Inhibitors_of_Cell_Wall_Synthesis_Lecture_Stu_Robert Parker.pptx

Inhibitors of Bacterial Cell Wall Synthesis/Destruction Wayne Parker, PharmD Notes • TopHat Questions assigned • Always can email me questions – [email protected] • We can also set up a Zoom/office (210) to discuss as well • I will NOT ASK SPECTRUM OF ACTIVITY QUESTIONS ON THIS TEST (I will on all...

Inhibitors of Bacterial Cell Wall Synthesis/Destruction Wayne Parker, PharmD Notes • TopHat Questions assigned • Always can email me questions – [email protected] • We can also set up a Zoom/office (210) to discuss as well • I will NOT ASK SPECTRUM OF ACTIVITY QUESTIONS ON THIS TEST (I will on all future tests – in system courses) – But I will introduce spectrum of activity now as you are learning antibiotics for the first time because I feel it’s the most appropriate way to learn 2 Learning Objectives • Mechanism of action and resistance – Explain the mechanism of action of each drug in each drug class. – Explain the mechanism of resistance of each drug in each drug class. • Pharmacokinetics – Describe, generally, the distribution and elimination of drugs in each class. – Describe the route of administration of drugs in each class. • Adverse effects, drug interactions and contraindications – Describe the main adverse effects of the drug of each class. – Describe the main contraindications of the drug of each class. • Therapeutic uses – Differentiate between the uses of these drugs in infectious diseases. • Identify penicillin allergies and proper alternatives in penicillin-allergic patients 3 Easiest Way to Learn Drugs • Start by learning the class and the facts about the class – B-lactams • Penicillins (nafcillin, amoxicillin, ampicillin, pipercillin, etc) • Cephalosporins (cephalexin, cefazolin, ceftriaxone, cefdinir, etc) • Cabapenems (imipenem, meropenem, ertapenem, etc) – Macrolides – Antipsychotics – SSRIs • Then learn the unique characteristics of the individual agents that differentiate themselves from the others in the class – Nafcillin is the only penicillin excreted non-renally (biliary) 4 How to Choose the Appropriate Antibiotic • Seriousness/emergency of infection – Strep throat vs sepsis • Patient characteristics = risk factors – Age, body weight, comorbidities • Antibiotic characteristics – guidelines make this decision for you – PK, PD, side effects, distribution to desired site of infection (CNS, skin, ear) • Spectrum of Activity of Antibiotic – Gram (+), Gram (-), anaerobes, atypicals • Start with the class of antibiotic (Beta-lactams, macrolides, FQ, etc) • Use your “Absolute Statements” 5 Drugs and Drug Classes to Consider BETA-LACTAM DRUGS Penicillins Narrow spectrum Broaderspectrum Penicillin G Penicillin V Cloxacillin Methicillin Nafcillin Amoxicillin Ampicillin Ticarcillin Piperacillin Carbapenems Cephalosporins 1st generation Cefazolin Cephalexin 2nd generation 3th generation 4th/5th generation Cefuroxime Cefotetan Cefoxitin Ceftriaxone Cefotaxime Cefdinir Cefoperazone Ceftazidime Cefepime (4th) Ceftaroline (5th) Monobactams Beta-lactamase inhibitors Clavulanate avibactam Imipenem (plus cilastatin) Tazobactam vaborbactam Meropenem, doripenem Aztreonam Sulbactam xxxxxxxxxxxxxxxxx ertapenem OTHER CELL WALL SYNTHESIS INHIBITORS Vancomycin Teicoplanin & Telavancin Fosfomycin Daptomycin Colistin 6 General Spectrum for B-lactams 7 Cell Wall Target Antimicrobials 8 B-lactam Mechanism of the antibacterial effect Mainly the two following actions: • Beta-lactam antibiotics bind to specific beta-lactam receptors called penicillin-binding proteins (PBPs) located on the cytoplasmic membrane. These proteins are enzymes with various catalytic functions which are inhibited by the binding with the antibiotic. • If only this mechanism is operative ultimate effect is bacteriostatic. • Autolytic enzymes (called autolysins or murein hydrolases) are present in the cell wall and degrade the peptidoglycan. Betalactam antibiotics can activate these autolysins (by blocking an autolysin inhibitor), promoting the lysis of bacteria. • If both mechanisms are operative the ultimate effect is bactericidal. • Bactericidal effect is time-dependent. Penicillin-binding proteins (PBPs) • The most important enzymes inhibited are transpeptidases which catalyze the final cross-link step in the synthesis of murein (peptidoglycan). Peptidoglycan layers are constituents of bacterial cell wall, the synthesis of this wall is blocked. More features of the antibacterial effect • Susceptibility of bacteria to beta-lactam antibiotics depends on: – the constitution of the outer layers of the cell envelope that the antibiotic must cross. – the thickness of peptidoglycan layer (thickness is much higher in gram-positive bacteria than in gram-negative bacteria). Microbial Resistance to Beta-Lactam Antibiotics Features: 1. Acquired resistance can develop in many microbial species (cocci, bacteroides, etc.) 2. Acquired resistance is mainly extrachromosomal and is mediated by a plasmid that can be transferred to other bacteria. 3. Cross-resistance occurs among all beta-lactamase sensitive penicillins. Some of these features can also be acquired so that a sensitive strain can become resistant a) lack a peptidoglyca n cell wall (mycoplasm a) b) have cell walls impermeable to the drug (many gramnegative bacteria) Natural resistance occurs in bacteria that: c) are betalactamase producing organisms d) have PBPs with low affinity for the drug Main Mechanisms of Microbial Resistance to Beta-Lactam Antibiotics 1) Production of beta-lactamase enzymes (most important mechanism!!). 4) Development of an active efflux pump (some Gram (-) bacteria) • Beta-lactamases hydrolyze beta-lactam rings producing penicilloic acids which lack antibacterial activity. • Genes can be transferred by a plasmid. 2) Development of PBPs with decreased affinity for the antibiotic (mechanism for penicillin resistance in pneumococci and MR staphylococci). • The genes can be transferred by a plasmid. 3) Decreased permeability of the cell membrane to the drug ( many Gram (-) bacteria) Example of How to Use B-lactamase Inhibitors B-lactam B-lactamase Inhib amoxicillin clavulanate pipercillin tazobactam • Example 1: A 6-year-old with otitis media infection caused by non-B-lactamase producing H. influenzae you may treat with just amoxicillin • Example 2: Same 6-year-old with repeat otitis media infection caused by a NOW BLACTAMASE producing H. influenzae you must treat with amoxicillin + clavulanate (Augmentin ®) • The addition of the clavulante (beta-lactamase inhibitor) neutralizes the betalactamase enzyme produced by the bacteria which allows amoxicillin to do it’s job and bind to PBP without getting chopped up 14 Classification of Penicillins Narrow-spectrum penicillins Penicillinase-sensitive: Anti – Staphylococcal (only): Oxacillin Nafcillin Methicillin Penicillin G (IM/IV) Penicillin VK (oral) Broader-spectrum penicillins Ampicillin Amoxicillin Amoxicillin + clavulanate Ticarcillin Ticarcillin + clavulanate Piperacillin Piperacillin + tazobactam 16 Pharmacokinetics of Penicillin ABSORPTION DISTRIBUTION • oral: variable • parenteral: good (procaine penicillin and benzathine penicillin are parenteral preparations that are slowly absorbed from the IM injection site) • Penicillin G – parenteral • Penicillin VK - oral • Widely distributed throughout the body • Concentrations low in CSF, joint and ocular fluids. • Concentrations are increased when meninges, joint spaces and eye are inflamed (ex: meningitis) • Increased concentration in CSF results from increased drug entry and decreased active efflux by the organic acid transport system in the choroid plexus. BIOTRANSFORMATIO N • Variable (amoxicillin ~5%, penicillin V ~ 60%), generally low. EXCRETION • By the kidney (mainly by tubular secretion) • Nafcillin is mainly cleared by biliary excretion -> feces. • Half-lives: 0.5 - 1.5 hours (half-lives can be very prolonged in case of kidney failure) • Dose multiple times a day Allergic Reactions to Penicillin Occur in 10-15% of persons with a history of a penicillin reaction and in 1-10% (lower end) of persons with no history The frequency of allergic reactions is the highest with repository penicillins (pen. G benzathine, pen. G procaine) and the lowest with oral penicillins. All penicillins are crosssensitizing to, and cross- reacting with all other beta-lactam antibiotics, except aztreonam. Serious allergic reactions have occurred after parenteral administration. Fatal anaphylactic reactions have occurred after oral ingestion or intradermal administration (skin test) of very small quantities of drug. Allergic reactions not due to penicillin itself but mainly to its breakdown products. The most important antigenic determinant is the penicilloyl moiety, formed when the beta-lactam ring is opened. What are our options? What do we do in a penicillin allergic patient? We may try a ceph (avoid 1st or 2nd gen), use aztreonam, or use a macrolide A large percentage of immunoglobulin (Ig)Emediated reactions are due to PMD Management of the patient potentially allergic to beta-lactam antibiotics Urticaria Associated with Ampicillin Allergy History of penicillin allergy? should be treated with a different type of antibiotic!! • Make sure it’s a TRUE ALLERGY AND NOT A SIDE EFFECT (GI UPSET) • A skin test may be of some help • A scratch test can be performed with a very dilute solution (5 units/mL), followed by a scratch test with a more concentrated solution (10000 units/mL). If this is negative, an intradermal“Desensitization test can be performed. with a beta-lactam” occasionally is recommended for patients who are allergic to beta-lactam antibiotics and who must receive these drugs (rare instances). Maculopapular Rash Associated with Flucloxacillin Allergy NEJM 2006;354:601-9. Summary of What to Do in PCN Allergic Patients • First, ask more details about the “allergy” – Does the patient think that GI upset is an allergy (it’s not!) – What happens last time you took this antibiotic? • If it is a mild, localized rash – May try cephalosporin • Try and avoid 1st and 2nd generation cephs due to similar side chains • May use 3rd generation ceph (ceftriaxone, cefdinir) • If previous occurrence caused anaphylaxis – Avoid all Beta-lactams!!! • May use a macrolide • May use aztreonam 20 Adverse Effects of Penicillin: Allergic reactions Skin • • • • • Maculopapular rash Urticarial rash Exfoliative dermatitis Stevens-Johnson syndrome Morbilliform rash, Vescicular rash, Bullous eruptions, Purpuric lesions (more common with ampicillin), Fixed eruptions. Other systems • • • • Fever Vasculitis Anaphylaxis Itching (genital, anal), Bronchospasm,Serum sickness, Hepatitis, Interstitial nephritis (more common with methicillin) Connective tissue • Angioedema • Erythema nodosum, Lupoid syndrome. Hematopoietic system • Eosinophilia, Granulocytopenia, Thrombocytopenia, Hemolytic anemia (rare), Agranulocytosis, Aplastic anemia (very rare) Adverse Effects of Penicillin Dosedependent toxicity Effects on intestinal microflora Anaphylactic reactions. Pain, sterile inflammatory reactions (when given IM) Thrombophlebitis (when given IV) Nausea, vomiting, diarrhea (with broad spectrum drugs) • Neurotoxicity (confusion, seizures) after high doses • Bleeding, due to impairment of platelet aggregation (more common with penicillin G or carboxypenicillins) • • • • • Superinfections (staphylococci, C. difficile, P. aeruginosa, yeasts) with broad spectrum penicillins (carbapenems, pip/tazo, ampicillin). Let’s talk about effects on normal flora and C. difficile associated diarrhea – see notes section Antibiotic-Associated Pseudomembranous Colitis (PMC) Occurs in up to 30% of hospitalized patients Clinical Descript Treatme Etiology manifestation ion nt s PMC is a toxin induced inflammatory process characterized by exudative plaques or peudomembranes attached to the surface of the inflamed colonic mucosa. Due to enterotoxins produced by C. difficile. PMC is an adverse reaction to almost any oral or parenteral antibiotics that alter colonic flora. Drugs most frequently associated with PMC are ampicillin, cephalosporins, clindamycin, and FQ, and other broad-spectrums. PMC may begin 1-40 days after the antibiotic therapy is started, or even 70 days after the therapy is discontinued. Common symptoms include profuse watery diarrhea, cramping abdominal pain, fever and leukocytosis. PMC must be suspected every time diarrhea starts during an antibiotic treatment. PMC usually subsides in 2-4 weeks but can be lethal if not treated properly. Discontinuati on of the offending drug Oral vancomycin or oral fidaxomicin for 10 days (oral metronidazole 2nd line). Fluid and electrolyte replacement. Exchange resins (cholestyramin e) Classification of Cephalosporins 1st generation drugs (more narrow spectrum – similar to amox) Cefazolin Cephalexin 3rd generation drugs (broad spectrum) Ceftriaxone Cefdinir Ceftazidime Cefotaxime Cefoperazone 2nd generation drugs (intermediate spectrum) Cefuroxime Cefprozil Cefoxitin (anaerobes – bacteroides) cefotetan (anaerobes) th th 4 / 5 generation drugs (broad spectrum) Cefepime (4th gen Pseudomonas) Ceftaroline (5th gen – MRSA) • 1st gen = better staph than strep and have gram (-) activity (very similar to amoxicillin) • 2nd gen = better gram (-) than 1st gen with similar gram (+) activity. Included anaerobic coverage • 3rd gen = better gram (-) coverage (includes many more gram (-). Less staph activity but enhanced strep activity Clinical Uses for Cephalosporins 1 generation st 2nd generation • • • 3rd /4th generation Surgical prophylaxis Soft tissue infections Intra-abdominal infections (better for anaerobes!) Cefdinir – otitis media Ceftriaxone: gonorrhea, meningitis Ceftriaxone/Cefotaxime • Serious pediatric infections especially meningitis, broad spectrum • Ceftazidime • Pseudomonas infections • Cefepime • Very broad spectrum • • • Ceftriaxone Neonatal conjunctivitis caused by N. gonorrhea Severe Lyme disease Prophylactic uses of beta-lactam antibiotics Surgical prophylaxis 1st – 2nd Gen Ceph or Ampicillin Type of surgery Common pathogen Drug of choice Thoracic, cardiac, vascular, orthopedic, gynecological, neurological Staphylococci Enteric gram negative rods Cefazolin (1st gen) Abdominal Trauma-contaminated wounds Enteric gram negative rods Anaerobes Cefoxitin, cefotetan Dental, oral (in patients with valvular heart disease) Streptococci Ampicillin, amoxicillin Pharmacokinetics of Cephalosporins DISTRIBUTION ABSORPTION • oral: variable • parenteral: very good BIOTRANSFORMAT ION • Variable. • Distribution: throughout the body (concentrations are low in the cerebrospinal, joint and ocular fluids). • Cefuroxime, cefotaxime, ceftazidime, ceftriaxone, can achieve therapeutic concentrations in the CNS when meninges are inflamed. EXCRETION • Most compounds eliminated by the kidney (tubular secretion). • In most cases, concentrations in urine are higher than those in plasma • Some agents are excreted through the biliary tract (ceftriaxone, cefoperazone) • What does this mean? Must adjust dose for all in kidney impairment except ceftriaxone • Half-lives can be very prolonged in case of kidney failure Adverse Effects of Cephalosporins Dose-dependent toxicity Allergic reactions • Hypersensitivity reactions equal to those of penicillins but less frequent. • Anaphylactoid reactions. • Pain, sterile inflammatory reactions (when given IM) • Thrombophlebitis (when given IV) • Nephrotoxicity (acute tubular necrosis, cephalothin after high doses or in patient with renal diseases). Compounds containing a methylthiotetrazole (NMTT) group (cefotetan, cefoperazone) may cause: • Bleeding disorders due to hypoprothrombinemia (bleeding) (prevented by vit. K administration). • Disulfiram-like reactions when given with alcohol (alcohol must be avoided!!) Pharmacology of Monobactam ztreonam is the only monobactam available in US. Antibacterial action: • Their spectrum of activity is limited to aerobic gram negative rods. Pharmacokine tics and administratio n • Administered either IM or IV (not oral) • Therapeutic concentrations are achieved in the CNS when meninges are inflamed. • Renal elimination Adverse effects: • Allergic reactions similar to those of penicillins (no cross allergenicity between aztreonam and other beta-lactam antibiotics) • Major toxicity uncommon, alternative to penicillin Pharmacology of Carbapenems Drugs: Imipenem (in combo w cilastatin), meropenem, ertapenem, doripene • Resistant to most beta-lactamases (broadAntibacterial action: spectrum). parenteral – use in hospital required Administration: infections Good penetration to all tissues Pharmacokineti Renal elimination: imipenem (inactivated by cs and dehydropeptidases found in the renal tubule). administration: Hydrolysis is prevented by cilastatin, a dipeptidase inhibitor which is administered together with •Imipenem. Allergic reactions similar to those of penicillins (cross sensitivity with other beta-lactam antibiotics often occurs). • Nausea and vomiting, diarrhea. Adverse effects: • Headache ,vertigo, tremor, mental confusion, seizures (in patients at risk, renal failure etc.) • Superinfections Pharmacology of Beta-Lactamase Inhibitors All are beta-lactam compounds: Clavulanate, sulbactam, tazobactam are most common on the market. They are • Poor administered together with intrinsic some penicillins. antimicrobial activity. • They bind irreversibly to beta-lactamases Pharmacodyna produced by a wide range of gram+ and grammics bacteria preventing the destruction of beta lactam antibiotics, which are substrates for these enzymes (suicide inhibitor). Pharmacokinet • Clavulanate, sulbactam; can be given orally or ics parentally • They extend the antimicrobial spectrum of ampicillin, amoxicillin, ticarcillin or piperacillin Therapeutic when given in combination (they extend the uses spectrum for more virulent gram (-) organism • They do not increase the activity of these penicillins against P. aeruginosa. Other Cell Wall Inhibitors (non Blactams) 32 Pharmacology of Vancomycin Vancomycin and teicoplanin are glycopeptides (MW ~1500) • Inhibits the transglycosylate reaction by binding to Mechanism the D alananyl-D-alanine terminus of cell wall of action precurssor. Prevents the formation of linear peptidoglycan chains, ultimate effect is bactericidal. Resistance Pharmacokin etics • Brought by genes that modify the binding site of vancomycin in cell wall, these genes can be present in a transferable plasmid. • Poorly absorbed from GI tract (must be given IV unless treating C. difficile (CDAD) infection). • Therapeutic concentrations achieved in CSF when meninges are inflamed – may be used for meningitis. • Urinary excretion (drug excreted by glomerular filtration) • Administration: oral (in case of GI infections), IV. Adverse Effects of Vancomycin • Hypersensitivity reactions: skin rashes, anaphylaxis (very rare). • Phlebitis (vancomycin is too irritant to be given IM) • Flushing, hypotension (the “red man” or “red neck” syndrome) after rapid IV injection, due to histamine release (anaphylactoid reaction). • Nephrotoxicity (vancomycin) and ototoxicity (vancomycin and teicoplanin) (both are uncommon and mild with current preparations) • 3rd year ACOM student recognized Red Man syndrome in a baby in November 2023!!!! Red Man Syndrome Therapeutic uses of Vancomycin Treats Gram (+) only Drug of choice for infections due to MR staphylococci (MRSA) - Second choice drug for enterococcal infections - First choice for C. difficile enterocolitis (guideline update December 2018) Oral formulation only use Drug of choice for infection due gram + bacteria sensitive to penicillin, in patient allergic to beta-lactam antibiotics Daptomycin Mechanis m of action Adverse effects Therapeuti c uses • Not fully understood, the drug appears to depolarize cell membrane causing potassium efflux and rapid cell death (cell membrane inhibitor) • Pulmonary surfactant inactivates the drug – cant use in respiratory infections (pneumonia, etc). • Myopathy, allergic pneumonitis (with prolonged therapy). • Infections due to vancomycin resistant enterococci or staphylococci. • DOC for VRE endocarditis (vancomycin resistant enterococci) • See the trend here? Used for bacteria that are Fosfomycin Mechani sm of action • Inhibits bacterial wall synthesis • Inhibition of enolpyruvate transferase which blocks the synthesis of N-acetylmuramic acid (essential precursor for peptidoglycan synthesis – cell wall). The ultimate effect is bactericidal Resistan ce • Resistance due to impairment of the system that actively transports the drug into bacterial cells. Adverse effects • Nausea and vomiting, diarrhea, vaginitis. Therape utic uses • Oral - Approved for use of uncomplicated UTIs in women for suscecptible strains of E. coli and Entercoccus faecalis. Colistin (Polymyxins) • Not a first line drug. Use only when others have failed (last line – “salvage therapy”) • MOA: – Cationic detergent and damages the bacterial cytoplasmic membrane causing leaking of intracellular substances and death • Bactericidal • Indications: – Treatment of acute or chronic infections due to sensitive strains of gram (-) baccili (particularly Pseudomonas) which are resistant to other antibacterials or in pts allergic to other antibacterials • Side Effects: – Acute Tubular Necrosis (ATN), neurologic disturbances (dizziness, tingling) 38 Therapeutic Uses of Beta Lactam Antibiotics Do not memorize these now, try to learn them as you will be tested on these later in the Systems’ Courses NEXT semester. 39 Therapeutic Uses of Beta-Lactam Antibiotics Diseases Drugs of choice Pneumococcal infections (pneumonia, meningitis, endocarditis) Penicillin sensitive strains Penicillin G Penicillin resistant strains 3rd Gen. cephalosporin + vancomycin Streptococcal infections (pharyngitis, scarlet fever, otitis media sinusitis, pneumonia, bacteremia) Penicillin G, ampicillin, amoxicillin Enterococcal or S. viridans endocarditis Staphylococcal infections (MS strains) (pneumonia, endocarditis, osteomyelitis, bacteremia) Neisseria infections (N meningitidis) N-Gonorrhea Corynebacteria infections (laryngotracheitis, pneumonia, endocarditis, infected foreign bodies, bacteremia, due to diphtheroids) Fusobacterium infections (ulcerative pharyngitis, lung abscess) Listeriosis Penicillin G ± gentamicin Oxacillin, nafcillin Penicillin G; ceftriaxone or cefotaxime Ceftriaxone Penicillin G ± an aminoglycoside Penicillin G Ampicillin ± gentamicin Therapeutic Uses of Beta-Lactam Antibiotics Diseases Gas gangrene Escheridia coli infections (UTI, bacteremia) Enterobacter infections (urinary tract and other infections) Proteus infections (Urinary tract and other infections) P. mirablis Other Proteus species Drugs of choice Penicillin G; cefoxitin (AD), cefotetan (AD) 1st Gen. cephalosporin 1st Gen. ampicillin + aminoglycoside Imipenem; ureidopenicillin (AD) Ampicillin, amoxicillin 3rd Gen. cephalosporins, imipenem Pseudomonas infections (UTI, pneumonia, bacteremia) Pip/tazo, ceftazidime, aztreonam, Imipenem (all ± aminoglycoside) Klebsiella infections (UTI, pneumonia) cephalosporin ± aminoglycoside Serratia and acinetobacter infections (Various nosocomial and opportunistic infections) H. influenzae infections (Otitis, supraglottitis, pneumonia, meningitis) Imipenem, 3rd Gen. cephalosporin, Pip/tazo + aminoglycoside ceftriaxone, cefotaxime, ampicillin/sulbactam AD = alternative drug Therapeutic Uses of Beta-Lactam Antibiotics Diseases Chancroid P. multocida infections (cat and dog bites) Actinomycosis Nocardiosis Spirochetal infections (Syphilis, yaws, leptospirosis) Drugs of choice -Ceftriaxone Penicillin G, amoxicillin / clavulanate Penicillin G, ampicillin Ceftriaxone (AD), imipenem (AD) Penicillin G; ceftriaxone (AD) AD = alternative drug Prophylactic uses of beta-lactam antibiotics Nonsurgical prophylaxis Infection to be prevented Rheumatic fever Diphteria (Corynebacterium diptheriae) Otitis media Pneumonoccemia Group B streptococcal (GBS) Indication Drug of choice History of rheumatic fever Known rheumatic heart disease Benzathine penicillin Unimmunized contacts Penicillin G (or erythromycin) Recurrent infection Amoxicillin Children with sickle cell disease Penicillin G Newborns to mothers with vaginal GBS colonization Penicillin G, ampicillin Antibacterial Spectrum Tables for the Penicillins and Cephalosporins Do not memorize these now, try to learn them as you will be tested on these later in the Systems’ Courses NEXT semester. 45 Top facts about penicillin • Mechanism of Action – Inhibits bacterial cell wall synthesis by binding and inactivating proteins (penicillin binding proteins) • Indication – Bacterial infections – Bactericidal – Mostly rheumatic fever prophylaxis, endocarditis, and neurosyphilis/syphilis • What to know – Covers gram positive organisms, gram negative cocci (which lack an outer membrane), and nonbeta lactamase producing anaerobes – 1-3% chance of cross reactivity with cephalosporins – Watch out for anaphylactic reactions – Usually give IV or IM – oral absorption is unreliable – Probenecid can block tubular secretion and prolong Penicillin G’s half life – Penicillin G benzathine is long acting penicillin given IM only for treatment of syphilis and secondary prophylaxis of rheumatic fever (given IV can result in cardiorespiratory arrest and death) Top Facts for cephalosporins • Mechanism of Action – Inhibits bacterial cell wall synthesis by binding and inactivating proteins (penicillin binding proteins) – Bactericidal • By generation – 1st – cefazolin (IV), cephalexin (PO) – 2nd – cefaclor (PO), cefuroxime (IV & PO), Cefoxitin (IV), and cefotetan (IV) – 3rd – ceftriaxone (IV), cefotaxime (IV), ceftazidime (IV), cefixime (PO), cefdinir (PO) – 4th – cefepime • Contraindications – Patients with anaphylactic reaction to penicillin • Side effects – Superinfections with enterococci, enterobacter, and candida Top facts for cephalosporins 1st generation -gram positive cocci – MSSA, Streptococci Group A, B, C ,G Strep viridans -S. pneumoniae -Gram negative H. influenzae , E. coli, Klebsiella pneumoniae, Proteus Mirabilis 2nd generation 3rd generation 4th generation - Same as first PLUS - Beta lactamase positive H. influenzae - Moraxella catarrhalis - Neisseria meningitides - E. coli - Klebsiella pneumoniae - Proteus - -oral anaerobes - Cefoxitin and cefotetan cover B. fragilis -same as first PLUS -Expanded gramnegative coverage - Oral anaerobes - N. gonorrhea - B. fragilis coverage except for cefotaxime and ceftazidime -good gram positive and gram negative coverage -anti-pseudomonal coverage -Penetrates CSF -limited anaerobic coverage Antibacterial Spectrum of Penicillin G Sensitive organisms Gram-positive bacteria: Streptococci (pyogenes, agalactia, pneumonia(1), viridans(1)), Enterococcus faecalis (1), Bacillus antracis, Listeria monocytogenes, Clostridia (perfringens, tetani), Corynebacteria (diphtheriae, diphtheroids), Actinomyces israelii, Nocardia asteroides (1) Gram-negative bacteria: Neisseria (gonorrheae (1), meningitidis), Fusobacterium nucleatum, Streptobacillus moniliformis, Pasteurella multocida, Bacteroides (not B. fragilis) (2) Spirochetes Treponema (pallidum, pertenue), Borrelia (burgdorferi, recurrentis), Leptospira Resistant organisms Some gram positive bacteria: Staphylococci(2), Bacteroides fragilis, Clostridium difficile Most gram negative bacteria: Mycobacteria, Mycoplasmas, Chlamydia, Rickettsia, Protozoa, Fungi, Viruses (1) several strains are now resistant to penicillin G (2) most strains are now resistant to penicillin G •Antibacterial spectrum of other narrow-spectrum penicillins is similar to that of penicillin G. Penicillinaseresistant penicillins are active against MS staphylococci. These penicillins are less active than penicillin G against other Antibacterial Spectrum of Aminopenicillins (Ampicillin – “good for the gut”) Sensitive organisms -All bacteria sensitive to penicillin G (2) -Streptococcus agalactiae (1) -Enterococcus faecalis (1) -Listeria monocytogenes(1) -Campylobacter (jejuni, fetus) -Helicobacter pylori -Haemophilus influenzae (3) -Salmonella species (3) -Shigella species (3) -Escherichia coli (3) -Proteus mirabilis (3) Resistant organisms -Some gram positive bacteria (Staphylococci, Bacteroides fragilis, Clostridium difficile) -Many gram negative bacteria -Mycobacteria -Mycoplasmas -Chlamydia -Rickettsia -Protozoa -Fungi -Viruses Spectrum of activity of these penicillins can be expanded (including Moraxella catarrhalis, Bacteroides fragilis ) by the concurrent administration of a beta-lactamase inhibitor. (1) more sensitive to ampicillin than to penicillin G (2) aminopenicillins are less active than penicillin G against penicillin-sensitive microorganisms. (3) 30-50% of strains are now resistant Antibacterial Spectrum of Carbapenems Sensitive organisms -All bacteria sensitive to ampicillin (1) -Bacteroides fragilis -Proteus vulgaris -Morganella morganii -Providencia rettgeri -Enterobacter species -Acinetobacter species -Serratia species -Pseudomonas aeruginosa Resistant organisms -Some gram positive bacteria (i.e. staphylococci, Clostridium difficile) -Some gram negative bacteria (legionella, bordetella, brucella,yersinia, Campylobacter jejuni) -Mycobacteria -Mycoplasmas -Chlamydia -Rickettsia -Protozoa -Fungi -Viruses Spectrum of activity of these penicillins can be expanded (including Moraxella catarrhalis) by the concurrent administration of a beta lactamase inhibitor (1) These penicillins are less active than ampicillin against ampicillin-sensitive microorganisms. Cephalosporin Spectrum •As one proceeds from 1st to 4th generation, the agents have progressively greater activity against gram negative organisms (and lose activity for gram (+)). •First generation Cephalosporins have the best gram positive activity. Others are variable •None are good for Enterococci, Listeria, MR Staph aureus. •Ceftoxitin and Cefotelan have good anaerobic coverage Not for listerosis Not for MR Staph aureus infection Not for enterococcal bacteremia Antibacterial Spectrum of Cephalosporins Sensitive organisms 1st GENERATION Gram-positive bacteria -Streptococci (pyogenes, agalactiae, pneumoniae) -MS staphylococci -Bacillus antracis -Corynebacteria -Clostridia (not C.difficile) -Actinomyces israelii Gram-negative bacteria -Klebsiella pneumoniae -Moraxella catarrhalis -Neisseria gonorrheae -Escherichia coli -Proteus mirabilis 2nd GENERATION -All bacteria sensitive to 1st generation drugs (1) -Neisseria meningitidis -Bacteroides fragilis (2) -Enterobacter -Haemophilus (influenzae, ducreyi) -Proteus vulgaris -Morganella morganii -Providencia rettgeri -Salmonella -Shigella 3rd and 4th GENERATION -All bacteria sensitive to 2nd –generation drugs (1) -Nocardia asteroides (3) -Enterobacteriaceae (3) -Pseudomonas aeruginosa (4) -Bacteroides fragilis (5) -Spirochetes (Treponema, Borrelia, Leptospira) (1) In general 2nd and 3rd generation cephalosporins are less active against grampositive bacteria than 1st -generation drugs. (2) only cefoxitin, cefotetan (3) also some 2nd generation drugs may be effective (4) only cefoperazone, ceftazidime, cefepime (5) only ceftizoxime Resistant organisms -Some gram positive bacteria (MR staphylococci, Enterococci, Listeria, Clostridium difficile) -Some gram negative bacteria (Legionella, Bordetella, Brucella, -Mycobacteria -Mycoplasmas -Chlamydiae Antibacterial Spectrums of other mentioned Drugs or Drugs Classes • Monobactams: – Active against gram negative aerobic bacteria, including P. aeruginosa – Resistant to beta-lactamases produced by most gram negative bacteria. – Gram-positive bacteria, anaerobic microorganisms, some gram negative bacteria, mycobacteria, mycoplasmas, chlamydiae, rickettsiae, protozoa, fungi and viruses are resistant. • Carbapenems: – Resistant to most beta-lactamases. – Active against most gram-positive and gram-negative, aerobic and anaerobic bacteria, including MS staphylococci, B. fragilis, E. faecalis and P. aeruginosa • Vancomycin – Most gram+ bacteria (E. faecalis, MR staphylococci, C. difficile and strains of E. faecium). • Daptomycin – Similar to that of vancomycin but active against MR and vancomycin resistant strains of staphylococci and enterococci. • Fosfomycin 54 – It includes some gram positive bacteria (E. faecalis, E. faecium) and several gram