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Antibiotics
| Question | Answer |
|---|---|
| Emergence of resistance | reduced effectiveness, increased toxicity, increased costs To preserve susceptibility – or to postpone development of resistance – antibiotics should be used rationally |
| Are antibiotics important? | -30-50% of hospitalized patients are under antibiotic treatment -In 2010, 0.8 antibiotic prescriptions were given for each person in the US in the outpatient setting -Up to 50% of antibiotics are inappropriately prescribed |
| Antimicrobial | Any substance of natural, semi-synthetic, or synthetic origin that in in vivo concentrations kills, or inhibits the growth of microorganisms by interacting with a specific target |
| Antibacterial | Antimicrobial with activity against bacteria |
| Antibiotic | a substance produced by, or derived (chemically produced) from a microorganism that selectively destroys or inhibits the growth of other microorganisms (often used to refer to antibacterial agents) |
| Antimicrobial therapy | empirical therapy: based on a reasonable informed clinical judgement regarding the most likely infecting organism; documented or definitive therapy: when identity and antimicrobial susceptibility of the infecting organism is known |
| Antimicrobial prophylaxis | the use of antimicrobials for the prevention of infections |
| Broad spectrum therapy | the use of antimicrobials with the intent of broadening the range of potential pathogens covered, typically during empirical therapy |
| Bactericidal drugs | kill target organisms. Aminoglycosides, Cephalosporins, Penicillins, Quinolones |
| Bacteriostatic drugs | inhibit or delay bacterial growth and replication but do not kill. Tetracyclines, Sulfonamides, and Macrolides |
| Inappropriate use and misuse of antimicrobials | A broad term that includes: unnecessary prescription wrong choice of antimicrobial agent / use of an agent to which the pathogen is resistant inadequate dosing wrong duration |
| Selecting an Antimicrobial: The host | Confirm the presence of infection: History and physical Signs and symptoms Predisposing factors |
| Selecting an Antimicrobial: The Bug | Identify the pathogen: Collection of infected material Stains Serologies Culture and sensitivity |
| Selecting an Antimicrobial: The Drug | -Select presumptive therapy: Drug factors Host factors -Monitor therapeutic response: Clinical assessment Lab tests Assessment of therapeutic failure |
| Culture Results | Minimum inhibitory concentration (MIC) The lowest concentration of drug that prevents visible bacterial growth after 24 hours of incubation in a specified growth medium |
| Antibiogram | An antibiogram is a laboratory test used to determine the sensitivity pattern of a given microorganism to a range of antibiotics |
| Why do we need an Antibiogram | Infections caused by resistant- and multidrug-resistant (MDR) bacteria not only increase morbidity and mortality, but also increase overall healthcare costs, primarily by prolonging hospital length of stay |
| Host factors affecting treatment | Diffusion in tissues Serum protein binding Drug interactions Immune system Multiple simultaneous infections Virulence of organism Site and severity of infection |
| Sites with lower concentration than serum: | Ocular fluid, CSF, abscess cavity, prostate and bone |
| Efficacy at the site of infection | The efficacy of antimicrobial agents depends on their capacity to achieve a concentration equal to or greater than the MIC at the site of infection and modification of activity at certain sites. |
| Other important factors of antimicrobial use | Bactericidal vs Bacteriostatic Therapy Pharmacodynamic Characteristics Oral vs Intravenous Therapy Selection of Antimicrobial Agents for Outpatient Parenteral Antimicrobial Therapy Use of Therapeutic Drug Monitoring |
| Considerations for continuing antibiotic therapy | -Duration of antimicrobial treatment -Assessment of response to treatment clinical and lab exam parameters -Adverse effects |
| Pharmacokinetic | An alteration in one or more of the object drug’s basic parameters |
| Pharmacodynamic | An alteration in the drug’s desired effects |
| Critical components of Antibiotic stewardship program in Healthcare settings: | -importance of physician and pharmacist leadership -need for infectious diseases expertise -role of measurement and feedback |
| Systematic review -> | implementation of guidelines on proper use of antibiotics in veterinary medicine has been reported to cause positive results |
| One Health | An approach to designing and implementing programmes, policies, legislation and research in which multiple sectors communicate and work together to achieve better public health outcomes. |
| One Health approach is particularly relevant in: | -food safety -control of zoonoses -combatting antibiotic resistance |
| Training in Antimicrobial stewardship | -Currently, there are no best practice or national guidelines for teaching antimicrobial stewardship in undergraduate and postgraduate medical education |
| Beta-lactams: | Are a group of antibiotics with a β-lactam-ring, this includes: → penicillins, carbapenems, monobactams, and cephalosporins 1. Inhibit cell wall synthesis in bacteria by blocking peptidoglycan crosslinking 2. Activate autolytic enzymes |
| Penicillins: | ● Naturally produced by Penicillium molds ● First discovered by Alexander Fleming in 1928 |
| Combination Therapy: | ● Bacterial resistance causes problems for treatment ● Monotherapy vs. drug combinations – Pros & Cons |
| CATS | Clavulanate, Avibactam, Tazobactam, Sulbactam are β-lactamase inhibitors. → A class of antibiotics that inhibit the bacterial enzyme beta-lactamase (prevent the destruction of β-lactam antibiotics): They increase the spectrum of the antibiotic activity!! |
| Classification (1): | 1. Natural (narrow spectrum): Penicillins G and V 2. Penicillinase-resistant Penicillins Antistaphylococcal (very narrow):Methicillin, Flucoxacillin, Dicloxacillin, Nafcillin and Oxacillin 3. Aminopenicillins (Broad spectrum ):Amoxicillin and Ampicillin |
| Classification (2): | 4. Antipseudomonal (Broad spectrum): Piperacillin, Ticarcillin, Azlozillin, Mezlocillin and Carbenicillin 5. Beta lactamase inhibitors: Beta lactamase inhibitors- Sulbactam, Clavulanic acid and Tazobactam |
| Pharmacodynamics | ● Penetrate cerebrospinal fluid ocular fluid ● Decreased gastrointestinal absorption |
| Resistance: | ● Bacteria are highly adaptable ● Quick regeneration ● 3 ways to acquire resistance: 1. Penicillinase-attacks beta lactam ring 2. Peptidoglycan change in PBPs- no longer binds 3. Bacterial efflux pumps |
| Indications: | ● Pneumococci ● Streptococci ● Meningococcal meningitis ● Listeria ● Anthrax ● Syphilis ● Tetanus ● Trench fever |
| Risks: | ● Breastfeeding ● Oral contraceptives ● Kidney disease ● Methotrexate ● Allergy to Penicillin |
| B-lactam combinations: | All b-lactam antibiotics are combination prescription antibiotics, which have a bactericidal effect. |
| RESISTANCE | The action of β-lactams, though extremely effective, is not entirely foolproof. Bacterial resistance against beta-lactam antibiotics is increasing at a significant rate and has become a common problem in primary care medicine. |
| SIDE EFFECTS | ● mild and predictable ● Infrequent adverse: effects include: Erythema, dermatitis, pseudomembranous colitis ● Allergic reactions ● severe conditions like: immune-mediated haemolytic anaemia and intravascular haemolysis |
| Cephalosporins: | • They are a class of bactericidal β-lactam antibiotics • Disrupt peptidoglykan formation in the cell wall |
| General Rule: | 1st Gen are predominantly active against gram-positives, with succeeding generations progressively more active against gram-negative strains (often with reduced gram-positive activity, except 4th, which are extended spectrum agents) |
| 1st Generation cephalosporins: | • First group of cephalosporins discovered. • Optimum activity is against gram-positive bacteria such as staphylococci and streptococci. • Little activity against gram-negative bacteria |
| 2nd Generation cephalosporins: | • Activity against gram-negative aerobes eg. Morganella morganii • Gram-positive aerobes eg. Streptococcus pneumoniae • More active against gram-negative bacteria than first generation cephalosporins |
| 3rd Generation cephalosporins: | • More effective against Gram (-) bacteria compared to both the f1st & 2nd gen • More active against bacteria that may be resistant to previous generations of cephalosporin • They are highly active against Enterobacteriaceae, Neisseria, and H influenzae |
| 4th Generation cephalosporins: | • Structurally related to 3rd generation cephalosporins but: extra ammonium group, This allows : penetration through the outer membrane of Gram-negative bacteria, enhancing their activity. |
| 5th Generation cephalosporins: | • Advanced-generation cephalosporins. • 1/5-generation- ceftaroline (Teflaro), available in the United States. • Treatment of bacteria eg resistant Staphylococcus aureus (MRSA) and Streptococcusspecies, that are resistant to penicillin antibiotics. |
| LAME | • Mnemonic "LAME" used to note organisms against which cephalosporins do not have activity • Listeria • Atypicals (including Mycoplasma and Chlamydia) • MRSA • Enterococci - Fifth-generation cephalosporins, however, are effective against MRSA. |
| Administration | • First-generation: some orally, some parenterally. • Second-generation: some orally, some parenterally. • Third-generation: some orally, some parenterally. • Fourth-generation: parenterally. • Fifth-generation: parenterally |
| Monitoring Complete blood count: | • Monitoring each case differently is very important, because they could be some sudden problems • Have to check Blood urea nitrogen (BUN) and creatinine |
| The Carbapenems antibiotics | The carbapenems are beta-lactam antibacterials with a broad-spectrum of activity which includes many Gram-positive and Gram-negative bacteria, and anaerobes; |
| The Monobactam antibiotics | Monobactams have a unique β-lactam structure and are a naturally occurring antibiotic isolated from Chromobacterium spp Monobactam agents have a narrow spectrum of activity. They work only against Gram (-) bacilli, including (+) Pseudomonas aeruginosa |
| New Carbapenem combinations | Imipenem/cilastatin/relebactam: A new carbapenem β-lactamase inhibitor combination to treat |
| Meropenem with Vaborbactam | Meropenem is a Carbapenem, vaborbactam is a β-lactamase inhibitor |
| Panipenem with Betamipron | Panipenem is a parenteral carbapenem with a broad spectrum betamipron inhibits panipenem uptake into the renal tubule and prevent nephrotoxicity. |
| Carbapenems mode of action | They act as mechanism-based inhibitors of the peptidase domain of penicillin-binding proteins and can inhibit peptide cross-linking as well as other peptidase reactions like the synthesis of the bacterial cell wall, which leads to cell death |
| Monobactams | They act by inhibiting the peptidoglycan synthesis process resulting in the bacteria to lose the ability to resist and burst, leading to cell death. |
| Important considerations here are the following: | •All cover MSSA, enterococcus, Streprococcus spp. • Ertapenem has a more limited spectrum, because it is not as active as imipenem or meropenem against non-fermentors • Meropenem is not as potent as imipenem or doripenem against Acinetobacter baumannii |
| Adverse Effects | Carbapenems have a safety profile similar to that of other beta lactam antibiotics. • The most common adverse effects are: -Injection site reactions -Diarrhea -Nausea -Vomiting -Skin rash -Pruritus |
| Carbapenem Allergy | • Generally, carbapenems are well tolerated with a low risk for allergic reactions • Carbapenem alternative agent may be used in patients with carbapenem allergy when there are no other options |
| Carbapenems – Penicillin | • If there is no valid indication for the antibiotic, the use of carbapenem seems to make the most sense in patients allergic to penicillin. |
| Aminoglycosides | - Group of potent antibiotics - Can be used to treat infections in the abdomen, urinary tract, skin, ears, blood, heart, and lungs - Among the first antibiotics to be introduced for routine clinical use, specifically antimicrobial chemotherapy |
| Cell death mechanisms induced by Aminoglycosides | 1. Entry into the cells by permeating cation channels 2. Cytochrome C released from mitochondria (caspase-dependent) → activates mechanisms leading to apoptosis 3. Caspase-independent mechanisms induce apoptosis |
| Cell death mechanisms induced by Aminoglycosides | 4. Can be transported to the ER and lysosome 5. Can induce lysosomal rupture → necrosis 6. Bind to CLIMP-63 within the lumen of the ER leading to mitochondrial apoptosis signaling 7. c-Jun transcription factor induces apoptotic gene transcription |
| Aminoglycosides Inhibit Protein Synthesis | - Inhibit Translation - Bind to the Aminoacyl binding site of the 16S ribosomal RNA with the 30S ribosomal subunit - Inhibit binding of new amino acids - Causes addition of incorrect amino acids - Abnormal protein is synthesized |
| Aminoglycosides - Subgroups | 1. Tobramycin 2. Amikacin 3. Neomycin 4. Gentamicin 5. Streptomycin |
| Aminoglycosides - Adverse Effects | Major Effects vary: 1. Nephrotoxicity (kidney injury) 2. Hearing Impairment But may also include: 1. Allergic Reactions 2. Anemia 3. Low Platelet Count 4. Neuropathy |
| Tetracyclines | -class of broad spectrum antibiotics -bacteriostatic action Administration - mainly through the oral route -oxytetracycline and tetracycline administered via intramuscular injection -should be taken on an empty stomach |
| Tetracyclines - Mode of Action | Inhibit Protein Synthesis - Inhibit Translation - Bind to the 30S subunit of microbial ribosomes - Inhibit binding of the aminoacyl-tRNA - Prevents the binding of new amino acids to create a polypeptide chain |
| Tetracyclines - 3 generations | -1st gen- from biosynthes is (Chlortetecycline, Oxytetracycline, Demeclocycline) -2nd gen - from semi-synthes is (Doxycycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Rolitetracycline) -3rd gen - from total synthes is (Tigecycline) |
| Tetracyclines - Adverse Effects | MORE COMMON (all tetracyclines) - Increased sensitivity of skin to sunlight - stay out of sun! - Cramps or burning of the stomach - Diarrhea |
| What other drugs can affect tetracyclines? | - Can make birth control pills less effective - Blood thinners (Warfarin, Coumadin, Jantoven) could have an interaction - Patients should avoid taking a vitamin or mineral supplement containing iron, zinc, calcium, or magnes ium |
| MACROLIDES | Class of drugs used against bacterial infections Organic, later evolved synthetic Characterized by a large lactone ring |
| MACROLIDES: 4 different categories: | Azithromycin, Clarithromycin, Dirithromycin Erythromycin Can be either bacteriostatic or bactericidal( at high concentrations) |
| ANTIMICROBIAL SPECTRUM | Gram-(+) Limited gram-(-) Legionella pneumophila Mycoplasma(STD- Chlamydia) Antimicrobial spectrum: slightly wider than that of penicillin |
| Mechanism of Action | Macrolides act as protein synthesis inhibitors in the following way: Macrolide binds to the 50S ribosomal subunit. Inhibits polypeptide chain elongation. Results in inhibition of growth and multiplication. |
| Indications | Macrolides can treat: Respiratory tract infections Skin and soft tissue infections Streptococcus infections Lyme disease STI(syphilis, gonorrhea, chlamydia |
| Contraindications | When are they not appropriate? Drug Allergy Pre-existing concerns such: GI dysfunction Cardiac dysfunction(arrhythmias, ECG disturbances) Hearing dysfunction Liver dysfunction(elevated liver enzymes) |
| Interactions | Potentiate effects/toxicity with: Digoxin (enhancement) Warfarin (increased risk of bleeding) |
| Side Effects | Integumentary system: thrombophlebitis, rash CNS: headache, dizziness, vertigo Cardiovascular system: chest pain, slow/fast heart rate Gastrointestinal system: nausea, vomiting, diarrhea, stomatitis, hepatotoxicity, jaundice, anorexia |
| Antimicrobial Spectrum | Three antibiotics in this group: lincomycin, pirlimycin, clindamycin Gram-positive all types of cocci (staphylococcus, streptococcus) Positive effect: anaerobic bacteria No effect to gram-negative bacteria |
| Contraindications | Lincosamides should be avoided in patients with ulcerative colitis liver disease Should be used cautiously in the elderly, because they cannot tolerate diarrhea |
| Administration | Orally Topically Intravaginal administration |
| Antimicrobial Spectrum | It is used for gram-positive bacteria that are resistant to other antibiotics like penicillin It is active against: MRSA VRE VRSA Does not show any cross-resistance |
| Fluoroquinolones | are highly effective antibiotics with many advantageous pharmacokinetic properties including high oral bioavailability. Antibiotics include: ciprofloxacin(Cipro),gemifloxacin(Factive),levofloxacin(Levaquin),moxifloxacin(Avelo) and ofloxacin(Floxin). |
| Where do we use Fluoroquinolones? | Doctors often prescribe it to treat mild-to-moderate respiratory and urinary infections, but it is also used in other situations. |
| Mechanism of Action | Fluroquinolones inhibit DNA synthesis by targeting 2 type II topoisomerases, DNA gyrase and topoisomerase IV. These 2 targets are not present in eukaryotic cells and they are essential for bacterial growth. |
| What are the side effects? | -Severe CNS reactions seem to be due to metabolic interactions with theophylline, especially when enoxacin is used. -Phototoxicity has been reported in varying frequencies with different fluoroquinolones. |
| What are the Adverse effects ? | -General:Tendonitis , Muscle pain , Muscle weakness , Joint pain/swelling -CNS Effects: Psychosis , Anxiety ,Suicidal thoughts , Confusion , Seizures. -Other: aortic aneurysm and dissection , Blood gluc problems,Hypersensitivity rxns and phototoxicity. |
| Sulfonamides | They are bacteriostatic and appear to act by inhibition of bacterial biosynthesis of folic acid, which is needed for cell growth. Humans rely upon dietary folic acid, they are usually resistant to the adverse effects of inhibition of folate synthesis |
| Common Sulfonamides | Sulfonamides include: Gantrisin (sulfisoxazole) Bactrim or Septra (trimethoprim and sulfamethoxazole) Sulfadiazine Azulfidine (sulfasalazine) Zonegran (zonisamide) |
| What are Sulfonamides used for? | -UTIs - Bacterial infections: -Crohn’s disease: eg, sulfasalazine -Diabetes: eg, glyburide, tolbutamide -High blood pressure: eg, chlorothiazide, hydrochlorothiazide |
| Side effects of Sulfonamides | Gastrointestinal effects Anorexia Fatigue Folate deficiency Allergies Dizziness Headache Photosensitivity Serious skin rashes include: Steven-Johnson Syndrome, which causes aching joints and muscles, redness, blistering, and skin peeling. |
| Polymyxins | -a class of medications used for infections caused by susceptible strains of multidrug-resistant organisms -compromise a class of antibiotics targeting gram(-) bacterial infections. Polymyxin B and Polymyxin E (colistin) are the two drugs used |
| When do we use Polymyxins? | -serious infections with multidrug-resistant gram-negative bacteria, especially those caused by Enterobacteriaceae, - infections that are resistant to other antibiotics. -They are useful in treating infections of the urinary tract and meninges. |
| Polymyxins- Adverse effects | -nephrotoxicity -hematuria, proteinuria, oliguria, and acute renal failure. -Neuromuscular blockade: can lead to respiratory failure. -Dizziness, numbness, slurred speech, tingling, vertigo, flushing, diarrhea, fever, headache, stiff neck. |
| Metronidazole | Nitroimidazoles Group Activated intracellularly and binds onto DNA, disrupted its’ helical structure Result: Death of the bacterial cell Some common drugs: Flagyl, MetroCream, MetroGel, Nuvessa, and Pylera |
| When do we use Metronidazole? | It is used to treat bacterial infections of the vagina. It is also used to treat trichomoniasis, an STD caused by a parasite. Not to be used against viral infections. Dosage varies on condition and response to the treatment. |
| Side effects of Metronidazole | Most of the side effects of metronidazole are similar to the previous ones like dizziness, headache, stomach upset, nausea, vomiting and diarrhea. But there are also loss of appetite , constipation and metallic taste in the mouth. |
| Drug Administration | Fluoroquinolones: through oral and intravenous(IV) routes Metronidazole: through oral and intravenous (IV) routes. Sulfonamides: through oral, topical, vaginal or ophthalmic routes. Polymyxins: through intravenous, intramuscular, intrathecal routes |
| safe in pregnancy? | Fluoroquinolones: YES Sulfonamides: NO Polymyxins: NOT ALWAYS Metronidazole: YES |
| What should fluoroquinolones not be taken with: | They should not be taken with aluminium and magnesium-containing antacids and sucralfate, as well as with other metal cations such as calcium and iron, since it can be significantly impaired when coadministered. |
| Sulfonamides interact with: | TRAMADOL DAPSONE PRILOCAINE BELZUTIFAN FINERENONE VOXELOTOR HALOPERIDOL |
| Metronidazole Severe interactions; | SELECTED NITROIMIDAZOLE ANTIMICROBIALS/DISULFIRAM FEXINIDAZOLE, METRONIDAZOLE,TINIDAZOLE/ET HYL ALCOHOL METRONIDAZOLE, TINIDAZOLE/PROPYLENE GLYCOL |
| Metronidazole Serious Interactions: | METRONIDAZOLE/MEBENDAZOLE METRONIDAZOLE/BUSULFAN METRONIDAZOLE, TINIDAZOLE/FLUOROURACIL METRONIDAZOLE, TINIDAZOLE/SLT ANTICOAGULANTS (VIT K ANTAG) |
| Glycopeptides | Are a class of drugs of microbial origin that are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Treat bacterial infections, caused by gram-positive organisms and enterococcal infections, which are resistant to other antibiotics. |
| Vancomycin | There are two generations of glycopeptides. In the first we have the main drugs vancomycin and teicoplanin. Vancomycin is used if infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected. |
| Lipopeptides | A lipopeptide is a molecule consisting of a lipid connected to a peptide Certain lipopeptides are used as antibiotics. Other lipopeptides are toll-like receptor agonists. Certain lipopeptides can have strong antifungal and haemolytic activities. |
| Subgroups of lipopeptides | Lipoglycopeptides : Dalbavancin --> teicoplanin -like molecule Oritavancin Telavancin --> derivative of vancomycin Lipopeptides: Daptomycin (only member of its class) |
| Glycopeptides antimicrobial spectrum | -Spectrum is narrow, they are active only against Gram +ve organisms (aerobic/anaerobic). Examples include Streptococci, Enterococci, , Bacillus spp., Clostridium spp., MSSA, MRSA… -Against Gram -ve organisms they are inactive (mycobacteria as well) |
| Lipoglycopeptides antimicrobial spectrum | Αgain narrow spectrum since they are active only against aerobic and anaerobic Gram +ve organisms (More potent than Vancomycin and Teicoplanin) Dalbavancin and Telavancin are not active against Vancomycin Resistant Enterococci as opposed to Oritavancin |
| Lipopeptides antimicrobial spectrum | Active only against aerobic and anaerobic Gram +ve organisms (narrow spectrum) and inactive against Gram -ve organisms or mycobacteria Spectrum includes Propionibacterium and Peptostreptococci on top of the organisms that glycopeptides are active against |
| ADVERSE EFFECTS OF GLYCOPEPTIDES | 1. Serious infusion reactions -> “red man syndrome” 2. Headache 3. Nausea,diarrhea 4. Rashes 5. Abdominal/back pain 6. Edema 7. Foamy urine 8. Flatulence |
| ADVERSE EFFECTS OF LIPOPEPTIDES | MAIN SIDE EFFECTS Nausea,vomiting,diarrhea Headache/dizziness Trouble sleeping Increased sweating Swelling at the injection site may occur |
| What are the antifungal medicines | They are medicines that kill or stop the growth of fungi that cause infections (fungal infections) |
| What do antifungals treat? | ● ringworm ● athlete's foot ● fungal nail infection ● vaginal thrush ● some types of severe dandruff 1. Aspergillosis (affects the lungs) 2. fungal meningitis (affects the brain) |
| You can get antifungal medicines as | • a cream, gel, ointment or spray • a capsule, tablet or liquid • an injection • a pessary: a small and soft tablet you put inside the vagina |
| Those at risk for fungal infections | Patients with weakened immune system: ● Patients with HIV ● Cancer patients ● Organ transplant patients ● Hospitalized patients ● Stem cell transplant patients ● Patients taking medicines that weakened the immune system e.g antibiotics |
| SIDE EFFECTS | ● Mild Symptoms include: ü itching or burning ü redness ü feeling sick ü abdominal pain ü Diarrhea ü Rash |
| Pharmacodynamic interactions | could be synergistic or antagonistic |
| Pharmacokinetic interactions | could possibly inhibit metabolizing enzymes and drug transport systems |
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