Antibiotics PDF

AfraTafreeh.com Last edited: 3/27/2023 ANTIBI...

AfraTafreeh.com Last edited: 3/27/2023 ANTIBIOTICS Antibiotics Medical Editor: Jona Frondoso OUTLINE I) INTRODUCTION & II) BACTERIAL COVERAGE IV) ADVERSE DRUG V) MECHANISMS OF VII) RISK FACTORS FOR MECHANISM OF (A) GRAM POSITIVE COVERAGE REACTIONS AND ANTIBIOTIC RESISTANCE ANTIBIOTIC RESISTANCE (C) GRAM NEGATIVE COVERAGE CONTRAINDICATIONS (A) REDUCED PERMEABILITY VIII) ANTIBIOTIC ACTION (D) ANAEROBIC COVERAGE (B) INCREASED EFFLUX (A) CELL WALL SYNTHESIS (E) ATYPICAL COVERAGE (A) MORE COMMON ADVERSE (C) DECREASED TARGET BINDING SUSCEPTIBILITY III) EMPIRIC ANTIBIOTICS FOR EFFECTS (D) INCREASED INACTIVATING (A) GETTING CULTURES (B) CELL MEMBRANE INTEGRITY (B) SPECIFIC ADVERSE EFFECT AND (C) FOLIC ACID PATHWAY COMMON INFECTIONS ENZYMES (B) ANTIBIOTIC SUSCEPTIBILITY CONTRAINDICATIONS TO (D) DNA INTEGRITY (A) PULMONARY ANTIBIOTICS REVIEW IX) SUMMARY (E) MESSENGER RNA SYNTHESIS (B) GASTROINTESTINAL VI) TRANSMISSION OF X) REVIEW QUESTIONS (F) DNA GYRASE FUNCTION (C) SKIN AND SOFT TISSUES (G) PROTEIN SYNTHESIS (D) URINARY TRACT ANTIBIOTIC RESISTANCE XI) REFERENCES (E) BONE AND JOINT (A) HORIZONTAL TRANSFER INHIBITORS (F) CNS (B) VERTICAL TRANSFER (G) BLOODSTREAM REVIEW I) INTRODUCTION & MECHANISM OF ACTION The mechanism of action of antibiotics is best categorized Either a bactericidal or bacteriostatic based on the structure of the bacteria. o Bactericidal – Kills the bacteria o Bacteriostatic – Inhibits the growth of the bacteria AfraTafreeh.com Figure 1. Mechanism of Action of Antibiotics (A) CELL WALL SYNTHESIS B ACTERICIDAL Structure MOA (Figure 1) Made of peptidoglycans Inhibit the enzymes that either the synthesize The glycan (sugar) component are N-acetylglucosamine the cell wall synthesis (NAM) and N-acetylmuramic acid (NAG) Limitations of not having a cell wall The peptide (protein) component are the tetrapeptides Bacteria won’t be able to divide properly Cross-linked by tetrapeptides the Susceptible to materials leaking in or out of the cell introducing opportunity for bacterial death Helps in stabilizing the cell wall Beta-Lactams are divided into four categories Penicillin Cephalosporin Carbapanem Monobactam ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 1 of 23  Beta-Lactam Antibiotics Decrease Decrease Crosslinking of Peptidoglycans Beta-Lactamase Peptidoglycan (Beta Lactams) Inhibitors Synthesis (a) Penicillin (a) Mechanism of (a) Vancomycin (i) Natural Penicillin Action (Figure 2) A glycopeptide  Penicillin G o The PROTEIN CALLED More commonly used PENICILLIN - BINDING IM or IV form PROTEIN (PBP)  Penicillin V (b) Fosfomycin PO form  Synthesizes the peptidoglycan layer by Used in acute cystitis (ii) Antistaphyloccocal Penicillin cross-linking N- acetylglucosamine  Oxacillin (NAG) and N- IV form acetylmuramic acid  Nafcillin (NAM) IV form  To which antibiotics bind  Dicloxacillin to inhibit the synthesis of Only PO form the peptidoglycan o Some bacteria have (iii) Amino-Penicillin developed a resistance  Amoxicillin mechanism via the Usually combined with a Beta- production of BETA- lactamase inhibitor LACTAMASE Amoxicillin + Clavulanate (Augmentin) o Beta-lactamase break down  Ampicillin the beta-lactam ring → Usually combined with a Beta- antibiotics can no longer bind lactamase inhibitor to PBP → cell wall synthesis Ampicillin + Sulbactam (Unasyn) remain uninhibited → bacteria survives (iv) Antipseudomonal Penicillin  Piperacillin Usually combined with a Beta- lactamase inhibitor Piperacillin + Tazobactam (Zosyn) AfraTafreeh.com (b) Cephalosporin (i) 1st Generation o Cefazolin o Cephalexin (ii) 2nd Generation o Cefaclor o Cefoxitin o Cefototen Figure 2. Mechanism of Action of (iii) 3rd Generation Beta-Lactamase. o Ceftriaxone o Cefotexime (b) Examples o Ceftazidime (i) Clavulanate (iv) 4th Generation Added to Amoxicillin o Cefepime (ii) Sulbactam (v) 5th Generation Added to Ampicillin o Ceftaroline (iii) Tazobactam (c) Carbapenem Added to Piperacillin (i) Doripenem (ii) Imipenem (iv) Avibactam (iii) Meropenem Added to Ceftazidime (iv) Ertrapenem (d) Monobactam (i) Aztreonam o Used in penicillin-allergic cases 2 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS AfraTafreeh.com  (B) CELL MEMBRANE INTEGRITY (E) MESSENGER RNA SYNTHESIS B ACTERICIDAL B ACTERICIDAL Antibiotics Mechanism of Action Daptomycin Inhibits RNA polymerase Create efflux pumps in the cell membrane → more pores in the membrane → ↑ Antibiotics permeability of the cell membrane → ↑ risk for cell lysis ( Rifampin Figure 1) Used in tuberculosis Polymyxin (F) DNA GYRASE FUNCTION Salvage therapy for multi-drug resistant bacteria Also known as TOPOISOMERASE Acts like as a cationic detergent that binds to B ACTERICIDAL the cell membrane increasing its permeability Mechanism of Action → ↑ risk for cell lysis ( Figure 1) DNA gyrase help in maintaining the topology ofAfraTafreeh.com the DNA by unwinding supercoils and making space for new DNA strands to be created (C) FOLIC ACID PATHWAY DNA gyrase inhibitors inhibit the ligating portion of the B ACTERIOSTATIC DNA gyrase while increasing the cutting portion of the DNA gyrase → fragments the DNA into pieces Nucleotide Synthesis of Bacteria Bacteria takes up para-aminobenzoic acid Fluoroquinolones Para-aminobenzoic acid is converted into dihydrofolate (DHF) via folic acid synthetase (S TEP 1) 1st Generation DHF is converted into tetrahydrofolate (THF) via Ciprofloxacin dihydrofolate reductase (S TEP 2) THF is utilized in nucleotide synthesis (DNA and RNA 2nd Generation synthesis) Levofloxacin Gemifloxacin Antibiotics Moxifloxacin Sulfamethoxazole (SMX) 3rd Generation AfraTafreeh.com 4th Generation Inhibits folic acid synthetase ( Figure 1) (G) PROTEIN SYNTHESIS INHIBITORS Trimethoprim (TMP) Inhibits dihydrofolate reductase ( 50S Ribosomal Subunit Figure 1) B ACTERIOSTATIC (D) DNA INTEGRITY Macrolides B ACTERICIDAL (a) Azithromycin Mechanism of Action ( (b) Erythromycin Figure 1) (c) Clarithromycin Increases the formation of reactive oxygen species (ROS) Clindamycin causing damage to the DNA, RNA, and/or proteins Chloramphenicol Linezolid Antibiotics 30S Ribosomal Subunit Metronidazole Aminoglycosides (BACTERICIDAL) Nitrofurantoin (a) Tobramycin (b) Amikacin (c) Gentamicin Tetracycline (BACTERIOSTATIC) (a) Doxycycline (b) Tetracycline ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 3 of 23  AfraTafreeh.com II) BACTERIAL COVERAGE (A) GRAM POSITIVE COVERAGE Methicillin Sensitive Staphylococcus aureus Group A & B Streptococcus (MSSA) Anti-staphylococcal penicillin  Nafcillin, Oxacillin, Dicloxacillin Group A: Streptococcus pyogenes 1st generation cephalosporins Group B: Streptococcus  Cephalexin, Cefazolin agalactiae Fluoroquinolones Methicillin Resistant Staphylococcus aureus Penicillin (MRSA) Aminopenicillins 5th generation cephalosporin 1st generation cephalosporins  Ceftaroline  Cephalexin Vancomycin Trimethoprim- sulfamethoxazole Trimethoprim-sulfamethoxazole Macrolides Clindamycin Clindamycin Linezolid Enterococcus Doxycycline Daptomycin Aminopenicillins Penicillin  Skin infections, right sided endocarditis Nitrofurantoin Streptococcus pneumoniae  Only for Urinary Tract Infections Penicillin  It is a urinary antiseptic Aminopenicillins Listeria 3rd generation cephalosporins Aminopenicillins  Ceftriaxone Trimethoprim-Sulfamethoxazole Fluoroquinolones  Moxifloxacin, Levofloxacin Vancomycin Macrolides Used for gram-positive organisms when: Clindamycin i. Patient who is allergic to penicillin ii. Resistance to other drugs Exceptions: VRSA, VRE 4 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS AfraTafreeh.com  AfraTafreeh.com (C) GRAM NEGATIVE COVERAGE HENS-PEcK organisms Extended spectrum beta lactamase bacteria (ESBL) Hemophilus influenzae Enterobacteriaceae Enterobacter E. coli Neisseria gonorrhoeae & Klebsiella meningitidis Serratia Proteus Escherichia coli Carbapenems Klebsiella Aminoglycosides Polymyxin Aminopenicillins 3rd generation cephalosporin+ beta lactamase  Do not cover Enterobacter, Serratia, Neisseria inhibitor  Ceftazidime+ avibactam Anti-pseudomonal penicillin Stenotrophomonas  Piperacillin-tazobactam 1st generation cephalosporins Anti-pseudomonal penicillin  Piperacillin-tazobactam  Cover PEcK organisms 2nd, 3rd, 4th generation cephalosporins Polymyxin Carbapenems Trimethoprim-Sulfamethoxazole  Doripenem, imipenem, meropenem, ertapenem Monobactams Fluoroquinolones  Don’t cover Neisseria Aminoglycosides  Don’t cover NeisseriaPseudomonas + Acinetobacter Aminopenicillins  Only Acinetobacter Anti-pseudomonal penicillin  Piperacillin-tazobactam 3rd generation cephalosporin  Ceftazidime 4th generation cephalosporin  Cefepime Carbapenems Monobactams  Except Acinetobacter Fluoroquinolones  Ciprofloxacin, levofloxacin- double coverage of Pseudomonas Aminoglycosides  Except Acinetobacter Polymyxin  Last resort ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 5 of 23 AfraTafreeh.com  AfraTafreeh.com (D) ANAEROBIC COVERAGE (E) ATYPICAL COVERAGE CBPFA organisms MCL organisms “Can’t breathe perfectly fresh air” Mycoplasma Clostridium Chlamydia Bacteroides Legionella Pepto streptococcus Fusobacterium Actinomyces Fluoroquinolones  Especially for Legionella Macrolides Chloramphenicol Clindamycin  Except Legionella Doxycycline Tick-borne bacteria Metronidazole AfraTafreeh.com Borrelia burgdorferi- Lyme Carbapenems disease Anti-pseudomonal penicillin Rickettsia-Rocky Mountain Fluoroquinolones?? Spotted Fever Erlichia- Ehrlichiosis  Ciprofloxacin?? Anaplasma- Anaplasmosis [EXCEPT Babesia] Metronidazole Doxycycline Vancomycin (PO) Chloramphenicol Ceftriaxone  Especially for neuroborreliosis as it can penetrate CNS Treponema pallidum Penicillin G Doxycycline 6 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS  AfraTafreeh.com III) EMPIRIC ANTIBIOTICS FOR COMMON INFECTIONS (A) PULMONARY Figure 3. Empiric antibiotics for common pulmonary infections. Community-acquired or hospital acquired pneumonia? Gives a basic idea of the pathogens common in those diseases Community-Acquired Pneumonia (CAP) Hospital-Acquired Pneumonia (HAP) Pathogens: S. pneumoniae, H. influenzae, M. catarrhalis Pathogens: Multidrug resistant bacteria such as and atypicals such as Legionella, Mycoplasma, and Pseudomonas and MRSA Chlamydia MRSA: vancomycin Fluoroquinolones (respiratory) Pseudomonas: antipseudomonal penicillin o Covers S. pneumoniae and all types of atypicals (Piperacillin-tazobactam), ceftazidime, cefepime, or especially Legionella an aminoglycoside Beta-lactam (Ceftriaxone) + Macrolide or Doxycycline Therefore, use a double therapy with vancomycin and o Provides better coverage for S. pneumoniae, antipseudomonals Legionella and Chlamydia o Doxycycline or macrolide: more targeted to the Get cultures to identify the specific agent, and use the atypicals antibiotic for that certain agent. Examples: CAP: S. pneumoniae is the specific causative pathogen; therefore, use Abx that only cover S. pneumoniae HAP: MSSA not MRSA. Get rid of the Abx for MRSA and Pseudomonas. Use MSSA-specific Abx such as nafcillin, oxacillin, dicloxacillin, cefazolin, cephalexin, and potentially a fluoroquinolone. (B) GASTROINTESTINAL Gram-Negatives and Anaerobes Pathogens: o Gram-negative rods (HACEK)  Particular emphasis on Enterobactericiae, E. coli, Klebsiella o Anarobes  Clostridium, Bacteroides, Fusibacterium, Peptostreptococcus, Actinomycedes Carbapenems o Can cover gram negatives and anaerobes o Very broad antibiotic Antipseudomonal penicillins (e.g. Pip-Tazo) Figure 4. Empiric antibiotics for common infections in the GIT. o Can cover gram negatives and anaerobes o Similarly very broad Includes: o Cholecystitis Metronidazole + fluoroquinolone (ciprofloxacin) o Cholangitis o Metronidazole: provides coverage against anaerobic o Appendicitis infection below the diaphragm o Diverticulitis o Ciprofloxacin: also gives additional anaerobic o Pancreatic walled-off necrosis coverage and Gram-negatives o Peritonitis Metronidazole + Ceftriaxone o Intra-abdominal abscesses o Ceftriaxone: gives good Gram-negative coverage Most importantly, for GIT infections think of gram- against E. coli, Klebsiella, Enterobacter negative rods and anaerobes Metronidazole + Cefepime o Cefepime: Good coverage and additional Pseudomonas coverage ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 7 of 23 AfraTafreeh.com  AfraTafreeh.com (C) SKIN AND SOFT TISSUES Two types of pathogens: o S. aureus (MSSA and MRSA) o Strep A Two types of drugs: PO and IV MSSA + Strep A PO: Dicloxacillin or Cephalexin o Provides coverage vs MSSA and Strep A IV: Nafcillin or Oxacillin or Cefazolin (cephalosporin) o Cefazolin: can be used in post-surgical prophylaxis for bacterial infections MRSA + Strep A PO: TMP-SMX, doxycycline or clindamycin IV: Vancomycin o Ceftaroline as alternative but very expensive ($$$$) Figure 5. Empiric antibiotics for common infections of the skin and soft tissues. (D) URINARY TRACT Figure 6. Empiric antibiotics for common infections of the urinary tract. Pyelonephritis Complicated UTI Most common pathogens: PEcK (Proteus mirabillis, E. Pathogens: “Nasty” bacteria such as Pseudomonas, coli and Klebsiella) and Enterobacter MRSA and Enterococcus Empiric antibiotics: o Therefore, need a broader antibiotic o Ceftriaxone Pseudomonas: Pip-Tazo, Cefepime, Aminoglycoside, o Fluoroquinolone (ciprofloxacin) Ceftazidime o Aminopenicillin (ampicillin) MRSA and Enterococcus: Vancomycin  Cannot cover Enterobacter but can cover some of o Usually in patients with prolonged Foley the PEcK catheterization Consider aminopenicillins Acute Cystitis o Primarily against Enterococcus Most common pathogens: PEcK (Proteus mirabillis, E. coli and Klebsiella) and Enterobacter Uses a subset of antibiotics: o TMP-SMX  For non-pregnant patients o Nitrofurantoin  Post-coital prophylaxis in UTI o Fosfomycin o Ciprofloxacin  2nd line agent due to resistance 8 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS AfraTafreeh.com  AfraTafreeh.com (E) BONE AND JOINT Examples: Septic arthritis, osteomyelitis MRSA Comes from the skin then spread inwards to the joint Vancomycin Neisseria If considering a sexually transmitted infection o N. gonorrheae can spread to joints Ceftriaxone Pseudomonas Cefepime and ceftazidime Figure 7. Empiric antibiotics for bone/joint infections. o Better than Pip-Tazo (F) CNS Community-Acquired Meningitis (CAM) Pathogens: S. pneumoniae, H. catarrhalis, N. meningitidis Vancomycin o Covers S. pneumoniae especially if resistant variant Ceftriaxone o Has good CNS penetration o Can cover H. catarrhalis and N. meningitidis Ampicillin o IF there is a concern for Listeria o Risk factors: Older patients (> 60 y/o; > 50 y/o in some studies), immunocompromised patients (HIV, transplant), babies Hospital-Acquired Meningitis (HAM) Figure 8. Empiric antibiotics for common CNS infections. Patients who had neurosurgical procedures, EVDs, or Symptoms of meningitis: any procedure/surgery that exposes the skull and o Photophobia meninges to hospital-acquired pathogens o Headache Pathogens: MRSA and Pseudomonas o Neck stiffness MRSA: Vancomycin o Fever Pseudomonas: Cefepime o Can penetrate the CNS better than Pip-Tazo Is this community- or hospital-acquired? o However, can cause encephalopathy and seizures (G) BLOODSTREAM Central Line Bloodstream Infection (CLABSI) For sterile or non-sterile procedures (e.g. IJV or subclavian line) that can introduce skin pathogens to penetrating instruments and then move along the bloodstream Pathogen: MRSA Symptoms include fever, hypotension, leukocytosis Empirics: o MRSA: vancomycin  Most likely pathogen o +/- Pip-Tazo  Covers gram-negatives  Usually for patients with femoral lines or who had non-sterile procedures Fem-lines are near the anus; can introduce Gram-negatives Sepsis Bloodstream infection o No idea what’s going on with the patient – hypotensive, tachycardic, febrile, blasting WBC count, on pressors and fluids, intubated Classic antibiotics: Figure 9. Empiric antibiotics for common bloodstream o Vancomycin: for MRSA and other Gram-positive infections. infection o Pip-Tazo: for Gram-negatives and anaerobes  Alternative: carbapenems ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 9 of 23 AfraTafreeh.com  AfraTafreeh.com IV) ADVERSE DRUG REACTIONS AND CONTRAINDICATIONS (A) MORE COMMON ADVERSE EFFECTS Taking the big common adverse effects and group which Worsen Myasthenia Gravis antibiotics have these effects. Myasthenia gravis: when patients produce Neurotoxicity autoantibodies against the nicotinic receptors present on Seizures, myoclonus, encephalopathy, serotonin the skeletal muscles syndrome Drugs: Penicillins Cephalosporins Fluoroquinolones Carbapenems Aminoglycosides o Big offenders especially at high doses Macrolides Clindamycin Polymyxins Linezolid Teratogenic o Produces serotonin syndrome and peripheral Teratogens can produce destructive effects to the fetus neuropathy during the gestational period o Can work against monoamine oxidase inhibitors → o Avoid during pregnancy! increasing levels of serotonin within the synapse → serotonin syndrome Drugs: AfraTafreeh.com TMP-SMX [Bactrum] Remember all your beta-lactams! o Can produce a kernicterus, which is accumulation of Pancytopenia unconjugated bilirubin in the brainstem, cerebellum, and basal ganglis Penicillins o Can cause pancytopenia and hemolytic anemia Fluoroquinolones o Contraindicated on 60 years or patients on steroids AfraTafreeh.com TMP-SMX Hyperkalemia 14 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS AfraTafreeh.com  AfraTafreeh.com V) MECHANISMS OF ANTIBIOTIC RESISTANCE If haven’t, take a little break o Review everything Zach has talked about with the mechanism of action, bacterial coverage, empiric antibiotics, adverse effects, and contraindications We’re going to talk about how these tricky little bacteria have figured out a way to develop resistance against certain types of antibiotics There are 4 mechanisms o Reduced permeability o Increased efflux o Decreased target binding o Increased inactivating enzyme (A) REDUCED PERMEABILITY (C) DECREASED TARGET BINDING When an antibiotic works The other way is to reduce the effectiveness of these o It has to be able to get into the bacteria antibiotics o Accumulate in high concentrations inside of the o Bacteria can reduce antibiotic binding to the actual bacteria target site → Binding onto its target sites and exert their We know some of the antibiotics are supposed to be able effects to bind onto these structures and exert their effect There are particular enzymes that are working to be able o DNA to try to inactivate the actual antibiotic o Proteins like ribosome subunits Generally, we want them to be able to evade the o Or specific proteins inside the cell wall inactivation by enzymes Now particular bacteria have altered their target side o That’s the way that they should work o Change amino sequence What if the actual bacteria have figured out a way to o Change particular structural morphology of a reduce the actual permeability of the antibiotics? protein o **Antibiotics are supposed to be able to work to To where now the actual antibiotic can’t bind to it anymore get into the bacterial cell to exert its effects by o They alter the ability of the antibiotic to bind to them binding onto the target sites and inhibit them o Now there are less of the actual antibiotics getting into the bacteria Antibiotics resistance due to decreased target binding  Now they can’t accumulate (FAT BVM LT) o Fluoroquinolone (B) INCREASED EFFLUX o Aminoglycosides o Tetracycline (Doxycycline) We can reduce their accumulation by reducing permeability or causing them to get pushed out of the o 𝜷𝜷-lactams bacteria o Vancomycin The bacteria figured out to push the antibiotic out of o Macrolides the bacterial cell o Reducing the amount of the antibiotic inside of o Linezolid the cell o Trimethoprim-Sulfamethoxazole TMP-SMX If we reduce the permeability by letting less of them come Remember they reduce the actual binding of the antibiotic in or push them out of the cell via increased efflux to their particular target sites o The result of both of these things o Reducing the ability of the antibiotic to exert its effect → Decreased amount of the antibiotic o The bacteria is resistant, it doesn’t die or it doesn’t accumulating within the cell stop growing Some bacteria have actually developed in resistance to (D) INCREASED INACTIVATING ENZYMES these specific antibiotics o Decreased permeability (VAT B) Normally, the antibiotics are supposed not to be broken  Vancomycin AfraTafreeh.com down by actual enzymes  Aminoglycosides o Able to evade the inactivation by particular enzymes  Tetracyclines (Doxycycline) What if we increase the production of inactivating enzymes?  𝜷𝜷-lactams These enzymes can o Increased efflux (FAT M) o Phosphorylate  Fluoroquinolones  Aminoglycosides o Acetylate  Tetracyclines (Doxycycline) o All different types of things that they can do to inactivate these antibiotics  Macrolides Antibiotics (BAM) o 𝜷𝜷-lactams  𝛽𝛽-lactamase  Carbapenemase o Aminoglycosides  Mainly via phosphorylation, acetylation, methylation reactions o Macrolides ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 15 of 23  AfraTafreeh.com REVIEW So now bacteria have developed resistance but how do more and more bacteria continue this These are particular ways that these actual bacteria have transmission, further growth of resistance? developed resistance to antibiotics o How does one bacteria that have develop these Either reduce the concentration of the drug inside of mechanisms to be become resistance to an antibiotic the bacteria by and then therefore pass that on to other bacteria? o Reducing its permeability (VAT B) o Pushing it out of the bacteria (FAT M) o Reduces the binding of the antibiotic to the target site (FAT BVM)  By changing the structure of the actual target site  Changing amino acid o Particular enzymes that the bacteria produce that inactivate or destroy the actual antibiotic and render it ineffective (BAM) VI) TRANSMISSION OF ANTIBIOTIC RESISTANCE So now bacteria have developed resistance but how do more and more bacteria continue this transmission, further growth of resistance? o How does one bacteria that have develop these mechanisms to be become resistance to an antibiotic and then therefore pass that on to other bacteria? Remember bacteria may become resistant to an antibiotic via o Reducing permeability o Pushing the antibiotic out o Changing the structure of its target side that actually the antibiotics are supposed to bind to o Producing enzymes that break down the actual antibiotics How does it pass it on to other bacteria? o Vertical gene transfer o Horizontal transfer  Transformation  Conjugation  Transduction (A) HORIZONTAL TRANSFER Transduction Transformation We have bacteriophage that can pass on the DNA/RNA material Let’s say we have a bacteria and it is get destroyed Bacteriophage contains some type of DNA/RNA material When it gets destroyed, it releases out some of the that carries the ability to DNA or RNA o Change the permeability of the bacterial cell o It may bring the opportunities to o Increase the efflux of the antibiotic out of the bacterial  Change the permeability of the bacterial cell cell  Increase the efflux of the antibiotic out of the o Change the actual target of the protein that the bacterial cell antibiotics supposed to bind to  Change the actual target of the protein that the o Increase the formation of inactivating enzymes antibiotics supposed to bind to  Increase the formation of inactivating enzymes And we can pass that on to this bacteria o The DNA encodes these particular mechanisms (B) VERTICAL TRANSFER What happens is a bacteria that doesn’t have the ability to The DNA/RNA inside of the bacteria has the ability to do those things (susceptible to antibiotics) produce resistance to particular antibiotics o It takes up the actual DNA/RNA from the bacteria What it can do is it can pass it through vertical gene o And gains the ability to be able to produce these transfer mechanism o It goes through binary fission Conjugation AfraTafreeh.com The bacteria replicates and produces two daughter We take one bacteria and we connect it to another bacteria bacteria via sex pilus o That now what DNA/RNA within it that allow for it In the actual bacteria, we have something called plasmid to be resistant to particular types of antibiotics o Plasmid may have a particular kind of DNA sequence REVIEW that allows for it to encode particular proteins or enzymes that can These are the ways that actual bacteria have developed  Change the permeability of the bacterial cell resistance to antibiotics via  Increase the efflux of the antibiotic out of the o Horizontal transfer bacterial cell  Conjugation  Change the actual target of the protein that the  Transduction antibiotics supposed to bind to  Transformation  Increase the formation of inactivating enzymes o Binary fission/vertical transfer o And pass these on to this bacteria  Once they’ve gathered all of the material  They can pass it on to their actual daughter cells 16 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS  AfraTafreeh.com VII) RISK FACTORS FOR ANTIBIOTIC RESISTANCE Now the question is, these bacteria all have the ability to do this o What actually increases these particular DNA/RNA sequences to undergo these particular mutations and produce resistance in the first place? o What triggers this? o What are the risk factors for antibiotic resistance? Hospital Overprescribing antibiotics In the hospital, we have patients who are super sick Unfortunately for clinicians o and in the hospital they develop some multi-drug We like to overprescribe medications like antibiotics when resistant pathogen it’s not really necessary So anytime we go to the hospital Example if we have a patient who has viral infection o There’s always a risk of multi-drug resistant o They don’t really need an antibiotic pathogens o And we put them on antibiotic o There’s obviously an opportunity to catch MRSA like We increase the opportunity for resistance to become  Pseudomonas available  Acinetobacter o Because now this person’s been exposed to an antibiotic o And bacteria can create a way to become resistant So, try to be able to prevent over prescription Antibiotic in food products Unfortunately, some of the actual meats that we eat o Now have particular antibiotics that were used in that meat Now we’ve been exposed to them → actual bacteria can develop ways to become resistant VIII) ANTIBIOTIC SUSCEPTIBILITY Now the question is now we know that bacteria can develop a lot of resistance to antibiotics through many different mechanisms o And a lot of risk factors → they have a lot of opportunity for transmission o How do we as a clinician figure out which antibiotic is best particularly utilized for a very specific pathogen?  We’ve already talked about the bacterial coverage of very specific pathogen Here’s the thing o Some of these pathogens may develop resistance to the antibiotics that we talked about o So, how do we know what is the best antibiotic for this pathogen that they haven’t developed resistance to it yet? ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 17 of 23 AfraTafreeh.com  (A) GETTING CULTURES Sputum culture Urinary culture We have a patient let’s say they come in, they have an We get urinary culture because we have patient with UTI infection We start treating them, whether it’s o There’s an obvious infection → let’s say pneumonia o Acute cystitis o We think it’s a community-acquired pneumonia or o Pyelonephritis hospital-acquired pneumonia o Complicated UTI  We start on the empirical antibiotics and we get Again we start figuring out what kind of actual bacteria sputum cultures comes back from the culture We get those sputum cultures, grow and see what kind of bacteria they grow Blood culture o And then which antibiotics would be best suited for We think somebody is septic or they have a concern for them CLABSI (central line associated bloodstream infection) Skin soft tissue In those situations we can take them on particular antibiotics We could do the same thing with skin soft tissue o Or whatever we think the actual most common If we have an abscess on the skin soft tissue infection pathogen is AfraTafreeh.com o We take a sample and culture it → send it off  And from there once we get the actual cultures o See what kind of bacteria come back, what antibiotics back are best suited  We figure out which antibiotics are best We can particularly target it Whole point is we’re getting cultures o Sputum cultures o Skin cultures o Urine cultures o Blood cultures (B) ANTIBIOTIC SUSCEPTIBILITY o This would determine minimum inhibitory Culture result concentration Once we do that, we treat them with the empiric antibiotic We can do this with therapy we talked about o Kirby-Bauer method o What happen is we take the bacteria and we grow them o Microdilution o We see which types of bacteria grow o Macrodilution Let’s say we had a patient with the pneumonia AfraTafreeh.com The whole point is what it tells us about minimum The pathogen that it actually grew is Klebsiella inhibitory concentration (MIC) pneumonia o Minimum amount of the actual drug that is needed o From there we want to say,” Okay Klebsiella to be able to kill the particular bacteria pneumonia was the one that grew.” o So we have a gram-negative rod, Klebsiella MIC tells us which types of bacteria are susceptible to pneumonia was the particular pathogen that grew on specific antibiotic that would cover it the culture from the sputum Choosing the best antibiotic The next thing we have to figure out is, “Okay, which Think about everything that would cover Klebsiella antibiotic would be best for this?” o There are plethora of drugs, sometimes we have no Well we know any of those gram negative ones idea which one to pick o So this is part of the HENS-PEcK o We want to prefer some of the narrow one, not super broad Antibiotics for HENS-PEcK  But what if the actual bacteria has developed o Aminopenicillin resistance to it? How do we know? o 3rd generation cephalosporins o 4th generation cephalosporins We do these methods o Carbapenems o Broth o Monobactams o Microdilution o Fluoroquinolones o Macrodilution o Aminoglycosides o Kirby-Bauer method But out of all of those antibiotics that we could pick from The whole point is we expose the actual bacteria to o We want to know which one is the best multiple drugs and figure out  There’s a bunch of different methods o Which one of these antibiotics had the best Broth coverage? Microdilution o Which one the actual antibiotics the bacteria are Macrodilution susceptible to? Kirby-Bauer method o Which one of these antibiotics the bacteria was resistant to? Diffusion o Which one of these antibiotics was the bacteria kind Coolest one and old school way of like in between? We take the bacteria and we introduce antibiotics This is the best way to be able to pick the perfect o We can see how much bacteria died around the antibiotic that will cover the bacteria very well antibiotic 18 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS  AfraTafreeh.com Example Because these are the ones that the Klebsiella pneumonia which we grew out of the sputum culture and Let’s say we have a patient who comes in, they have we tested against multiple antibiotics pneumonia o These were the ones that the actual bacteria was o We start them on antibiotics whether it’s CAP or HAP susceptible to and would actually kill the bacteria We have sputum culture, it comes back with Klebsiella pneumonia o Maybe we had them on let’s say on ceftriaxone and doxycycline  But it comes back Klebsiella pneumonia and we weren’t covering it particularly well o From there we have to figure out which one of these antibiotics would be the best within the HENS-PEcK category? Out of the HENS-PEcK category, which one would the actual bacteria be very susceptible, resistant to, or intermediate? Result Let’s say we took the Klebsiella, we grew it, we found that out AfraTafreeh.com o We expose it to multiple antibiotics o And we did, we found that  Ceftriaxone there was susceptibility → good  Ceftazidime → resistance  Piperacillin + tazobactam (Pip-Tazo) → susceptibility  Meropenem → susceptibility  Gentamicin → resistance  Levofloxacin → resistance  Ampicillin-sulbactam → intermediate Out of all these, which ones do we not pick? Ceftazidime because it’s resistant to it based upon the susceptibility testing which we did with o Microdilution o Macrodilution o Kirby-Bauer method Don’t give them gentamycin o Because there’s resistance to it Don’t give levofloxacin because it’s resistance to it Avoid ampicillin-sulbactam because it’s intermediate o Pick something else o Or if we really like this drug, give higher dose than we usually need to cover Which one of these would we pick? Try to pick the one with the narrow coverage o So we don’t have too much broad coverage Remember o Pip-tazo → super broad agent o Meripenem → not necessarily super broad We’ll just go with ceftriaxone o Not super broad → good choice So again we have options here o Obviously more of a provider preference o But we could pick  Ceftriaxone  Pip-tazo  Meropenem ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 19 of 23  AfraTafreeh.com IX) SUMMARY Table 1. Summary of empiric antibiotics for common infections. Disease Entity Pathogens Antibiotics S. pneumoniae, H. influenzae, M. catarrhalis and atypicals such Community-Acquired Fluoroquinolones as Legionella, Mycoplasma, and Pneumonia Ceftriaxone + Macrolide or Doxycycline Chlamydia Pulmonary Double therapy with: Pip-Tazo, Ceftazidime, Cefepime, or an Hospital-Acquired Pseudomonas and MRSA AG (Pseudomonas) Pneumonia Vancomycin (MRSA) Gram-negative rods (HACEK) Cholecystitis, cholangitis, Carbapenems Anaerobes: Clostridium, appendicitis, diverticulitis, Antipseudomonal penicillins Bacteroides, Fusibacterium, Gastrointestinal pancreatic walled-off Metronidazole + Ciprofloxacin Peptostreptococcus, necrosis, peritonitis, intra- Metronidazole + Ceftriaxone Actinomycedes abdominal abscesses Metronidazole + Cefepime PO: Dicloxacillin or Cephalexin MSSA + Strep A IV: Nafcillin, Oxacillin or Cefazolin Skin and Soft Cellulitis, etc. PO: TMP-SMX, Doxycycline, or Tissues MRSA + Strep A Clindamycin IV: Vancomycin Ceftriaxone Pyelonephritis Fluoroquinolone (ciprofloxacin) Aminopenicillin (ampicillin) PecK (Proteus mirabillis, E. coli, Klebsiella) and Enterobacter TMP-SMX (for non-pregnant patients) Nitrofurantoin Acute cystitis Fosfomycin Urinary Tract Ciprofloxacin (2nd line) Pip-Tazo, Cefepime, Aminoglycoside or Ceftazidime (Pseudomonas) MRSA, Enterococcus, and Complicated UTI Vancomycin (MRSA and Enterococcus) Pseudomonas Aminopenicillins (primarily on Enterococci) MRSA Vancomycin Septic arthritis Bone and Joint Neisseria Ceftriaxone Osteomyelitis Pseudomonas Cefepime and ceftazidime Vancomycin Community-acquired S. pneumoniae, H. catarrhalis, Ceftriaxone meningitis N. meningitidis Ampicillin (IF there is a concern for CNS Listeria) Hospital-acquired Vancomycin Pseudomonas and MRSA meningitis Cefepime AfraTafreeh.com MRSA Vancomycin +/- Pip-Tazo (for Gram- CLABSI Gram-negatives (if there is a negatives) Bloodstream femoral line) Gram-positives Vancomycin Sepsis Gram-negatives Pip-Tazo 20 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS  AfraTafreeh.com Table 2. Summary of adverse effects of antibiotics. Antibiotic NT PCT RF NpT OT MG TT DR QT CY HA PhT Others Penicillins Anaphylaxis Vitamin K deficiency ↑biliary sludge Cephalosporins ↑↑AKI (with AGs) (ceftri) ↑risk of C. difficile (3rd and 4th gen) Carbapenems ↑risk of C. difficile Polymyxins Lactic acidosis Linezolid Serotonin syndrome Peripheral neuropathy ↑risk of C. difficile TMP-SMX Hyperkalemia Chloramphenicol Nitrofurantoin Aminoglycosides Phlebitis Vancomycin Red Man syndrome DRESS ↑risk of C. difficile Hypo- and hyperglycemia Fluoroquinolones Arthropathies Achilles tendon rupture Motility dysfunction Arrhythmias Macrolides Cholestasis Rash Eosinophilia Clindamycin ↑risk of C. difficile Pill-induced Doxycycline esophagitis Teeth discoloration Metronidazole Daptomycin Rhabdomyolysis - NT: Not Tested - DR: Diarrhea - TMP-SMX: Trimethoprim- - PCT: Prolonged Prothrombin Time - QT: QT Prolongation Sulfamethoxazole - RF: Renal Failure - CY: Photosensitivity - DRESS: Drug Reaction with - NpT: Neuropathy - HA: Headache Eosinophilia and Systemic - OT: Ototoxicity AfraTafreeh.com - PhT: Phlebitis Symptoms - MG: Myasthenia Gravis - AGs: Aminoglycosides - TT: Tinnitus - AKI: Acute Kidney Injury ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 21 of 23  X) REVIEW QUESTIONS 1) What is the mechanism of action of Levofloxacin? 11) The following drug can be used in both community- a) Inhibits 30S ribosomal subunit and hospital-acquired meningitis: b) Inhibits mRNA transcription a) Cefepime c) Inhibits enzyme nitro-reductase b) Vancomycin d) Inhibits enzyme topoisomerase c) Ampicillin 2) What is the mechanism of action of Vancomycin? d) Ceftriaxone a) Inhibits 50S ribosomal subunit 12) The following pairing of drugs and its teratogenic b) Inhibits mRNA transcription effect is correct: c) Inhibits dihydrofolate reductase a) Chloramphanicol: pancytopenia d) Decrease peptidoglycan synthesis b) Fluoroquinolones: respiratory failure 3) Which drug is NOT used for pseudomonas c) TMP-SMX: kernicterus infections? d) Aminoglycoside: neurotoxicity a) Cefepime 13) Which of these drugs increase the risk of b) Cefixime ventricular fibrillation? c) Imipenem a) Clarithromycin d) Piperacillin b) Bactrum 4) A patient noticed redness and pus oozing out from c) Vancomycin his stitches, 3 days after surgery. Specimens were d) Ampicillin sent for antibiotic susceptibility testing, which 14) This antibiotic needs a monitoring of CK enzymes showed resistance to the drug most commonly used because it can destroy muscle cells: for this particular organism. Which drug will you give a) Penicillin to treat this patient’s infection? b) Daptomycin [Hint: which organism most commonly causes infection in this c) Vancomycin setting? Which drug is commonly used for this organism?] d) Doxycycline a) Oxacillin b) Piperacillin 15) A triad of rashes, muscle spasms and hypotension c) Vancomycin are side effects of the following: d) Doxycycline a) Vancomycin b) Clindamycin 5) A patient presents with facial nerve palsy and c) TMP-SMX arthritis. On examination, you find erythema migrans. d) None of the above What is the first line of treatment for this patient? a) Doxycycline 16) Which below are the mechanisms of antibiotic b) Clindamycin resistance, EXCEPT? c) Cefepime AfraTafreeh.com a) Increased efflux of the antibiotics d) Penicillin b) Increased inactivating enzyme c) Decreased target binding of the antibiotics 6) A patient presents with a maculopapular rash on d) Increased permeability of the cell wall toward palms and soles, with painless lesions on genitals. antibiotics What is the mechanism of action of the drug used to treat this patient’s condition? 17) Which below are categorized as horizontal mode of a) Cell wall inhibitor gene transfer in bacteria that contributes to further b) Protein synthesis inhibitor growth of resistance, EXCEPT? c) Beta lactamase inhibitor a) Binary fission d) mRNA synthesis inhibitor b) Conjugation c) Transformation 7) Which of the following is NOT an anti-Pseudomonal d) Transduction antibiotic? a) Piperacillin-tazobactam b) Ceftazidime c) Vancomycin d) None of the above 8) In treating gram-negatives and anaerobes of the gastrointestinal tract, a dual therapy of metronidazole and _____ can be used EXCEPT: a) Ciprofloxacin b) Ceftriaxone c) Ertapenem d) Cefepime 9) Which of the following can be used conveniently in methicillin-susceptible S. aureus infection of the skin? a) Nafcillin b) Bactrum c) Clindamycin d) Dicloxacillin 10) Which of the following can be used in a pregnant patient with acute cystitis? a) TMP-SMX b) Ampicillin c) Nitrofurantoin d) Vancomycin 22 of 23 ANTIBIOTIC PHARMACOLOGY: NOTE #5. ANTIBIOTICS AfraTafreeh.com  AfraTafreeh.com XI) REFERENCES Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC. Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Eds (2018) Lippincott Illustrated Reviews: Pharmacology. 6th ed. Philadelphia, PA: Wolters Kluwer, (2015) Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic & Clinical Pharmacology, 14e. McGraw Hill (2018) Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC. Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Eds (2018) Lippincott Illustrated Reviews: Pharmacology. 6th ed. Philadelphia, PA: Wolters Kluwer, (2015) Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic & Clinical Pharmacology, 14e. McGraw Hill (2018) Le, Tao; Bhushan, Vikas; and Sochat, Matthew. First Aid for the USMLE Step 1 2021. New York: McGraw-Hill Education, 2021. SlideShare. (2019, July 19). Gray Baby Syndrome. Retrieved from SlideShare: https://pt.slideshare.net/JagirPatel3/chloramphenicol-156480414/9 UK Teratology Information Service. (2017, June). Tetracyclines. Retrieved from UK Teratology Information Service: https://www.medicinesinpregnancy.org/Medicine-- pregnancy/Tetracycline/ Chrysant, S. (2019). Proton pump inhibitor-induced hypomagnesemia complicated with serious cardiac arrhythmias. AfraTafreeh.com Expert Review of Cardiovascular Therapy. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC. Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Eds (2018) Lippincott Illustrated Reviews: Pharmacology. 6th ed. Philadelphia, PA: Wolters Kluwer, (2015) Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic & Clinical Pharmacology, 14e. McGraw Hill (2018) ANTIBIOTICS ANTIBIOTIC PHARMACOLOGY: NOTE #5. 23 of 23