Lecture 20: Cell Wall Synthesis Inhibitors II (PDF)

Cell Wall Synthesis Inhibitors II Telavancin & Daptomycin included  Cephalosporins are similar to penicillins chemically, in mechanism of action and toxicity. See the structures with different R1 and R2 groups....

Cell Wall Synthesis Inhibitors II Telavancin & Daptomycin included  Cephalosporins are similar to penicillins chemically, in mechanism of action and toxicity. See the structures with different R1 and R2 groups. They have 6-memberd sulfur containing ring adjoining a beta- lactam ring. They are highly resistant to penicillinases. Some bacteria express a beta lactamase namely cephalosporinase but most cephalosporins are resistant to the Cephalosporins enzyme. They are classified into first-, second-, third- or fourth- generation drugs on the basis of bacterial susceptibility and resistance to beta lactamases. Cephalosporins are usually ineffective against methicillin resistant Staph. aureus, Listeria monocytogenes, Clostridium difficile, and Enterococci  Pharmacokinetics of cephalosporins Cephalosporins are administered parenterally as well as orally. A majority of cephalosporins do not penetrate CNS. Half-lives vary widely. Although some cephalosporins are excreted via the bile, most are excreted in the urine via renal tubular secretion. Probenecid blocks the tubular secretion and increases plasma concentration. All cephalosporins are active against gram-positive cocci including staphylococci and many strains of gram-positive bacilli. Cephalosporins are generally ineffective against enterococci.  S. aureus infections including skin infections, osteomyelitis and endocarditis. Cephalosporins are drugs of choice in Klebsiella pneumoniae, infections, and Pneumococcal pneumonia infections caused by S. pyogenes. Parenteral cephalosporins are used in Gonococcal disease. Therapeutic Respiratory and urinary gram-negative bacterial infections. applications of cephalosporins The expanded spectrum activity includes effectiveness against Proteus Bacteroides fragilis, Serratia, Enterobacter, and some activity against Pseudomonas. These agents are useful in meningitis caused by susceptible organisms. Prophylactic use of cephalosporins are mainly in perioperative infections.  First generation cephalosporins Cefazolin (Ancef, Kefzol), Cefadroxil (Duricef), Cephalexin (Keflex), Cephradine (Anspor, Velosef), Cephalothin (Keflin), Cephapirin (Cefadyl) etc. are examples. They all can be Penicillin G substitutes, that are resistant to Staphylococcal penicillinase. Active against Proteus, E. coli, and Klebsiella pneumoniae (thus called PEcK drugs). Some Specifics: They are not active against enterococci or pseudomonas aeruginosa. Excretion mainly by glomerular filtration and tubular secretion. Cefazolin (Ancef, Kefzol) is the drug of choice in surgical prophylaxis. Cefazolin is almost the only first-generation parenteral cephalosporin in use. Cefazolin is the alternative to ant-Staph. penicillins in penicillin allergic patients.  Second generation cephalosporins Cefaclor (oral av. Ceclor), Cefamandole (Mandol), Cefmetazole (Zefazone), Cefprozil (oral av. Cefzil), Cefoxitin (Mefoxin), Cefonicid (Monocid), Cefotetan (Cefotan), Cefuroxime (oral av. Ceftin, Kefurox, Zinacef), Loracarbef (oral av. Lorabid) etc. They have greater activity against more gram-negative organisms, Haemophilus influenzae, Enterobacter aerogenes, Neisseria plus the PEcK organisms (thus called HENPEcK drugs). Knowledge about each drug is recommended (but not feasible?) because within second-generation drugs, there are varying activity for different strains of bacteria (refresh your pharmacology before prescribing). Second generation cephalosporins are not recommended against enterobacter because of chromosome mediated beta-lactamase. As with first generation agents, they are not active against enterococci or pseudomonas aeruginosa Cefaclor is highly susceptible to beta-lactamase and its use has therefore diminished. IM injections are painful  Third Generation cephalosporins (broad spectrum): The major features of these drugs are their expanded gram-negative coverage and the ability of some to cross the blood-brain barrier. Third generation include Cefdinir (Omnicef), Cefixime (Suprax), Cefoperazone (Cefobid), Cefotaxime (Claforan), Ceftazidime (Fortaz, Tazidime), Ceftizoxime (Cefizox), Ceftriaxone (Rocephin), Ceftibuten (Cedax), Cefditoren (Spectracef), Cefpodoxime (Banan, Vantin) Ceftriaxone (Rocephin) and Cefixime (Suprax) are first line drugs for N. gonorrhoeae infections. Cefixime use is declining due to resistance. For patients with uncomplicated genital, rectal, and pharyngeal gonorrhea, CDC now recommends combination therapy with ceftriaxone 250 mg as a single intramuscular dose, plus either azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice daily for 7 days. In instances where ceftriaxone cannot be used, CDC recommends cefixime 400 mg orally, plus either azithromycin 1 g orally or doxycycline 100 mg orally twice daily for 7 days. For patients with a severe allergy to cephalosporins, CDC recommends a single 2-g dose of azithromycin orally. Third Generation cephalosporins (broad spectra): Ceftriaxone (Rocephin) and Cefixime (Suprax) are first line drugs for N. gonorrhoeae infections Ceftazidime and Cefoperazone are two third generation cephalosporins with useful activity against P. aeruginosa (compare this statement to first and second generation drugs) Ceftizoxime, and Moxalactam are active against Bacteroides fragilis (gram-negative anaerobic rod) Cefoperazone and Ceftriaxone are excreted through biliary tract, and no dosage adjustment is necessary in renal insufficiency. Third generation cephalosporins are used to treat meningitis due to their CNS penetration. Cefditoren is a broad-spectrum, third generation cephalosporin that is a very effective oral beta-lactam antibiotic. It is active against both beta- lactamase negative and positive Haemophilus influenzae. Cefditoren activity against Staphylococci is comparable to that of oxacillin. It is also very active against Escherichia coli, Klebsiella spp, Proteus mirabilis, and Salmonella spp. Meningitis caused by highly penicillin-resistant strains of pneumococci may not respond even to these drugs, and addition of rifampin or vancomycin is recommended. Third generation cephalosporins are hydrolyzable by constitutively produced Enterobacter chromosomal beta lactamases, and they are not reliably active against Enterobacter. They are less active against gram positive cocci when compared to first generation and enhanced activity against gram negative bacilli.  Cefepime (Maxipime) is a 4th generation cephalosporin. Exblifep (Cefepime/enmetazobactam) (2024) approved for the treatment of Complicated Urinary Tract Infections Cefepime (Maxipime). This Fourth drug is similar to third generation cephalosporins but Generation has more resistance to cephalosporins hydrolysis by chromosomal beta-lactamases produced by Enterobacter. Cefepime is 100% renally eliminated. Cefepime has great activity against P. aeruginosa, Enterobacteriaceae, S. aureus, S. pneumoniae, Hemophilus and Neisseria.  Ceftaroline (Teflaro) is approved for the treatment of complicated skin and skin structure infections (cSSSIs) and community- acquired pneumonia (CAP). It has extended activity against gram- positive organisms and has activity Fifth or against common gram-negative organisms. Ceftaroline is an Advanced intravenous drug. Generation Ceftaroline is the first cephalosporin to be active against resistant gram- cephalosporins positive pathogens including Ceftaroline methicillin-resistant S. aureus (MRSA), vancomycin-resistant S. aureus (VRSA), vancomycin-insensitive S. aureus (VISA), and hetero-resistant vancomycin-insensitive S. aureus (hVISA). Ceftaroline was approved by the FDA in October 2010.  Ceftobiprole medocaril (ZEVTERA) is a broad-spectrum 5th- generation cephalosporin with activity against Gram-positives such as methicillin- resistant Staphylococcus Fifth or aureus and penicillin- resistant Streptococcus Advanced pneumoniae, and against Gram- Generation negatives such as Pseudomonas cephalosporins aeruginosa. Ceftobiprole Given as infusions. Uses are in the treatment of community-acquired pneumonia and nosocomial pneumonia, with the exception of ventilator- associated pneumonia. Very useful antibiotic for the treatment of pneumonia.  Cephalosporins currently available for oral administration: Cefadroxil, Cephalexin, Cephradine (first generation), Cefaclor, Cefprozil, Other Cefuroxime axetil (second generation) and Cefdinir, Cefixime, Cefpodoxime, Ceftibuten (third facts generation). Cephalosporin Resistance: same as penicillins Cephalosporins elimination: Same as penicillins (except two!)  Cephalosporin Adverse Hypersensitivity (in 5% patients), cross sensitivity occasionally with penicillin allergic patients. Drugs with methyl thio-tetrazole group, such as Moxalactam, Cefmetazole, Cefotetan, Cefamandole (second generation) and Cefoperazone (third generation) cause bleeding due to anti-vitamin K effects. Disulfiram like symptoms due to aldehyde accumulation with methyl thio-tetrazole group containing cephalosporins when ingested with alcohols (thus to avoid alcohol and alcohol containing medications). Superinfections, renal damage, local tissue reactions such as thrombophlebitis etc. are also adverse effects.  Carbapenems Originally from thienamycin (Streptomyces cattleya) They are synthetic beta lactam antibiotics. Imipenem gets metabolized in the renal tubules to potentially nephrotoxic compounds by dipeptidase (dehydropeptidase). Cilastatin is a dehyropeptidase inhibitor. Imipenem is compounded with Cilastatin because of its cleavage by dehydropeptidases in the kidney to produce a nephrotoxic metabolite. Imipenem/cilastatin (Primaxin) is the broadest spectrum of all the beta lactam antibiotic available. Used against gram-positive and gram-negative cocci (exception methicillin resistant S. aureus)  Other Carbapenems Meropenem (Merrem IV) is similar to imipenem but has slightly greater activity against gram-negative aerobes and has slightly less activity against gram-positives. It is not significantly degraded by renal dehydropeptidase and does not require an inhibitor. Ertapenem (Invanz) is a carbapenem, highly stable against beta- lactamases and has activity against a wide variety of gram-positive, gram-negative and anaerobic microorganisms, particularly the Enterobacteriaceae. Ertapenem is administered parenterally for complicated urinary tract infections, skin and skin-structure infections, community-acquired pneumonia and intraabdominal infections. Doripenem (Doribax): In October 2007, the FDA approved doripenem (Doribax). Doripenem has the profile of meropenem, except for its increased potency of in vitro activity against P. aeruginosa. It is indicated for patients with complicated intra-abdominal infections and UTIs, including pyelonephritis, when the infection is caused by susceptible bacteria. It is not known to cause convulsions like other carbapenems. Resists hydrolysis by beta lactamases. Used in empiric therapy. Razu, Tebi, Lena & Tomo are coming! Carbapenem Kinetics: Given I.V. Adverse: Nausea, vomiting diarrhea, skin rashes etc. Excessive levels in patients with renal impairment can lead to seizures. Meropenem is less likely to cause seizures than imipenem. Patients allergic to penicillins may be allergic to carbapenems.  Aztreonam (Azactam) with a free beta lactam ring (not fused to another ring). They are specific for enterobacteria. They are active against gram-negative rods such as Pseudomonas and Serratia marcescens (Serratia is hospital acquired). Monobactams have very poor activity against gram-positive cocci, and anaerobic bacteria. Given I.V. or I.M (100% bioavailability I.M.). Can cause phlebitis, skin rash and Monobactams abnormal liver function. Aztreonam has low immunogenicity (low allergic reactions), so is good as alternative in penicillin sensitive patients with gram-negative infection! Aztreonam can be substituted for aminoglycosides in the treatment of urinary tract and respiratory tract infections. Also used in osteomyelitis, gonorrhea, gynecologic and intra- abdominal infections, etc. Aztreonam is administered parenterally. Beta lactamase inhibitors: Clavulanic acid, Sulbactam, Tazobactam etc. inactivates beta lactamases. They protect penicillins. VANCOMYCIN (Vancocin, Vancoled): Vancomycin is a tricyclic glycopeptide used orally and parenterally. Use: Vancomycin is a good drug against methicillin-resistant staphylococcal infections. The main indication of parenteral vancomycin is sepsis or endocarditis caused by staphylococcus. Action: Inhibits synthesis of cell wall phospholipids and peptidoglycan polymerization by binding to D-alanyl-D-alanine cell wall precursors. Use of vancomycin is restricted to serious infections by beta-lactam resistant gram-positive (Eg. Strep. and Staph. infections) microorganisms. In enterococcal infections, aminoglycosides are given synergistically for bactericidal effect (caused by E. faecium and E. faecalis). Vancomycin is used in colitis caused by Clostridium difficile ORALLY (anaerobic gram-positive rod). Prophylactically in dental surgeries in prosthetic device implanted patients. Resistance: Plasmid mediated. Kinetics: Parenteral administration is by slow I.V (Vancocin HCl) in systemic infections. More than 90% is excreted by glomerular filtration. Given orally in case of antibiotic induced pseudomembranous colitis (PMC) due to C. difficile. Adverse: Fever, chills, phlebitis etc. Irritating to tissue. Ototoxicity and nephrotoxicity are mild with current preparations but simultaneous use of aminoglycosides increases the risk. Among the more common reactions is the so-called “red man” or “red neck” syndrome that is caused by flushing due to histamine release. FOSFOMYCIN (Phosphonomycin, Monurol): Inhibits very early stage of cell wall synthesis. An analogue of phosphoenolpyruvate that inhibits enolpyruvate transferase, thus inhibiting formation of N-acetyl muramic acid. Works well against gram-positive and gram negative organisms. In the United States it is approved as a single, oral dose (3 grams) for treatment of uncomplicated UTI in women. It is safe during pregnancy. BACITRACIN: Mixture of polypeptides that inhibit cell wall synthesis. It is active against a variety of gram- positive cocci and bacilli. It is markedly nephrotoxic, if administered systemically, producing proteinuria, hematuria, and nitrogen retention. Therefore, used only topically. It is absorbed poorly therefore topical application results in local antibacterial activity without significant systemic toxicity. Bacitracin in an ointment base is often combined with polymyxin and neomycin. Used in dermatologic and ophthalmic infections. Solutions of bacitracin are sometimes employed for irrigation of joints, wounds and pleural cavity. POLYMYXIN B, POLYMYXIN E (Colistin) Polymyxins are peptides that are active against gram negative bacteria and are restricted to treating gram-negative bacterial infections. Due to their nephrotoxicity, only Polymyxins B and E are used. Only Polymyxin B is used in the USA. Polymyxin E is otherwise known as Colistin. Polymyxins are cationic basic peptides. Action: Polymyxins are bactericidal for many gram-negative rods including Pseudomonas in concentration 1-5 ug/ml. Being cationic detergents, they attach to and disrupt bacterial cell membranes. Polymyxins are surface-active amphipathic agents (with lipophilic and lipophobic groups). They interact with phospholipids and disrupt the cell membranes. They also bind and inactivate endotoxins. Gram-positive organisms Proteus and Neisseria are resistant. Toxicity: Due to availability of several alternative antimicrobials, Polymyxins are not used for systemic administration because of their high nephrotoxicity, neurotoxicity and poor tissue distribution. Use: Polymyxins are restricted to ophthalmic, optical and topical use. Corneal ulcers and external otitis caused by Pseudomonas is treated with polymyxins. Combinations of Neomycin, Polymyxins and Bacitracin are used for skin infections. Local reactions and hypersensitivity are rarely observed. CYCLOSERINE (SEROMYCIN) Cycloserine is a water-soluble antibiotic readily absorbed upon oral administration. Cycloserine is active against many gram-positive and gram-negative strains. Cycloserine is used almost exclusively to treat tuberculosis caused by M. tuberculosis resistant to first line agents. Cycloserine is a structural analogue of D-alanine, thus inhibits of D-alanine into peptidoglycan (inhibits enzymes alanine racemase that converts L-alanine to D-alanine and alanine synthetase). Cycloserine inhibits many strains of mycobacteria. The drug gets widely distributed in tissues. IT is used orally as 250 mg capsules. Most of the drug is excreted in active form into the urine. Adverse: Cycloserine can cause CNS toxicity with headaches, tremors, psychosis and convulsions. Daptomycin  DAPTOMYCIN (Cubicin) Daptomycin is a bactericidal lipopeptide antibiotic. MOA: Disrupts the membrane, inhibits also protein & DNA synthesis. Daptomycin is used for treating complicated skin and skin structure infections and bacteremia caused by S. aureus, including infective endocarditis. Its action resembles linezolid and quinupristin/dalfopristin, for treating infections caused by resistant gram-positive organisms, including MRSA and vancomycin-resistant enterococci (VRE). Daptomycin is inactivated by in pulmonary tissue and is not used in the treatment of pneumonia.  TELAVANCIN (Vibativ) Telavancin is bactericidal lipoglycopeptide antibiotic and is similar to vancomycin in structure. Telavancin has dual mechanism of action similar to that of daptomycin plus vancomycin. It is classified as advanced drug in treating complicated skin and skin structure infections, caused by MRSA, and for nosocomial hospital acquired and ventilator-associated bacterial pneumonia (HABP/VABP). The drug causes renal impairment and interferes with anticoagulation tests. It is contraindicated in pregnancy and has caused some cardiac abnormalities.