoglycosides 3.1.1 Aminoglycosides Altered target site: Methicillin-resistant decreased affinity of the Staphylococci (MRSA) Irreversibly bind 30S ribosomal proteins antibiotic to the bacteria (bactericidal) Resistance Altered permeability of Beta-lactams ○ Mutation of ribosomal binding site bacterial cell wall Fluoroquinolones ○ Decreased uptake ○ Enzymatic modification of antibiotic An alternate pathway Sulfonamides by-passing Trimethoprim 3.1.1 Tetracyclines antimicrobial action Block tRNA binding to 30S ribosome-mRNA complex (bacteriostatic) For an antibiotic to be effective, it must reach its target in Resistance active form, bind to the target, and interfere with its ○ Mutation of ribosomal binding site function. ○ Decreased penetration Bacterial resistance to an antimicrobial agent is ○ Active efflux of antibiotic out of cell attributable to the general mechanisms as provided: ○ Protection of 30S ribosome ○ When the drug does not reach its target ○ The target is not active 3.2 50s Ribosome Site ○ The target is altered 3.2.1 Chloramphenicol A. FIVE BASIC MECHANISMS OF ANTIBIOTIC ACTION Binds peptidyl transferase component of 50S AGAINST BACTERIAL CELLS ribosome, blocking peptide elongation (bacteriostatic) Resistance 1. INHIBITION OF CELL WALL SYNTHESIS ○ Plasmid-encoded chloramphenicol transferase 1.1 Beta-Lactams ○ Altered outer membrane (chromosomal mutations) Inhibition of peptidoglycan synthesis (bactericidal) 3.2.2 Macrolides Resistance ○ Fails to cross the membrane (gram negatives) Reversibly bind 50S ribosome, block peptide ○ Fails to bind to altered PBPs elongation (bacteriostatic) ○ Hydrolysis of beta-lactamases Resistance ○ Methylation of 23S ribosomal RNA subunit 1.2 Vancomycin ○ Enzymatic cleavage (erythromycin esterase) ○ Active efflux Disrupts peptidoglycan cross-linkage Resistance 3.2.3 Clindamycin ○ Fails to cross gram negative outer membrane (too large) Bind 50S ribosome, blocks peptide elongation ○ Some intrinsically resistance (pentapeptide Inhibits peptidyl transferase by interferon with binding terminus) of amino acid-acyl-tRNA complex Resistance: methylation of 23S ribosomal RNA subunit Pharmacology - Mod 5 🏠 Introduction to Chemotherapy of Infectious Diseases 6 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 4. INHIBITION OF NUCLEIC ACID SYNTHESIS Bone and tooth malformation Inhibit antibody production 4.1 DNA Effects Respiratory paralysis Life threatening Seizures 4.1.1 Quinolones Inhibit DNA gyrases of topoisomerases required for XIII. MISUSE OF ANTIBIOTICS supercoiling of DNA; bind to alpha subunit Resistance A. TREATMENT OF NONRESPONSIVE INFECTIONS ○ Alteration of alpha subunit of DNA gyrase A common misuse of these agents is in infections that (chromosomal) have been proven by experimental and clinical ○ Decreased uptake by alteration of porins observation to be nonresponsive to treatment with (chromosomal) antimicrobial agents. Most of the diseases caused by viruses are self-limited 4.1.2 Metronidazol and do not respond to any of the currently available anti-infective compounds. Metabolic cytotoxic byproducts disrupt DNA Antimicrobial therapy of measles, mumps, and at least Resistance 90% of infections in the upper respiratory tract, and ○ Decreased uptake many gastrointestinal infections are ineffective and ○ Elimination of toxic compounds before they interact useless. 4.2 RNA Effects B. THERAPY OF FEVER OF UNKNOWN ORIGIN 4.2.1 Rifampin Fever of undetermined causes may persist for only a few days to a week or for a longer period. Binds to DNA-dependent RNA polymerase, inhibiting Both of these are treated frequently and initiation & Rifabutin of RNA synthesis inappropriately with empirical antimicrobial agents. Resistance Physicians should search for its cause. ○ Altered of beta subunit of RNA polymerase (chromosomal) ○ Intrinsic resistance in gram negatives (decreased TYPES OF FEVER uptake) SHORT DURATION WITH 4.2.2 Bacitracin (Topical) ABSENCE OF UNKNOWN ORIGIN LOCALIZING SIGNS Inhibits RNA transcription Resistance: inability to penetrate outer membrane Associated with undefined Persist for only a few days viral infections to 2 weeks or for a longer 5. ANTIMETABOLITE ACTIVITY period 5.1 Sulfonamides & Dapsone Antimicrobial therapy is Treated frequently with unnecessary empirical antimicrobial 5.2 Trimethoprim agents Recovery is spontaneous Has variety of causes with 5.3 Trimethoprim-Sulfamethoxazole Synergism occuring in a week or less only 1⁄4 caused by infections XII. ADVERSE EFFECTS OF ANTIBIOTICS C. IMPROPER DOSAGE A. HYPERSENSITIVITY REACTION Dosing error or the wrong frequency of e.g. Beta-Lactams and sulfonamides administration. Use of excessive or subtherapeutic doses are B. BIOLOGIC common. Alteration of normal flora producing: Although antimicrobial drugs are among the safest and ○ Superinfection/Suprainfection (e.g. Candidiasis) least toxic of drugs, excessive amounts will still result ○ Antibiotic-associated Enterocolitis (e.g. in toxicities. Ampicillin, Tetracyclines, Clindamycin/Lincomycin) Patients with impaired drug excretion or metabolism must be taken into consideration. C. DIRECT TOXIC EFFECTS Too low a dose may result in treatment failure and may result in microbial resistance. Abdominal discomfort D. INAPPROPRIATE RELIANCE ON CHEMOTHERAPY Nausea and vomiting ALONE Unpleasant Tooth discoloration Infections complicated by abscess formation, the Dizziness presence of necrotic tissue, or presence of a foreign Diarrhea body cannot be cured by antimicrobial therapy alone. Hearing loss Severe Nephrotoxicity Pharmacology - Mod 5 🏠 Introduction to Chemotherapy of Infectious Diseases 7 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Tuberculosis and disseminated fungal infections may require treatment with antimicrobial agents that are not used only in bacterial infections. Occult abscesses may require surgical drainage Prolonged use of pathogen specific therapy as in the case of bacterial endocarditis. Inappropriately administered antimicrobial therapy may mask underlying infections, delay the diagnosis and by rendering cultures negative, prevent identification of the infectious pathogen. Non-infectious causes (i.e. lymphoma, renal cell carcinoma, otitis, Collagen vascular disorders and drug fever) DO NOT respond to antimicrobial therapy Drainage, debridement, and removal of the foreign body are as important as the choice of antimicrobial agents. GENERAL RULE: when a feasible amount of quantity of pus, necrotic tissue, or foreign body is present, the most effective treatment is: ○ An antimicrobial agent given in adequate doses ○ Properly performed surgical procedure E. LACK OF ADEQUATE BACTERIOLOGICAL INFORMATION Antimicrobial therapy administered to hospitalized patients too often is given in the absence of supporting microbiological data. Bacterial cultures and gram stains of infected materials are obtained too infrequently. ○ Results when available are disregarded in the selection and application of drug therapy Frequent use of drug combinations or drugs that cover a broad spectrum is a cover for diagnostic imprecision. Agents are usually chosen by habit rather than for specific indications. Dosages employed are routine than individualized based on the clinical situation, microbiological information, and pharmacological considerations. Pharmacology - Mod 5 🏠 Introduction to Chemotherapy of Infectious Diseases 8 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.