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 mechanismBeta-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)
Resistance mechanismBeta-lactamase • 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
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
Beta lactams • Penicillins • Beta-lactamase inhibitors • Cephalosporins • Cephamycins • Carbapenems • Monobactams Bactericidal
Beta-lactamsPenicillins • 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)
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)
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 penicillinsnafcillin, 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.
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 • Piperacillinis 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
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-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-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
Beta-lactams Cephalosporins • 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)
Beta-lactams Cephalosporins • 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
Beta-lactams Cephalosporins Spectrum of activity • 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.
Beta-lactams CephalosporinsSpectrum 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 CephalosporinsSpectrum 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 CephalosporinsSpectrum 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 CephalosporinsSpectrum 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 CephalosporinsSpectrum 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 CephalosporinsSpectrum 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 CephalosporinsSpectrum 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
Beta-lactams CephalosporinsTreatment 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
Beta-lactams Carbapenems • 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)
Beta-lactams Carbapenems • Imipenem- • Inactivated in the proximal renal tubule by dehydropeptidase I, (prevented by co-administration of cilastatin) • Imipenem-cilastatintherapy 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
Beta-lactams Carbapenems • 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/KetolidesAzithromycin, 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- 15-20% • 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
AminoglycosidesTwo 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
AminoglycosidesResistance • 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)