Overview of Antimicrobial Therapy (Sulfonamide and Quinolone) PDF

Ove iew of antimicrobial therapy
Sulfonamide and quinolone PHAD301 Dr. Abdulhadi Burzangi 1 Objectives 1. Discuss the general concepts of antibacterial drugs which would ensure safety and e ectiveness to therapy. 2. List the di erent cl...

Ove iew of antimicrobial therapy
Sulfonamide and quinolone PHAD301 Dr. Abdulhadi Burzangi 1 Objectives 1. Discuss the general concepts of antibacterial drugs which would ensure safety and e ectiveness to therapy. 2. List the di erent classes of antimicrobial agents 3. Recognize the development of resistance to antibacterial agents and methods to limit it. 4. Discuss indications for drug combination and prophylactic use of antibacterial drugs. 5. Identify the mechanisms of action and indications of sulfonamides and uoroquinolones. 6. Mention the adverse e ects of sulfonamides and uoroquinolones. 2 Terms to know Antimicrobial drugs are e ective in the treatment of infections because of their selective toxicity; that is, they have the ability to injure or kill an invading microorganism without harming the cells of the host. Bacteriostatic versus bactericidal drugs. 3  Terms to know Susceptibility testing laborato methods to determine the sensitivity of the isolated pathogen to antimicrobial drugs. Antimicrobial prophylaxis the use of antimicrobial drugs to decrease the risk of infection. e.g. pretreatment of patients undergoing dental extractions who have implanted prosthetic devices, such as a i cial hea valves, prevents seeding of the prosthesis (Amoxicillin). Empiric (presumptive) initiation of drug treatment before identi cation of a speci c pathogen. antimicrobial therapy Combination antimicrobial the use of 2 or more drugs together to increase e cacy more than can drug therapy be accomplished with the use of a single drug. Minimum inhibito an estimate of the drug sensitivity of pathogen for comparison with concentration (MIC) anticipated levels in blood. Post antibiotic e ect Antibacterial e ect persists after drug concentration falls below the MIC. (e.g. Aminoglycoside) 4 Common Bacterial Pathogens for Select Sites of Infection 7 I. Selection of the most appropriate antimicrobial agent requires knowledge of 1) the identity of the organism, 2) the susceptibility of the organism to a pa icular agent, 3) the site of the infection, 4) patient factors, 5) the safety and e cacy of the agent, 6) the cost of therapy. However, most patients require empiric therapy (immediate administration of drug(s) prior to bacterial identi cation and susceptibility testing) 8 Chemotherapeutic spectra Narrow spectrum Extended spectrum Broad spectrum Antibiotics acting only on a single Antibiotics are e ective against Antibiotics a ect a wide variety or a limited group of gram-positive and some gram- of microbial species. microorganisms negative bacteria (e.g. E.g. carbapenems, tetracycline E.g. isoniazid is active only against ampicillin). and uoroquinolones. Mycobacterium tuberculosis. Side e ect: Superinfection 9 II. ree impo ant factors that have a signi cant in uence on the frequency of dosing: 1. Concentration-dependent killing 2. Time-dependent (concentration-independent) killing 3. Post antibiotic e ect (PAE): a persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below the MIC. Antimicrobial drugs exhibiting a long PAE (e.g. aminoglycosides and uoroquinolones) often require only one dose per day, pa icularly against gram-negative bacteria. Utilizing these proper ties may optimize antibiotic dosing regimens, improve clinical outcomes and possibly decrease the development of resistance. 10 Aminoglycosides β-lactams, glycopeptides, macrolides, clindamycin, and Linezolid 11 III. Complications of antibacterial therapy 1.Hypersensitivity Hypersensitivity or immune reactions to antimicrobial drugs or their metabolic products frequently occur. E.g. the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from u icaria to anaphylactic shock. 2. Direct toxicity Aminoglycosides can cause ototoxicity by inter fering with membrane function in the audito hair cells. ey can also induce nephrotoxicity in the form of acute tubular necrosis (ATN). 3. Superinfections Drug therapy, par ticularly with broad-spectrum antimicrobials or combinations of agents, can lead to alterations of the normal microbial f lora of the upper respirator y, oral, intestinal, and genitourinar ytracts, permitting the overgrowth of oppor tunistic organisms, especially fungi or resistant bacteria. 12 IV. Drug resistance mechanisms 1. Alterations of the target site through mutation (e.g. modi cation of the target enzyme, DNA gyrase, has resulted in resistance to uoroquinolones). 2. Decreased accumulation of an antibiotic (decrease its permeability/uptake and increase its e ux). 3. Enzymatic inactivation: Examples of antibiotics-inactivating enzymes include: 1- β-lactamases that inactivate the β-lactam ring of penicillin, cephalosporin, 2- Acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides. 3- Esterases that hydrolyze the lactone ring of macrolide. 13  V. Solutions to minimize antibiotic resistance Avoiding indiscriminate use by ensuring that the indication for, the dose and duration of treatment are appropriate. Using antimicrobial combinations, e.g. tuberculosis Constant monitoring of resistance patterns in a hospital or community (changing recommended antibiotics used for empirical treatment when the prevalence of resistance becomes high), Good infection control in hospitals (e.g. isolation of carriers, hand hygiene practices for ward sta ) to prevent the spread of resistant bacteria Restricting drug use, limiting the use of the newest member of a group of antimicrobials so long as the currently-used drugs are e ective. 14 VI. Antibiotic drug combinations Advantages: 1. To obtain synergism, the combination is more potent and e ective than either of the drugs used separately e.g. penicillin plus gentamicin for enterococcal endocarditis. 2. To avoid the development of drug resistance, especially in chronic infections where many bacteria are present, e.g. tuberculosis. 3. To broaden the spectrum of antibacterial activity in a known mixed infection, e.g. peritonitis following gut pe oration Disadvantage: A number of antibiotics act only when organisms are growing. us, combination of a bacteriostatic agent plus a bactericidal agent may result in drug inte ering the action of the second drug. e risk of the development of antibiotic resistance when giving unnecessa combination therapy. 15 VII. Prophylactic antibiotics Some clinical situations require the use of antibiotic for the prevention rather than the treatment of infections. Chemoprophylaxis in surge is justi ed when: o the risk of infection is high because of the presence of large numbers of bacteria in the viscus which is being operated on, e.g. the large bowel o the risk of infection is low but the consequences of infection would be disastrous, e.g. infection of prosthetic joints or prosthetic hear tvalves, or of abnormal hear tvalves following the transient bacteraemia of dentist. 16 
How do Antibacterial agents act? 17  Inhibitors of Essential Metabolites
(Sulfonamides) Folic acid antagonists: Inhibitors of bacterial folate synthesis (sulfonamides) Inhibitors of bacterial folate reduction (Trimethoprim) Inhibitors of synthesis and reduction (co-trimoxazole) 18 Sulfonamides mechanism of action; 19  erapeutic applications of Sulfonamides 1) Meningococcal infections 2) Urina tract infections. 3) Intestinal infections. 4) Ulcerative colitis: sulfasalazine: this is a combination of sulfapyridine and 5- aminosalicylic acid. It is not absorbed orally. It is split by intestinal microf lora to yield sulfapyridine and 5-aminosalicylate. 5) Local uses: sodium sulfacetamide: locally in the eye (trachoma), silver sulfadiazine for burns. 20 Sulfonamides adverse e ects 1. C stalluria 2. Hypersensitivity reactions such as rashes, angioedema and Stevens-Johnson syndrome 3. Hematopoietic disturbances (hemolytic anemia) 4. Kernicterus: sulfonamides can displace bilirubin from plasma protein binding sites. In the newborn, conjugation mechanisms are not adequate to inactivate the displaced bilirubin, and this may result in passage of the pigment across BBB and may cause kernicterus. 5. Drug interaction: sulfonamides displace drug from binding sites on serum albumin (e.g. sulfamethoxazole potentiate the anticoagulant e ect of wa arin) 21  Trimethoprim Trimethoprim exhibits antibacterial spectrum similar to the sulfonamides. However, it is a 20- to 50-fold more potent than the sulfonamides. Mecahnism of action: a potent inhibitor of bacterial dihydrofolate reductase. USE: Trimethoprim may be used alone in the treatment of UTIs and bacterial prostatitis Pharmacokinetics: It is a weak base, higher concentrations of trimethoprim are achieved in the relatively acidic prostatic and vaginal uids. Side Ef fects: Trimethoprim can produce the ef fects of folic acid def iciency. T hese ef fects include megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those having ver ypoor diets. T hese blood disorders may be reversed by the simultaneous administration of folinic acid, which does not enter bacteria. 22  CO-TRIMOXAZOLE Co-trimoxazole, is a combination of trimethoprim and sulfamethoxazole in the ratio of 1:5 Mechanism of action? Trimethoprim results in a marked (synergism) of the activity of sulfonamides. Combinations of trimethoprim with sulfonamides have potent bactericidal prope ies. Sulfamethoxazole is of par ti cular interest because it has similar absorption pharmacokinetics to trimethoprim. 23 Typical therapeutic applications of Cotrimoxazole 24  Inhibitors of Bacterial DNA Replication ( uoroquinolones) 25 Fluoroquinolones generations Adapted from Owens RC Jr, Ambrose PG. Clinical use of the 26 fluoroquinolones. Med Clin North Am 2000;84:1447–69 Mechanism of action Fluoroquinolones enter bacteria through porin channels and inter fere with bacterial DNA synthesis. ey exhibit antimicrobial e ects on DNA gyrase (bacterial topoisomerase II) and bacterial topoisomerase IV. Inhibition of DNA gyrase results in relaxation of supercoiled DNA, inte ering with DNA replication. Inhibition of topoisomerase IV impacts chromosomal stabilization during cell division, thus inte ering with the separation of newly replicated DNA. 27 Fluoroquinolones Indications 28 Pharmacokinetics Absorption: Ingestion with aluminum - or magnesium-containing antacids, or dietar yiron, zinc and calcium inter fere with the absorption of these agents. T he graph shows the ef fect of dieta calcium on the absorption of cipro oxacin Distribution: Binding to plasma proteins ranges from 10% to 40%, distribute well into all tissues and body f luids, as bone, urine (except moxif loxacin), kidney, and prostatic tissue (but not prostatic f luid), and concentrations in the lungs exceed those in serum. Elimination: Most f luoroquinolones are excreted renally. Moxif loxacin is excreted primarily by the liver 29  Adverse E ects Adverse reactions also include: Phototoxicity A icular ca ilage erosion (a hropathy) o Fluoroquinolones age. should be avoided in pregnancy and lactation and in children under 18 years of o Careful monitoring is indicated in children with cystic f i b rosis who receive pulmona exacerbations due to increased risk of tendinitis or tendon rupture. f l u oroquinolones for acute o and Warnings for seizures). peripheral neuropathy and CNS ef f e cts (hallucinations, anxiety, insomnia, confusion, 30 31