Antimicrobial Drugs PDF

Antimicrobial Drugs MERVAT BARAKAT Pharmacology Department Faculty of Medicine Alex. University  What are antimicrobial drugs? ⚫ Antimicrobial drug – a chemical that destroys pathogens, includes antibiotics and chemically synthesized drugs ⚫ Antibiotic...

Antimicrobial Drugs MERVAT BARAKAT Pharmacology Department Faculty of Medicine Alex. University  What are antimicrobial drugs? ⚫ Antimicrobial drug – a chemical that destroys pathogens, includes antibiotics and chemically synthesized drugs ⚫ Antibiotic – an antimicrobial agent produced naturally by a bacterium or fungus ⚫ Have target specificity. Injure target organism without affecting the host. What are the principles of antimicrobial therapy ? ⚫ Appropriate indication ⚫ Appropriate dosage ⚫ Suitable length of treatment period (usually given for 7-10 days) ⚫ When to start treatment ⚫ Target of therapy (prophylaxis or treatment). ⚫ Host defense mechanism should be intact ⚫ Good knowledge of the drug's pharmacokinetics and potential risk. ⚫ Combination only under certain conditions and right 3 choice of combination. Identification culture and sensitivityof the organism : Acute ill patient as: Selection of antibiotic as directed Meningitis or neutropenic patient by site of infection, patient history, community acquired or hospital acquired and age Coverage by antibiotic combination against G+ve, G-ve and anaerobes Combination of G-ve and G+ve or broad spectrum antibiotic. Status of the Patient: (Patients factors) 1.Immune system 2. Renal dysfunction 3.Hepatic dysfunction 4.Pregnancy 5.Lactation 6.Age Bacteriostatic versus Bacteriocidal drugs Bacteriostatic: Arrest the growth and replication of bacteria, thus limiting the spread of infection while the body’s immune system attack, immobilize and eliminates the pathogens. Bacteriocidal: Kill bacteria and the total number of viable organisms decrease. Spectrum of Activity – Broad spectrum ⚫ affecta wide range ⚫ can disrupt the normal flora of the body ⚫ cases of rapid onset life-threatening infections, no time to culture the causative agent – Extended spectrum – Narrow spectrum ⚫ limitedrange ⚫ requires the identification of the pathogen  Prophylaxis GOALS OF ANTIBIOTICS USE Prevent an initial infection or its recurrence after infection  Meningitis; ciprofloxacin in > 12 yrs or rifampicin in < 12 yrs or ceftriaxone in pregnant contacts Empiric Therapy Infecting organism(s) not yet identified. More “broad spectrum”(usually up to 72 hours) Definitive Therapy Organism(s) identified and specific therapy chosen. More “narrow” spectrum  Principles of antibiotics use 1. Antibiotics can't distinguish between the "good" and the "bad" bacteria. There is a delicate balance of billions of bacteria inside the body. Bifido bacteria in large intestine and acidophilus in small intestine and vagina protect against infection by yeast and other bad bacteria. Also "friendly" bacteria found on the skin protect against bad bacteria, yeast and fungal infections. ◦ Continued use of antibiotics, especially broad-spectrum antibiotics, can seriously disrupt the normal ecology of the body and render anyone more susceptible to pathogenic (disease causing) bacteria, yeast, viral and parasitic infection. 2. The worst thing one can do is to take antibiotics shorter than prescribed ◦Shortened course of antibiotics often kills only the most vulnerable bacteria, while allowing relatively resistant bacteria to survive. Not only do they survive, but since they have "seen" the antibiotic, they can change their structure so that antibiotic will not kill them in the future(antibiotic resistance) 3. The dosage is a very important factor in antibiotic effectiveness  If the dosage of the antibiotic is not adequate, it will not be effective for treatment of the infection and bacteria are more likely to develop resistance. 4. Broad spectrum Antibiotics may interfere with immune system development.  It is necessary to have a broad spectrum of flora to stimulate a healthy immune system.”  Children who are given broad-spectrum antibiotics before two years of age are three times more likely to develop asthma than are children who are not given such antibiotics. Antibiotics destroy bacteria that are helpful to the developing immune system.  What are the purposes for use of antibiotics ? (Target of therapy ) ⚫ Prophylaxis A – Medical: 1. Exposure to virulent pathogen (HIV, N. meningitis. Pretreatment may prevent tuberculosis or meningitis among individuals who are in close contact with infected patients. 2. Pretreatment may prevent streptococcal infections in patients with a history of rheumatic heart disease. Patients may require years of treatment. B –surgical Pretreating of patients undergoing dental extractions who have implanted prosthetic devices, such as articial heart valves, prevents Endocarditis 12 ⚫ Treatment  Combinations Of Antimicrobial Drugs Indication: 1. Treatment of severe infection of unknown etiology 2. In mixed infections 3. To delay emergence of resistant strains (TB) 4. To achieve an effect not obtained by either alone 5. To reduce the incidence and intensity of adverse reactions 13  Drug resistance ⚫ Bacteria are said to be resistant to an antibiotic if their growth is not halted by the maximal level of that antibiotic that can be tolerated by the host  What are the causes of Misuse of antibiotics? ⚫ Treatment of untreatable infection ⚫ Treatment of fever of undetermined origin ⚫ Improper dose ⚫ Reliance on chemotherapy with omission of surgical drainage of purulent exudates or necrotic or vascular infected tissue ⚫ Lack of adequate bacteriological information 15 Complication of antibiotic therapy 1. Hypersensitivity reactions, ex: penicillin can produce from urticaria to anaphylactic shock 2. Direct toxicity: High serum level → toxicity Ex: aminoglycosides → ototoxicity by direct toxic effect the membrane in hair cell 3. Super infection: by using broad spectrum antibiotic→ alterations of normal flora in upper respiratory, intestinal and geniotourinary tract → overgrowth of opportunistic organisms specially fungi and resistant bacteria which is difficult to treat Failure of treatment Incorrect indication. Ineffective antibiotic. Inappropriate dosage. Inadequate duration. Development of resistance. Change of causative pathogens. Classify Antibiotics ⚫ Classification of Antibiotics according: ⚫ Chemical Structure ⚫ Spectrum of Activity& effects ⚫ Mechanism of Action 18 Classify Antibiotics ⚫ Spectrum of Antibiotic activity – Narrow spectrum Antibiotic – Broad spectrum Antibiotic ⚫ Effects of Antibiotics – Bacteriostatic – Bacteriocidal Mechanism of action (site of action) What are main targets of Antibiotics?  The Beta-lactams ⚫ Beta-lactams are a broad class of antibiotics that have in common a four membered beta-lactam ring structure. They include: 1. Penicillins, 2. Cephalosporins, 3. Carbapenems, 4. Monobactam 22  -lactam Antibiotics All of the drugs in this group contain a β-lactam ring in their structure S S Share similar N N O O features of Penicillins chemistry, Cephalosporins mechanism of action, pharmacologic and clinical effects. N N O O Carbapenems Monobactams 23 PENICILLINS ⚫ Bacteriocidal ⚫ Mainly against G+ve Penicillin are among the most widely effective and the least toxic drugs known. nafcilin & oxacilin What is the mechanism of action of penicillin ? ⚫ Penicillins enter the bacteria via the cell wall ⚫ Inside the cell, they bind to penicillin-binding protein ⚫ Once bound, normal cell wall synthesis is disrupted ⚫ Result: bacteria cells die from cell lyses ⚫ Penicillins do not kill other cells in the body 26 What is the mechanism of action of penicillin ?  Penicillin Groups 1. Penicillin G 2. Depot preparations: (long actin preparations) 3. Acid resistant penicillins (penicillin V) 4. ß -Lactamase -resistant penicillins 5. Extended spectrum penicillins 6. Antipseudomonal penicillins 1- Penicillins G Pharmacokinetics ⚫ Penicillin G is rapidly hydrolysed by gastric acidity, so it is not given orally but only parenterally ⚫ It is relatively unstable in acid, thus the bioavailability is low. ⚫ There is poor penetration into the cerebrospinal (CSF), unless inflammation is present. 29 What are the disadvantages of Penicillins G? ⚫ 1. Short duration of action. ⚫ 2. Instability in acidic medium. ⚫ 3. Destroyed by b-Lactamase enzymes. ⚫ 4. Possess a narrow spectrum of activity.  2- Depot preparations:(long actin preparations) ⚫ penicillin G procaine (used every 18-24 hours) ⚫ penicillin G benzathine (duration of antimicrobial activity in the plasma is up to one month) ⚫ Such agents release penicillin G slowly from the area in which they are injected and produce relatively low but persistent concentrations of antibiotic in the blood.  3-Acid-stable Penicillins- penicillin V The oral form of penicillins - Indicated only in minor infections because of: 1. Poor bioavailability. 2. Frequent dosing 4-6 times per day. 3. Narrow spectrum of activity. 4. ß-Lactamase sensitivity. 32  4- ß -Lactamase -resistant penicillins ⚫ Nafcillin,(I.V) nephrotoxic ⚫ Dicloxacillin (oral) ⚫ These antibiotics are most useful against infections caused by ß - Lactamase -producing staphylococcin 33  5- Extended spectrum penicillins (ampicillin, amoxicillin) - Developed to increase activity against gram-negative aerobes - Broad-spectrum penicillin - Amoxicillin is often combined with clavulanate (clavulanate inhibit penicillinases), and this combination can be used for beta-lactamases producing organisms.  6- Antipseudomonal penicilins Chiefly used to treat serious infections caused by G-ve microorganisms, particular P.aeruginosa e.g Ticarcillin & pipercillin 35  Beta-lactamase inhibitors What are Beta-lactamase inhibitors? Give an example. - Inactivate bacterial beta-lactamases - Are used to enhance the antibacterial actions of beta-lactam antibiotics. Example: Clavulanic acid, Sulbactam 36 Penicillin-beta-lactamase inhibitor ⚫ Available only in fixed combinations with specific penicillins ⚫ Combination drugs: – Ampicillin + Sulbactam = Unasyn – Amoxicillin + Clavulanic acid = Augmentin  Penicillins: Therapeutic uses 1. Meningitis, 2. Pneumococcal infections, 3. Bacterial pneumonia, 4. Streptococcal infections, 5. Syphilis, 6. Prophylactic for – Gonococcal infection – Throat infections in rheumatic patients. Penicillin is considered to be the first-line drug and the gold standard for the treatment of odontogenic infections because of its cost-effectiveness, low incidence of side effects, and appropriate antimicrobial activity In this regard, previous reports have mentioned that the most common antibiotic that is prescribed in dental practice is amoxicillin followed by amoxicillin and clavulanic acid Adverse Reactions: 1. Hypersensitivity reactions: Approximately 5% of patients have some reactions, ranging from rashes to angioedema and anaphylaxis. Cross- allergic reactions occur among the β-lactam antibiotics.. Diarrhea: Diarrhea is a common problem that is caused by a disruption of the normal balance of intestinal microorganisms. Normal microflora are typically reestablished shortly after therapy is stopped; however, in some patients, superinfection results. Pseudomembranous colitis, related to overgrowth and production of a toxin by Clostridium difficile, follows oral and, less commonly, parenteral administration of penicillin. .Clindamycin, broad spectrum penicillins, and cephalosporins tend to be the worst offenders in antibiotic induced pseudomembranous colitis (PMC).  PMC treatment: 1. Stop offending antibiotic 2. Give metronidazole or vancomycin orally. Neurotoxicity: Penicillin are irritating to neuronal tissue and they can provoke seizures if injected intrathecally or if very high blood levels are reached. Epileptic patients are particularly at risk 2- CEPHALOSPORINES 5 generations They are grouped into five generations based on their spectrum of antimicrobial activity. Each newer generation of cephalosporins has significantly broader Gram- negative antimicrobial spectrum than the preceding generation, and in most cases decreased activity against Gram-positive organisms. Fourth generation, however, have the broadest spectrum activity. The fifth-generation cephalosporin has activity against many Gram-positive organisms (including MRSA and many other resistant Gram-positives), as well as some Gram-negative organisms (but not Pseudomonas). How do they work? Binding to PBPs Inhibit cell wall synthesis by blocking transpeptidase step of peptidoglycan synthesis Cephalosporins : ›All are bactericidal broad spectrum ›All are beta lactamase resistant ›All are not active against gram positive bacilli, enterococci, MRSA. ›All are renally eliminated. (Dose adjustment need for cefotaxime in hepatic impairment). How do the characteristics of cephalosporins change from first to to fourth generations in Gram+ve coverage in Gram-ve coverage in CNS penetration in resistance to -lactamases  Clinical Uses of 1st generation  Uncomplicated, community-acquired infections of the skin and soft tissue and urinary tract as well as respiratory tract infections caused by penicillin sensitive streptococci  Parenteral 1st generation agents are used for surgical wound prophylaxis  Not used for meningitis What are the clinical uses of first generation cephalosporins? Skin infection Prophylaxis against infection following surgery. Urinary tract infection  Clinical Uses of 2nd generation  Use Useful for community-acquired infections of the respiratory tract and uncomplicated UTI (Escherichia coli).  Upper respiratory tract infections › sinusitis › peritonsilar abscess › otitis media  Lower respiratory tract infections › pneumonia › acute bacterial bronchitis  Urinary tract infection  Intra-abdominal infections › intra-abdominal abscess, peritonitis, cholecystitis, etc.,  Not used for meningitis  Cephalosporines :Third Generation : ceftriaxone 1. Ceftriaxone is approved for treatment of meningitis. However, highly penicillin- resistant strain may not respond even to these agents, and addition of vancomycin is recommended. 2. Community acquired and hospital acquired pneumonia. 3. Complicated urinary tract infection. 4. Sepsis of unknown cause in both the immunocompetent and the immunocompromised patient. Can third generation cephalosporins penterate BBB? YES Especially ceftriaxone  Cephalosporines: Fourth generation Cefepime The largest spectrum USES: 1. Hospital-acquired pneumonia. 2. Complicated urinary tract infection.  Cephalosporines: Fifth generation Ceftaroline Therapeutic Uses: Empiric treatment of infections where MRSA is among suspected microorganisms, e.g., acute bacterial skin and skin structure infections.  Patients with history of penicillin allergy may tolerate cephalosporins. But patients with history of anaphylaxis should never receive cephalosporins. Adverse Reactions of cephalosporins: 1. Allergic reactions. 2. Gastrointestinal upsets. 3. Superinfection: They might predispose to infection by other bacteria or fungi. N.B.: Patients with a history of penicillin allergy may tolerate cephalosporins, but patients with history of anaphylaxis to penicillin should never receive cephalosporins. Glycopeptides Vancomycin a bactericidal antibiotic. It is active only against Gram-positive bacteria including MRSA. It is not significantly absorbed from the normal gastro-intestinal tract; therefore, it is given parenterally as slow intravenous injection or intravenous infusion. It is eliminated by the kidney; thus, the dose should be adjusted according to creatinine clearance. Therapeutic Uses: 1. Infections caused by MRSA. 2. Vancomycin is used in combination with: a) Third generation cephalosporins for treatment of meningitis caused by penicillin resistant pneumococci. 3. It is used orally for the treatment of Staphylococcal enterocolitis and pseudomembranous colitis due to Clostridium difficile. Adverse Reactions: 1. Irritation leading to phlebitis at the site of infection. 2. Ototoxicity: 3. Nephrotoxicity: 4. Histamine release leads to ‘Red man syndrome’, if given by rapid intravenous infusion. It can be prevented by slow intravenous infusion over 1-2 hours.  Bacitracine It is a polypeptide antibiotic, used against Gram-positive bacteria usually topically with neomycin and polymyxins to prevent superficial skin and eye infections.