Antibiotics.

Antibiotics

מבנה דופן חיידק

סינתזת דופן החידק

Resistance mechanism Beta-lactamases (eg. ESBLs, Carbapenemase)
Target modifying enzymes (PBP) Drug modifying enzymes Porin loss Efflux pump VISA/VRSA VANs

Resistance mechanism Penicillin Binding Protein (PBP)
Low affinity of beta lactam to penicillin binding proteins (transpeptidases) MRSA- low affinity to PBP2a (mecA gene) Pneumococci- PBP2b, 2x Enteroccoci- PBP5 (also some of them have beta-lactamase)

Resistance mechanism Beta-lactamase
Enzymes produced by some bacteria, hydrolyzing the beta-lactam ring Plasmid, chromosomal Class A (all inhibited by calvulanate) Penicillinase (SA, E.coli, KP, HI, NG) penicillinase+cefalosporinase penicillinase+cefalosporinase+ cefalosporinase s 3 (ESBLS) carbapenemase Class B (metalloenzymes, not inhibited by calvulanate)) hydrolyse penicillins, cefalosporins, carbapenems Class C -Amp C chromosomal, induced, not inhibited by calvulanate (SPICE) Cefalosporinase 3 Class D oxacillanase (usually with penicillinase, sometimes carbapenemase)

ESBLs- Augmentin-S, Cefotaxime-R, Ceftazidime-R, cefamycin-S Most of them also resistance to AG, resprim and quinolones, and beta lactam+inhibitor Members of enterobacteriacea commonly express plasmid encoded beta lactamases (TEM, SHV) or extended beta lactamases (CTX-M) AmpC- class C- chromosomal inducible Augmentin-R, Cefotaxime-R, Ceftazidime-R, Cefamycin-R Carbapenemase PA, acinetobacter KPC- derived from class A and contains carbapenemase

Hodge test for KPC

Resistance mechanism Staphylococcus aureus
Beta lactamase- resistance to penicillin Low affinity to PBP2a (mecA gene)- resistance to methicillin (MRSA) VISA VRSA- VANA from enterococcus

Resistance mechanism- enterococci
Intrinsic resistance to AG Modifying enzymes- acetyltransferase, adenyltransferase, phosphotransferase Intrinsic (relative) resistance to penicillin through PBP5 (totally R to cefalosporins) Beta lactamase- rare, fecalis, IE VRE- VANA– produced ligase which produces D-lactate end, resistance to vancomycin and teicoplannin VANB- R to vancomycin

Bactericidal Beta lactams Penicillins Beta-lactamase inhibitors
Cephalosporins Cephamycins Carbapenems Monobactams Bactericidal

Beta-lactams Penicillins
Penicillin G Antistaphylococcal penicillins nafcillin, oxacillin, cloxacillin and dicloxacillin Broad spectrum penicillins Second generation (ampicillin, amoxicillin and related agents) Third generation (carbenicillin and ticarcillin) Fourth generation (piperacillin)

Penicillin G- spectrum of activity
Beta-lactams Penicillin G- spectrum of activity Penicillin G is highly active against: Gram-positive cocci (except penicillinase-producing staphylococci, penicillin-resistant pneumococci, enterococci, and oxacillin-resistant staphylococci) Gram-positive rods such as Listeria Gram-negative cocci such as Neisseria sp (except penicillinase-producing Neisseria gonorrhoeae) Most anaerobes (with certain exceptions, such as Bacteroides)

Penicillin G- spectrum of activity
Beta-lactams Penicillin G- spectrum of activity Penicillin G is only bacteriostatic for enterococci Serious infections with enterococci are generally treated with combination therapy of a cell wall active antibiotic such as penicillin, ampicillin, or vancomycin plus gentamicin or streptomycin Penicillin G is not active against gram-negative bacilli because of poor penetration through the porin channel.

Beta-lactams Antistaphylococcal penicillins nafcillin, oxacillin, cloxacillin and dicloxacillin Inhibit penicillinase-producing staphylococci but are inactive against oxacillin-resistant staphylococci for strains of S. aureus sensitive to oxacillin, antistaphylococcal penicillins are preferable to vancomycin Antistaphylococcal penicillins have less intrinsic activity than penicillin G for most bacteria and are ineffective for enterococci, Listeria, and Neisseria sp.

Broad spectrum penicillins (2nd, 3rd, 4th generations)
Beta-lactams Broad spectrum penicillins (2nd, 3rd, 4th generations) Activity against gram-negative bacilli None of the broad spectrum penicillins is effective against penicillinase-producing staphylococci The third and fourth-generation penicillins are generally considered together as anti-Pseudomonal penicillins Second generation Ampicillin, amoxicillin Can penetrate the porin channel of gram-negative bacteria but are not stable to beta-lactamases Active against the majority of strains of Escherichia coli, Proteus mirabilis, Salmonella, Shigella, and Haemophilus influenzae Active against non-type b hemophilus influenza.

Beta-lactams Broad spectrum penicillins (2nd, 3rd, 4th generations) Third generation (Carbenicillin and ticarcillin) Can penetrate the porin channel of gram-negative bacteria, but they are less active than ampicillin on a weight basis. More resistant to the chromosomal beta-lactamases of certain organisms, such as indole-positive Proteus species, Enterobacter species, and Pseudomonas aeruginosa. Ticarcillin has the same spectrum of activity as carbenicillin but is two to four times more active on a weight basis against P. aeruginosa; Ticarcillin is a disodium salt (which may cause a problem in patients with volume overload) and may cause a bleeding diathesis by inhibition of platelet function and prolongation of the bleeding time.

Beta-lactams Broad spectrum penicillins (2nd, 3rd, 4th generations) Fourth generation (piperacillin) Piperacillin is a derivative of ampicillin . The same spectrum as carbenicillin and ticarcillin but is more active in vitro on a weight basis. .It is more active than carbenicillin or ticarcillin against enterococci and Bacteroides fragilis Piperacillin is somewhat more active against Enterobacteriaceae than carbenicillin or ticarcillin and more active than ticarcillin against P. aeruginosa. Piperacillin has less effect than ticarcillin on platelet function

Penicillins- pharmacology
Beta-lactams Penicillins- pharmacology Time dependent killing High therapeutic levels in pleural, pericardial, peritoneal and synovial fluids, as well as urine High bile level Penetrate the CSF poorly in the absence of inflammation but achieve therapeutic levels in patients with meningitis who are given high dose parenteral therapy

Beta lactamase inhibitors
Beta-lactams Beta lactamase inhibitors A drug given in conjunction with a beta-lactam antibiotics. The inhibitor does not have usually antibiotic activity It inhibits activity of plasmid mediated beta lactamase Calvulanic acid Sulbactam Tazobactam Amoxicillin-calvulanate (Augmentin) Oxacillin-sensitive SA and beta-lactamase producing HI in addition to the usual organisms inhibited by amoxocillin alone Can be used orally for AOM, sinusitis, LRTI, UTIs and bite wounds

Beta lactamase inhibitors
Beta-lactams Beta lactamase inhibitors Ampicillin-sulbactam (Unasyn)- IV Beta lactamase producing SA, HI and enterobacteriacea, anaerobes Abdominal infections Diabetic foot Sulbactam has activity against AB Ticracillin-calvulanate and piperacillin-tazobactam (timentin and tazocin) Beta lactamase producing SA, HI, NG, enterobacteriacea and anaerobes Not effective for ticracillin or piperacillin resistant strains of PA

Cephalosporins Beta-lactams First generation (cefazolin)
Second generation activity against Haemophilus influenzae (cefuroxime) Cephamycin subgroup with activity against Bacteroides Third generation poor activity against Pseudomonas aeruginosa (cefotaxime, ceftriaxone) good activity against Pseudomonas aeruginosa (cefoperazone and ceftazidime) Fourth generation (cefepime)

Cephalosporins Beta-lactams
First and second generation should not be used to treat infections of the central nervous system The third generation cephalosporins achieve much more reliable CSF levels in patients with meningeal irritation Cefotaxime, ceftizoxime, ceftriaxone, and ceftazidime are approved for the treatment of bacterial meningitis

Spectrum of activity Cephalosporins
Beta-lactams Spectrum of activity Cephalosporins First generation- cefazolin Most gram-positive cocci (including penicillinase-producing staphylococci) Does not have clinically useful activity against enterococci, Listeria, oxacillin-resistant staphylococci, or penicillin-resistant pneumococci Active against most strains of Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, but has little activity against indole-positive Proteus, Enterobacter, Serratia, and the non-enteric gram-negative bacilli such as Acinetobacter spp and Pseudomonas aeruginosa. Gram-negative cocci (such as the gonococcus and meningococcus) and H. influenzae are generally resistant.

Cephalosporins Spectrum of activity
Beta-lactams Cephalosporins Spectrum of activity Second generation less active against gram-positive cocci than the first-generation agents but are more active against certain gram-negative bacilli Two subgroups: Activity against HI Cephamycins- activity against bacteroides

Beta-lactams Cephalosporins Spectrum of activity Second generation Activity against HI- cefuroxime More active than cefamezine against HI Approved for HI meningitis but ceftriaxone preferred Active against Beta- lactamase producing Moraxella catarrhalis Cephamycin subgroup (active against Bacteroides) Cefoxitin, cefotetan Active against gram negative the same as cefamezine Stable to plasmid mediated beta-lactamase prophylaxis and therapy of infections in the abdominal and pelvic cavities

Beta-lactams Cephalosporins Spectrum of activity Third generation cefalosporins stability to the common beta-lactamases of gram-negative bacilli highly active against Enterobacteriaceae (E.coli, Proteus mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter), Neisseria and H. influenzae Mutants of Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal beta-lactamase, are resistant to these antibiotics

Beta-lactams Cephalosporins Spectrum of activity Third generation cefalosporins Less active against most gram-positive organisms than the first-generation cephalosporins and are inactive against enterococci, Listeria, oxacillin-resistant staphylococci, and Acinetobacter cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third generation cephalosporins as well

Beta-lactams Cephalosporins Spectrum of activity Third generation cefalosporins Poor activity against pseudomonas - Ceftriaxone, cefotaxime Ceftriaxone- longest half life (6h), sludge Activity against PA- Ceftazidime - stable to the common plasmid-mediated beta-lactamases , highly active against Enterobacteriaceae, Neisseria, and H. influenzae, and against P. aeruginosa. Ceftazidime has poor activity against gram-positive organisms

Beta-lactams Cephalosporins Spectrum of activity Fourth-generation - cefepime Better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third-generation cephalosporins for certain chromosomal beta-lactamases of gram-negative bacilli. Similar activity to cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and oxacillin-sensitive S. aureus. Active against the Enterobacteriaceae, Neisseria, and H. influenzae (like cef3) Greater activity against the gram-negative enterics that have a broad-spectrum, inducible, chromosomal beta-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and Serratia) Cefepime is as active as ceftazidime for Pseudomonas aeruginosa, and is active against some ceftazidime-resistant isolates increased all-cause mortality?

Beta-lactams Cephalosporins Spectrum of activity Fifth generation- Ceftobiprole capable of binding to penicillin binding protein 2a, the protein conferring S. aureus resistance to beta-lactam antibiotics It can also bind penicillin binding protein 2x in penicillin-resistant S. pneumoniae It has in vitro activity similar to that of ceftazidime or cefepime against Enterobacteriaceae; it also has activity against enterococci

Cephalosporins Treatment indicators for 3rd or 4th generation drugs
Beta-lactams Cephalosporins Treatment indicators for 3rd or 4th generation drugs May be complicated by superinfection (particularly with enterococci or Candida) or by the emergence of resistance on therapy (particularly when used as single agents for Enterobacter, indole-positive Proteus, or P. aeruginosa infections) Therapy of choice for gram-negative meningitis due to Enterobacteriaceae. Ceftriaxone is a therapy of choice for penicillin-resistant gonococcal infections and meningitis due to ampicillin-resistant H. influenzae. Ceftriaxone is also one of the recommended therapies for Lyme disease involving the CNS or joints

Carbapenems Beta-lactams
Carbapenems are generally resistant to cleavage by most plasmid and chromosomal beta-lactamases and have a very broad spectrum of activity: Gram negative organisms (including beta-lactamase producing H. influenzae and N. gonorrhoeae, the Enterobacteriaceae, and P. aeruginosa), including those that produce extended-spectrum beta-lactamases Anaerobes (including B. fragilis) Gram positive organisms (including Enterococcus faecalis and Listeria) PA- resistance may emerge on therapy when used as single agent Porins/membrane channels (not those used by other beta lactams)

Carbapenems Beta-lactams Imipenem-
Inactivated in the proximal renal tubule by dehydropeptidase I, (prevented by co-administration of cilastatin) Imipenem-cilastatin therapy has been associated with central nervous system (CNS) toxicity, especially evident in patients with underlying CNS disease or impaired renal function. Imipenem should not be used for the therapy of meningitis. The dosing of imipenem should be carefully titrated; patients with glomerular filtration rates of <5 mL/min should generally not receive imipenem

Carbapenems Beta-lactams Meropenem Stable to dehydropeptisase1
Can be administrated without cilastatin Lower risk of seizures Approved for bacterial meningitis Ertapenem- Enterobacteriacea and anaerobes but less active against PA, AB, gram positive bacteria particularly enterococci and PRSP Doripenem

Monobactams Aztreonam Gram negative bacteria including PA
No activity against anaerobes or gram positive bacteria Similar to AG Absence of cross allergenicity

Macrolides/Ketolides Azithromycin, Clarithromycin and Telithromycin
Derivatives of erythromycin Bind to the 50s ribosomal subunit newer macrolides are more acid-stable than erythromycin, providing improved oral absorption, tolerance, and pharmacokinetic properties. The newer macrolides have a broader spectrum of antibacterial activity than erythromycin acquired resistance: A methylase encoded by the ermB/A gene alters the macrolide binding site on the bacterial ribosome, usually confers a high degree of resistance (MLSB) An active macrolide efflux pump encoded by the mef (macrolide efflux) gene, which confers a low to moderate degree of macrolide resistance (msrA in SA) Pneumococcal resistance U.S % Azithro, clarithro, telithro have enhanced gram negative activity compared with erythromycin

Staphylococcus aureus
Erythromycin R Clindamycin S No induction, macrolide efflux (msrA gene). Can use clindamycin D test, induction of ribosomal methylation (erm gene). Do not use clindamycin.

Azithromycin, Clarithromycin and Telithromycin
URT infections: erythro-sensitive SP, Hemophillus sp., M. catarrhalis, legionella, chlamidophila pneumonia, Mycoplasma pneumonia usually active against other gram-positive organisms including Staphylococcus aureus (except for MRSA), and Group A, B, C, G streptococcus The gram-negative spectrum includes activity against Escherichia coli, Salmonella spp, Yersinia enterocolitica, Shigella spp, Campylobacter jejuni, Vibrio cholerae, Neisseria gonorrhoeae, and Helicobacter pylori MAC

Azithromycin, Clarithromycin and Telithromycin
Tissue and intracellular penetration — All macrolides and ketolides distribute and concentrate well in most body tissues and phagocytic cells Prolonged half life- azithro Major adverse events: Hepatotoxicity (telithro) GI upset 2-5% (azithro, clarithro) Long QT- erythro, clarithro (usually with other drugs)

Aminoglycosides Gentamicin, Aamikacin, Tobramycin
binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation Treatment of serious infections caused by gram negative bacilli Treatment of selected staphylococcal and enterococcal infections in combination with beta lactams Antiprotozoa (paromomycin), NG (spectinomycin), mycobacteria (streptomycin) bactericidal against susceptible aerobic gram-negative bacilli The microbiologic activity of aminoglycosides is pH dependent

Aminoglycosides Two important pharmacodynamic properties of aminoglycosides
Postantibiotic effect (PAE) persistent suppression of bacterial growth that occurs after the drug has been removed in vitro or cleared by drug metabolism and excretion in vivo described for gram-negative bacilli, also against Staphylococcus aureus (but not against other gram-positive cocci) approximately 3 hours Concentration-dependent killing ability of higher concentrations of aminoglycosides (relative to the organism's MIC) to induce more rapid, and complete killing of the pathogen

Aminoglycosides Resistance
Amikacin is usually reserved for serious gram-negative infections due to a gentamicin or tobramycin-resistant organism or as part of combination therapy against atypical mycobacterial infection Gram negative organisms: (acquired resistance) Inactivation of the drug by phosphorylation , adenylylation, or acetylation Another mechanism is methylation of 16S ribosomal RNA, associated with high level resistance to all parenteral aminoglycosides in current use Decreased accumulation of the drug

Aminoglycosides Resistance
Enterococci- Intrinsic resistance to low-moderate levels of aminoglycosides synergy exists when enterococci with low-level resistance, are exposed to a combination of the aminoglycoside with a cell wall agent increasing reports of acquired high-level enterococcal resistance to aminoglycosides (MIC >2,000)

Aminoglycosides Spectrum
Aaerobic gram-negative pathogens (Enterobacteriaceae, Pseudomonas, Haemophilus influenzae) In vitro activity against Burkholderia cepacia, Stenotrophomonas maltophilia, and anaerobic bacteria is usually poor or absent Activity in vitro against methicillin-susceptible S. aureus (MSSA) Activity against pneumococci is generally considered insufficient Empiric therapy of serious infections such as septicemia, nosocomial respiratory tract infections, complicated urinary tract infections, complicated intra-abdominal infections, and osteomyelitis caused by aerobic gram-negative bacilli.

Aminoglycosides Spectrum
Combination (usually with a beta-lactam) for serious infections due to Pseudomonas spp, indole-positive Proteus, Citrobacter spp, Acinetobacter spp, and Enterobacter spp. Combination therapy with gentamicin is frequently used for the treatment of invasive enterococcal infections not exhibiting high-level aminoglycoside resistance and sometimes for serious staphylococcal and viridans streptococcal infections.

Aminoglycosides Toxicity
Nephrotoxicity 10-20% (highly variable) Mostly reversible Ototoxicity Vestibular or cochlear Neuromuscular blockadge MG

Aminoglycosides Monitoring serum concentrations
Trough concentrations are measured within 30 minutes of the next dose and peak concentrations 30 to 45 minutes after the end of an intravenous infusion Frequency Target peak for genta/tobra: Serious invasive infections 6-8 mcg/ml, life threatening 7-9 Synergy (gram positive cocci) 3-4 Trough Less than 2

vancomycin (glycopeptide)
Inhibition of cell wall synthesis in gram positive bacteria Binds to D-alanyl-D-alanine in the NAM/NAG peptide Invasive gram positive infections (MRSA, enterococci), penicillin allergy, PMC Should not be used for MSSA!!! AUC/MIC- best predictor of efficacy (time to MIC) High clinical failure rate in patient infected with SA isolates with MIC≥2mcg/ml

Adverse events Mississippi mud Rash Red man syndrome- histamine mediated flushing ( no more than 500 mg/hr), sometimes angioedema and hypotension Serum concentration monitoring: Trough vs peak Trough- at least 10mcg/ml Serious infections: trough 15-20 MIC >1, trough 15-20 MIC≥2, daptomycin Whom to monitor Therapy longer than 3 days

Resistance Staphylococcus aureus: VISA, VRSA Enterococcus: VAN-A/B

New agents Streptogramins Linezolide Lipopeptides Tigecycline
Doripenem Glycolipopeptides Ceftobiprole

Streptogramins- Quinpristin-dalfopristin (Synercid)
Type B and A streptogramins Target the late and early stages of bacterial protein synthesis Synergistic In vitro- MRSA, VRE- not fecalis!! Indicated for (FDA approved) VRE faecium infections Complicated skin and skin-structure infections caused by MSSA ans S. pyogenes Not enough evidence for its use in VRE endocarditis MRSA skin and skin structure infections- 70% clinical success (open labeled), less if bacteremia or RTI (40%) Gram-positive nosocomial pneumonia- success rate comparable to vancomycin (55%) Adverse events: high rate of phlebitis, myalgias or arthralgias, cholestasis Resistance- low MLSB (gram positive rods)

Linezolide Oxazolidinone, IV and PO
In vitro- gram positive cocci including MRSA and VRE Bacteriostatic Inhibiting bacterial protein synthesis FDA-approved indications: VRE faecium Resistant SA, S.pypgenes, pneumococci, S. agalactiae Nosocomial and community acquired pneumonia, uncomplicated or complicated skin and skin-structure infections, including diabetic foot but not those with osteomyelitis or decubitus ulcer VRE faecium Endocarditis- not enough data. Acceptable to VRE with concomitant resistance to AG and penicillins

Daptomycin Cyclic lipopeptide
Gram positive pathogens, staphylococci and enterococci regardless of their resistance profile to methicillin or vancomycin Rapidly bactericidal Membrane depolarization FDA approved indications: Complicates skin and skin-structure infections caused by susceptible isolates of specific gram positive pathogens SA bloodstream infections including right sided endocarditis VRE. Faecium endocarditis- scarce data, may be considered Should not be selected for pulmonary infections (inactivation by surfactant) VISA- diminished susceptibility to daptomycin because of trapping of the drug in the thickened cell wall

Tigecycline Derivative of minocycline Glycylcycline
Broad spectrum- aerobic and anaerobic gram positive and gram negative pathogens, atypical pathogens, but not p. aeruginosa FDA approved indications: Complicated skin and skin-structure infections Complicated intra-abdominal infections Community acquired pneumonia Adverse events: mainly GI

Newer carbapenems Ertapenem- lacks in vitro activity against P. aeruginosa , other non-fermentative gram negative bacteria, enterococci Once daily administration FDA approved for complicated abdominal infections, complicated skin and skin structure infections (including diabetic foot without osteomyelitis), CAP, complicated UTI, PID Doripenem FDA approved for complicated intra-abdominal infections and complicated UTIs In comparison with tazocin and imipenem/cilastatin for nosocomial pneumonia and VAP was found favourable No convulsions

colistin Reintroduced to clinical practice Gram negative pathogens
AB, PA

New glycopeptides and lipoglycopeptided (not yet on clinical practice)
Oritavancin- potent bactericidal against MRSA, VISA and VRE, mainly had been evaluated in clinical trials for csssi Dalbavancin- MRSA, not against VRE with VANA, x1/w,csssi telavancin- MRSA, VRE, csssi, nosocomial pneumonia

When man extinct, micro-organisms will rule the world, as they always did.

Quinolones Fluoroquinolones inhibit DNA gyrase and topoisomerase IV
Bactericidal Resistance- mutation at DNA gyrase/topoisomerase gene or efflux pump, plasmid encoded qnr genes (kp, ecoli enterobacter) Related to intensity and duration of therapy Increasing resistant NG, c.jejuni, SP Related to MRSA appearance in hospitals Spectrum Aerobic gram negative bacilli Haemophilus sp Gram negative cocci (neisseria and moraxella) Non enteric GNR Staphylococci Atypical bacteria- chlamydophila pneumoniae, mycoplasma pneumonia, legionella pneumophila, chlamydia trachomatis, ureoplasma urealiticum, mycoplasma hominis

Quinolones Ciprofloxacin- the most potent against gram negatice bacteria Levofloxacin, moxifloxacin- better acticity against gram positive cocci Moxifloxacin- anaerobes Mycobacteria Pulmonary TB- Moxifloxacin vs ethambutol, Moxifloxacin vs INH Levofloxacin and moxifloxacin have increased potency relative to ciprofloxacin and ofloxacin against SP Gemifloxacin is the most potent against SP (rash) Marginal activity against enterococci High bioavailability Use in pregnancy- safety has not been established Use in children- not recommended for routine use <18y Adverse events: GI (5-15%), CNS (1-10% ), rash-1%(gemi), arthropathy- rare and reversible, tendinitis and tendon rupture 3/1000 adults and dose related

Newer fluroquinolones
Moxifloxacin, gemifloxacin Enhanced invitro activity against gram positive pathogens, in comparison with ciprofloxacin (particularly SP, PRSP) Activity against anaerobic and atypical bacteria Less active than ciprofloxacin for P. aeruginosa Good bioavailability Main indication- CAP Moxi is approved for sinusitis, skin infections and abdominal infections

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