Antimicrobials Summary.pdf

Drug Cheat Sheet Joodi Mourhli_BSN3 AUB_2021-2022 Map Key Commented [JM(1]: Gram negative...

Drug Cheat Sheet Joodi Mourhli_BSN3 AUB_2021-2022 Map Key Commented [JM(1]: Gram negative Gram positive ANTIMICROBIALS Anaerobes Atypical SULFONAMIDES: Pseudomonas - Bacteriostatic - Gram negative - Inhibition of DNA synthesis via: o Inhibition of dihydropteroate enzyme o Inhibition of dihydropteroate and dihydrofolate enzymes (Bactrim/ Co-trimoxazole= trimethoprim+ sulfamethoxazole) - First antimicrobial to ever be used - Used to treat simple gram negative UTIs. - Toxicity includes: o Kernicterus, for sulfonamides compete with bilirubin on albumin binding, and albumin usually binds with bilirubin to transport it to the liver and prevent its accumulation to the organs including the brain. o Hemolytic anemia o Photosensitivity o Renal damage → drink a lot of water - Toxicity of trimethoprim includes: o Folate deficiency in naturally deprived patients (alcoholic, pregnant, malnourished) QUINOLONES: - 4 generations - First has a narrower spectrum - Fourth has a broader spectrum - Have an awesome coverage: positive, negative, atypical, and even anaerobes - They are bactericidal that affect DNA integrity by inhibiting topoisomerase II - Used to treat a wide range of diseases: o UTIs o STIs o Infectious diarrhea o Diabetic foot o Bacterial TB o RT Infections - Generations: o First: gram negative only o Second: gram negative, some gram positive, and atypical Commented [JM(2]: Tavanic is a 2nd generation o Third: gram negative, a lot of gram positive, atypical, and anaerobes quinolone that treats gram-positive, negative, and atypical bacteria o Fourth: gram negative, gram positive, atypical, and many anaerobes - Quinolones have an overall excellent distribution in lungs, kidneys, stool, bile, joints, but not in the brain → do not cross the BBB - Ciprofloxacin is given as 500 mg single dose for meningococcal prophylaxis so that the bacteria does not even reach the meninges - Toxicity includes: o Gastrointestinal: nausea, vomiting, diarrhea o CNS: headache, dizziness, fatigue, sleep disorders, hallucinations, depression, and seizures o Skin: phototoxicity (exaggerated sunburns) and hypersensitivity (rash, pruritis) o Arthropathy (joint inflammation) → reason for contraindication in kids and pregnancy o Tendon rupture → reason for contraindication in kids and pregnancy (Remember that the difference between gram positive and negative bacteria is that gram positive have a thicker layer of peptidoglycan and lack an outer lipid membrane that allows only hydrophobic drugs to enter. Also remember that all beta lactams have to bind to the penicillin binding protein on the bacterium to work. So, they have to penetrate the lipid outer layer in case of gram-negative bacteria. In case they couldn’t, they will have to go through a channel called porin.) BETA LACTAMS: - Cell wall active antimicrobial - Bactericidal - Divided into 4 types o Penicillin o Cephalosporins o Monobactams o Carbapenems - They are called beta lactams because of the unique b-lactam ring that they possess in their structure. - They look very similar to the d-ala-d-ala in the bacterial cell wall and thus fool the PBP or transpeptidase enzyme of the bacteria and bind to it, preventing it from synthesizing d-ala-d-ala, which is an essential precursor of bacterial peptidoglycan Penicillin: - Discovered by Sir Alexander Fleming in 1929 - Has some side effects such as allergy due to the presence of b-lactam ring, GI toxicity, and sodium overload especially with ticarcillin when given IV. - Main mechanism of resistance are Beta lactamases. This is why we sometimes add Beta lactam inhibitors such as Clavulanic ACID in Augmentin which is a combination of Amoxicillin plus Clavulanic acid. - Divided into: o Penicillin G has PK problems such as instability in acids, erratic absorption in PO form, very short half-life, so it is given only IV o Pharmacologically improved penicillin: PK improvements and oral bioavailability o Procaine penicillin G: slowly absorbed so given IM o Benzathine penicillin G: very slowly absorbed so given only IM to treat syphilis and prevent rheumatic fever (activity is after 26 days) o Penicillinase-resistant penicillin: for specific staph. Aureus infections o Extended spectrum aminopenicillin: (gram positive and negative) o Ampicillin: 50% bioavailability → causes GI toxicity and rash that is not allergy o Amoxicillin: 100% bioavailability → less GI toxicity and no rash o Anti-pseudomonal: divided into carboxypenicillin and aminopenicillin ▪ Carboxypenicillin: Carbenicillin and ticarcillin (twice as potent as carbenicillin and causes sodium overload if given with normal saline via IV) ▪ Aminopenicillin: Piperacillin and Tazobactam Cephalosporin: - Same MOA as penicillin - Divided into generations depending on their spectrum of activity: Commented [JM(3]: Keep in mind that the first 2 o First: gram positive bacteria (skin infections) generations of cephalosporins are not additive like those of quinolones. Each covers a particular range of bacteria and o Second: gram negative bacteria (E. coli) and even anaerobes does not necessarily include the range that is covered by the o Third: gram positive, negative, and pseudomonas generation before it. o Fourth: more resistant to beta-lactamases and covers some pseudomonas  o Fifth: as good as the 3rd and 4th, better for pseudomonas, and most importantly MRSA - Adverse Effects: o Hypersensitivity reactions: cross reactivity with penicillin o Neutropenia o Anemia o Reduced platelets aggregation → risk of bleeding o Nephrotoxicity o GI toxicity o Abnormal liver function test + liver toxicity o Miscarriage o Defects of newborn babies o Bleeding (cefamandole, cefoperazone, ceftriazone) Carbapenem: - Imipenem: o Same MOA as penicillin and cephalosporin o Very broad spectrum (gram positive, negative, anaerobes, and pseudomonas) o No atypical bacteria coverage though o Used as empirical treatment for serious hospital infections o Resistance is rare so far o Resistant to most b-lactamases o Excessively metabolized in the kidney o Inactivated by dehydropeptidases I in renal tubules, resulting in low urinary concentrations (Imipenem + Cilastatin) o Toxicity includes: ▪ Nausea and vomiting ▪ Seizure risk (patients in ICU are at higher risk due to electrolyte imbalances) ▪ Cross allergy with other beta lactams ▪ Increased bleeding tendency - Meropenem: o It has a lower risk of causing seizures than imipenem Monobactam: called “mono” because it has only 1 ring which is a beta lactam ring with no other cyclical structures around it - Aztreonam: o Non-aminoglycoside “aminoglycoside: o Gram-negative coverage only o Well-tolerated o No cross allergy with penicillin except for ceftazidime that’s a cephalosporin similar in structure to it o The half-life is 1–2 hours and is greatly prolonged in renal failure NON-BETA LACTAMS: - Vancomycin: o Gram positive bacteria only o Used to treat C. difficile colitis → taken in PO and not IV or else it won’t have an effect o Used for treatment of MRSA and MRSE o Excreted renally - Toxicity includes: o Hypersensitivity o Phlebitis o Red man syndrome: due to flushing of IV o Ototoxicity and nephrotoxicity (this is why a Vanco-trough is ordered at the hospital for people maintained on vancomycin. Their plasma concentration of the drug is measured regularly and is maintained within the therapeutic range. If it exceeds that, the dose is lowered to prevent nephrotoxicity) RIBOSOME INHIBITORS: INHIBITORS OF TRANSLATION: - Bactericidal: o Aminoglycosides (30S- subunit) - Bacteriostatic: o Tetracyclines (30S- subunit) o Linezolid (50S- subunit) o Chloramphenicol (50S- subunit) o Clindamycin (50S- subunit) o Macrolides (50S- subunit) o Streptogramins (50S) Aminoglycosides: - Inhibit the small ribosomal subunit and are bactericidal - Rarely used alone because of toxicity - Gram negative bacteria only - Used in the hospital for severe infections caused by aerobic (since these drugs are positively charged, they need aerobic conditions to enter the cell) and gram-negative bacteria - Can be used in combination with beta-lactams to treat gram-positive bacterial infections (example of AMPIGENTA: amoxicillin and gentamycin to rule out sepsis in a newborn)[remember that amoxicillin and gentamycin cannot be mixed in the same saline bag because if they are, the amoxicillin will inactivate the gentamycin] - Toxicity includes: o Nephrotoxicity: common, cumulative dose, DDI with vancomycin, cephalosporin, and NSAIDs o Ototoxicity (e.g. vertigo and hearing loss): uncommon, trough level (drug concentration right before the next dose) and not cumulative dose, DDI with ethacrynic acid o Neuromuscular paralysis: very rare, risk increases with fast infusion, we have to be careful with myasthenia gravis patients and those who use NMJ blockers. Tetracyclines: - Inhibit the small ribosomal subunit and are bacteriostatic - Originally, they were very awesome and such broad-spectrum drugs that covered gram positive and negative in addition to aerobic and anaerobic bacteria; however, due to resistance, they are reserved only for atypical organisms now. - Pharmacokinetics: o Absorption: oral absorption impaired by milk, antacids, Fe and Zn (so, we must tell patients to space the milk, antacids, milk, Fe, Zn, and the drug by at least 2 hours) o Distribution: they get deposited with calcium in bone and enamel of non-erupted teeth (so, we cannot prescribe them for children whose teeth are not permanent, yet) & they cross the placenta (so, we also cannot prescribe them for pregnant ladies or else the newborns will suffer from the same deposition problem as their teeth are non-erupted yet) o Excretion: renal and biliary, in addition to milk (so, we cannot prescribe them for lactating or breast-feeding mothers due to the same enamel problem) - Adverse Effects: o Gastrointestinal: ▪ Most common ▪ Take with food but not milk (due to the limited absorption featured when taken with milk) ▪ Pseudomembranous colitis o Thrombophlebitis with IV administration o Photosensitivity (exaggerated sunburns) o Effect on teeth: ▪ Deposition of tetracycline-calcium orthophosphate ▪ upon exposure to sunlight, darkened bands appear on teeth ▪ important from the last few days of pregnancy through about 6 years (can’t be prescribed then) Linezolid: - Prescribed for the worst of the worst gram-positive bacteria - Used for vancomycin-resistant enterococcus (VRE), Vancomycin resistant Staph, and methicillin- resistant Staph. Aureus (although here we would rather give vancomycin or 5th generation cephalosporins and not linezolid) - Adverse effects: o MAO inhibition o Minor: ▪ Headache, nausea, diarrhea o Rare: ▪ Hypotension ▪ Myelosuppression ▪ Hematological Toxicity Clindamycin: - We used to give it to gram positive cocci, but now we have less-toxic drugs - It is prescribed to mostly treat anaerobic bacteria - Toxicity: o Pseudomembranous Colitis: highest association in comparison with other antimicrobials o Treatment ▪ Metronidazole (Oral or IV) ▪ Oral vancomycin (remember that if we give vancomycin IV, we will treat MRSA or MRSE but not C. difficile) Macrolides: - Used to treat atypical bacteria - Used in case of penicillin allergy to treat gram-positive bacteria (strep. Pneu., group A strep) - Examples:  o Erythromycin (prototype) ▪ Cheap ▪ GI Side Effects o Azithromycin ▪ Once Daily ▪ Expensive o Clarithromycin ▪ Expensive ▪ Twice Daily - Toxicity: o Nausea and vomiting o Erythromycin and Clarithromycin inhibit CYP3A (risk for DDI or drug-drug interactions) Metronidazole/Flagyl: Commented [JM(4]: Keep in mind that even if this drug sounds similar to most antifungals, it is NOT AN - IV therapy for serious anaerobic infections ANTIFUNGAL. - Oral therapy for amebiasis, giardiasis, trichomoniasis (genital infections) - Oral (and IV) therapy for colitis due to C. Difficile - MOA: o A reduced form interacts with bacteria DNA, causing DNA strand breakage. o Bacterial Resistance: ▪ Decreased activity of reductases ▪ Less common with anaerobes. ▪ Common with H.Pylori - Adverse Effects: o GI disturbance and metallic taste (loss of taste) o Neurotoxicity (dizziness & vertigo) o Blood dyscrasias (destructing bone marrow cells) and neutropenia o Disulfiram (Antabuse) like reaction with alcohol consumption Commented [JM(5]: No alcohol with antibiotic: why? o CYP interactions (risk for DDI) Increased GI side effects Some antimicrobials such as metronidazole and cephalosporins have disulfiram reaction. Alcohol is metabolized into acetaldehyde, which is then metabolized via acetaldehyde dehydrogenase into acetic acid. This enzyme is inhibited by these antimicrobials. Thus, the concentration of acetaldehyde is increased and this is the reason behind the GI effects and flushing with acetaldehyde. Disulfiram or Antabuse is a pill given to alcoholic patients after they are discharged from the rehabilitation center so that they do not drink again, as this drug increases the concentration of acetaldehyde and makes them experience adverse effects such as GI disturbance and flushing every time they drink again.  ANTIFUNGALS Amphotericin B: - Used for serious systemic mycosis - MOA: o Binds to ergosterol → more permeable membrane → leakage of ions - Toxicity: o Infusion related ▪ Chills, fever, rigors, nausea, headache ▪ Pretreatment with diphenhydramine, acetaminophen, glucocorticoid (so, we suppress the allergic response) o Nephrotoxicity o Anemia (monitor with regular CBC) -azole Fungal Agents: - MOA: o Inhibit CYP enzyme→ inhibit ergosterol synthesis - Itraconazole (Sporanox) o Therapeutic uses: ▪ Systemic and superficial fungal infections o Pharmacokinetics: ▪ IV and PO ▪ Variable absorption ▪ Inhibits CYP3A4 (risk for DDI) o Toxicity ▪ Cardiac suppression ▪ Liver injury ▪ Drug-drug interactions - Fluconazole (Diflucan) - Clotrimazole (vaginal suppository) - Miconazole (Daktarin cream) - Ketoconazole (Nizoral cream) - Note: Oil based creams may weaken latex condoms and diaphragms Lecture 6: Antimicrobials Gram +ve bacteria - Streptococcus pneumonia (pneumonia) - Staphilococcus aureus (skin infection) - Group A streptococcus (tonsillitis, pharyngitis) Gram -ve bacteria - Escherishia coli (UTI) - Neisseria Gonorrhea (STD) - Haemophilus influenza (tonsillitis, otitis) - Pseudomonas Aeroginosa (hospital acquired infection) Atypical bacteria are bacteria that have the following characteristics: - Size is smaller than typical bacteria - They are obligate parasites - Colorless with gram staining - They do not have cell walls - They have complicated reproduction Eg: mycoplasma pneumonia, chlamydia trachoma (sti), legionella pneumophilia (pneumonia) Antimicrobial classifications depends on multiple characteristics such as chemical structure, source (natural, fungi, bacteria, or synthetic or semisynthetic), spectrum of activity (narrow or broad), antimicrobial activity (bacteriostatic or bactericidal), kinetics (oral, systemic) and mechanism of action Mechanism of action: selective inhibition of similar targets Each type of antimicrobials targets a certain function in the development of bacteria (each of these below are what is targeted by what antimicrobials) 1- Cell wall synthesis o Beta lactams o Vancomycin o Bacitracin o Cell membrane 2- Nucleic acid synthesis o Folate synthesis o DNA gyrase o RNA polymerase 3- Protein synthesis o 50S subunit o 30S subunit Hydrophilic antibiotics: - Examples: β-lactams (Penicillins, Cephalosporins, Carbapenems), Glycopeptides, Aminoglycosides. - Characteristics: - Limited Volume of Distribution (VD): These antibiotics are primarily confined to the extracellular fluid and do not distribute widely throughout the body. - Inability to Passively Diffuse through the plasma membrane (PM) of eukaryotic cells: Hydrophilic drugs can't easily cross cell membranes, which limits their ability to act on intracellular pathogens. - Inactive Against Intracellular Pathogens: Since they can't penetrate cell membranes, hydrophilic antibiotics are ineffective against bacteria that reside inside cells. - Eliminated Renally as Unchanged Drugs: These drugs are excreted by the kidneys without being metabolized in the liver, meaning they are eliminated in their original form through urine. Lipophilic Antibiotics: - Examples: Macrolides, Fluoroquinolones, Tetracyclines, Chloramphenicol, Rifampicin, Linezolid. - Characteristics: - Large Volume of Distribution (VD): Lipophilic antibiotics can diffuse into tissues more widely, resulting in a larger distribution across the body. - Freely Diffuse Through Plasma Membranes: Their lipophilic nature allows them to easily pass through the lipid bilayer of cell membranes. - Active Against Intracellular Pathogens: Due to their ability to cross cell membranes, lipophilic antibiotics can target bacteria that live inside cells. - Eliminated by Hepatic Metabolism: Unlike hydrophilic drugs, lipophilic antibiotics are metabolized by the liver before being excreted. - Hydrophilic antibiotics are effective against extracellular bacteria and are excreted unchanged through the kidneys. - Lipophilic antibiotics, on the other hand, can target intracellular pathogens and undergo hepatic metabolism. Choice of antimicrobials and determinants of successful therapy Many factors affect the choice of antimicrobial agent and its dosage such as the age, renal function, pregnancy, host genetic factors as well as the site of infections and if there are any poor vascularity or anaerobic conditions of the infected site. Pharmacokinetics such as the formulation of the drug also affects the choice of antimicrobial. The drug given should be able to target the area wanted. For example, a drug given for UTI should be renally excreted, and a drug to treat the CNS should be able to cross the Blood brain barrier to be effective. Combinations of antimicrobials: can result in 3 different types of effects 1- Additive (indifferent) effect: two drugs combined are equal to the sum or partial sum of their activity when they are used each alone. Yaane their effect sawa bizid 2- Synergistic effect: two drugs combined have greater activity then when used each alone. 3- Antagonistic effect: two drugs combined have less activity then when each is used alone. Yaane the sum of their activity aeal men waeta ykun kel Wahad used la halo. 4- Empiric therapy in neutropenic patients: For neutropenic, critically ill patients with an unknown infection cause, broad-spectrum antibiotics are initiated empirically to cover potential pathogens due to their high risk for severe infections. 5- Treatment of polymicrobial infections: In abdominal infections involving aerobic and anaerobic organisms, combination antibiotics are used to cover a wide range of bacteria, ensuring effective treatment of all potential pathogens. 6- Enhancing antimicrobial activity: In Pseudomonas infections, combining a β-lactam agent (for cell wall inhibition) with an aminoglycoside (for protein synthesis inhibition) enhances bacterial killing, often providing synergistic effects. If both drugs are bactericidal → they can have either an additive or synergistic effect depending on the drugs being combined If one drug is bactericidal and the other is bacteriostatic → have an antagonistic effect since one of the drugs inhibits the bacteria and the other helps it. Synergistic effect: two bacteriostatic drugs produce bactericidal action when combined There are some complications of combining antimicrobials such as increased toxicity and adverse effects, increased costs, superinfection (inducing a new infection) Acquired microbial resistance: Types of Mutations in Drug Resistance: 1- The drug does not reach its target because of: - Efflux: Bacteria pump the drug out, reducing its concentration.  - Reduced permeability: Changes in the bacterial cell membrane prevent the drug from entering 2- Drug inactivation because of: - Enzymatic degradation: Bacteria produce enzymes (e.g., β-lactamases) that break down the drug, rendering it ineffective. 3- Target modification/overproduction: - Target modification: The drug’s target site is altered, preventing the drug from binding effectively. - Overproduction: The bacteria produce excess amounts of the target, overwhelming the drug's effect. How Resistance is Spread: - Vertical transmission: Acquired resistance is passed from parent bacteria to offspring during cell division. - Horizontal transmission: Resistance is transferred between bacteria, leading to rapid spread and multidrug resistance (MDR). - Transduction: Resistance genes are transferred via viral DNA (bacteriophages). - Transformation: Bacteria take up free DNA from the environment and incorporate it into their genome. - Conjugation: Resistance genes are transferred between bacteria through direct contact using a sex pilus. Classes of Antimicrobials Each of the classes act on a specific mechanism of destruction of microbes which are the names of the classes A- Antifolates:  1- Sulfonamide: different classes of drugs derived from or associated with sulfonamides, which are a group of synthetic antimicrobial agents. a- Children's antibacterial drugs b- Hepatitis C antivirals c- Anticonvulsants d- Stimulants e- Anti-diabetic agents f- Antiretrovirals g- Diuretics h- Dermatologicals Sulfonamides activity: - Bacteriostatic effect against a wide range of gram +ve and -ve bacteria microorganisms - They are active against toxoplasma, noocardia species and chlamydia. - They are usually reserved for treatment of nocardiosis and toxoplasmosis - Mechanism of action: competitive inhibitor of dihydropteroate synthase Microbes can synthesize dihydrofolic acid, dihydropteroate sythesase and are impermeable to folic acid. 2- Trimethoprim - Mechanism of action: synergistic effect both microbes and humans can reduce dihydrofolic acid using dihydrofolate reductases, however microbe dihydrofolate reductase is different than humans as Trimethoprim inhibit theirs. If you combine sulfonamides with Trimethoprim: o Since they are both bacteriostatic drugs, they produce bactericidal action when combined o Trimethoprim enters tissue and has larger distribution volume o The combination has a wider antibacterial spectrum, delays the development of bacterial resistance o Minimal inhibitory concentration of each component can be reduced 3-6 times Sulfonamide toxicity: - They can cause photosensitivity (use sunscreen) - They can cause hemolytic anemia - Diabetic patients most probably have sensitivity to sulfonamide, so the addition of trimethoprim is to stop the cell cycle and inhibit the replication of bacteria, making it static. - Competition for bilirubin binding sites on albumin can cause kernicterus in neonates since their BBB is not fully developed. - Can cause renal damage due to crystals deposition - Idiosyncratic reactions due to hemolysis in glucose 6 phosphate dehydrogenase deficiency which can cause drug fever, skin rashes, joint pain and lymphadenopathy - Long-acting sulfonamides can cause stevens Johnson syndrome. Trimethoprim toxicity: - Rare and might cause rash, nausea and/or vomiting - Can cause folate deficiency in nutritionally deprived patients (folate deficient, pregnancy, malnourishment, alcoholic) which can cause megaloblastic anemia, thrombocytopenia and neutropenia. B- DNA Gyrase: Quinolones 1st generation: - Highly protein bound, mostly used in UTIs Fluoroquinolones (2nd, 3rd, 4th generations) are modified 1st generation quinolones, not highly protein bound and are distributed to urine as well as to other tissues. They have limited CSF penetration. Mechanism actions: fluoroquinolones inhibit 2 types of DNA topoisomerases 1- Topoisomerase IV It untangles intertwined DNA to allow proper separation of chromosomes into cells during replication. Inhibiting topoisomerase IV, mainly in gram-ve bacteria prevents the bacteria from dividing properly. 2- DNA gyrase (topoisomerase II) Introduces negative supercoils into DNA that relaxes +ve twists that build up ahead of the replication fork during replication. Bacteria that lack topoisomerase IV, DNA gyrase act as its replacement. By inhibiting DNA gyrase, mainly in gram +ve bacteria, proper unwinding of DNA is prevented, disrupting replication. Quinolones therapeutic uses: - UTIs, STIs - Infectious diarrhea - Diabetic foot infection - Mycobacterial diseases (tuberculosis..) - Respiratory tract infections Quinolones have excellent distribution in lungs, kidneys, stool, bile, joints and soft tissues. Not good in CNS Adverse reactions: - Nausea, vomiting, diarrhea, headache, dizziness, insomnia. - In cardiovascular system causes: hypotension, tachycardia and prolonged QT interval  - In CNS, they cause: Headache, dizziness, sleep disturbances, mood change, confusion, psychosis, tremor, seizures - Integumentary: Rash, pruritis, photosensitivity, leg pigmentation, urticaria - Hepatic: increase in aminotransferases, cholestatic, jaundice, hepatitis, hepatic failure - Musculoskeletal: Arthropathy, tendinitis, tendon rupture: CONTRAINDICATED IN CHILDREN - Renal: Azotemia, crystalluria, hematuria, interstitial nephritis, nephropathy, renal failure - Drug fever, chills, serum sickness-like reaction, anaphylaxis, angioedema, bronchospasm, vasculitis, hypo/hyperglycemia C- Antimicrobials that weaken the bacterial cell wall: Beta-lactams 1- Penicillin Penicillin-binding proteins have 2 enzymatic activities that are crucial to synthesize the peptidoglycan layers of bacterial cell wall that reinforce the bacteria. Beta lactams (penicillin) binds on TP (cross links amino acids side chains) and inhibits transpeptidase which leads to the inhibition of GT (linking subunits of glycopeptide polymer) and stops by that the replication of bacterial cells - Penicillin is the first true antibiotic antibacterial produced by microorganisms Bacterial resistance against penicillin: o Alteration of PBP site: bacteria can mutate their PBP making antibiotics like penicillin ineffective. o Reduced permeability: bacteria can reduce the permeability of their cell membranes, limiting the entry of antibiotics into the cell. o Beta-lactamase production: bacteria produce beta-lactamase enzyme which degrades beta-lactam antibiotics (penicillin). a- Beta lactamase hydrolyzes (opens) beta-lactam rings b- Beta-lactamase inhibitors: clavulanate competes with penicillin for access to beta-lactamase active site, so beta lactamase hydrolyzes clavulanate instead of penicillin. Penicillin families are classified on the basis of: - Source (natural, semisynthetic) - Route of administration (oral, parenteral) - Spectrum of activity (narrow, broad, intermediate, extended) - Resistance to enzymes (resistance to beta lactamase, nonresistance to beta lactamase) - Resistance to acids (acid stable, acid unstable) Natural Penicillin: Penicillin G pharmacokinetics: - Short half life  - Not well absorbed, acid unstable, erratically absorbed when given PO - Distribution → CSF penetration is increased with inflammation - Elimination → only 10% metabolized, excreted renally PK enhancement: Orally available → Penicillin V (acid stable) Longer acting → procaine penicillin, benzathine penicillin (slowly absorbed IM, STD) Extended spectrum Aminopenicillins Ampicillin: spectrum includes some gram -ve bacteria, oral bioavailability (50%), toxicity includes diarrhea and skin rash Amoxicillin: 100% bioavailability Penicillinase resistant penicillin: not hydrolized by beta lactamase (oxacillin, cloxacillin, dicloxacillin, nafcillin) Anti-pseudomonal carboxypenicillins: carbenicillin (no longer used), ticarcillin, ticarcillin with clavulanate. Broad spectrum, including pseudomonas. Anti-pseudomonal aminoacylpenicillins: class drugs (azlocillin, mezlocillin, piperacillin, tazobactam), extended spectrum including pseudomonas, broader coverage than ticarcillin. Beta-lactamase inhibitor combinations: a- Amoxicillin and clavulanate oral (augmentin) b- Ampicillin and sulbactam IV (Unasyn) c- Piperacillin and tazobactam (Tazocin) Penicillin adverse effects Allergy due to beta lactam ring, non-allergic Common: GI symptoms, Sodium overload (ticarcillin) Less common: bone marrow depression, hepatitis, seizures, impairment of platelets aggregation