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Antibiotics

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... who are given high dose parenteral therapy Beta-lactams Beta lactamase inhibitors A drug given in conjunction with a beta-lactam antibiotics. – PowerPoint PPT presentation

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Title: Antibiotics


1
Antibiotics
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Resistance mechanism
  • Beta-lactamases (eg. ESBLs, Carbapenemase)
  • Target modifying enzymes (PBP)
  • Drug modifying enzymes
  • Porin loss
  • Efflux pump
  • VISA/VRSA
  • VANs

9
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)

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11
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)
  • penicillinasecefalosporinase
  • penicillinasecefalosporinase 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)

12
Resistance mechanismBeta-lactamase
  • ESBLs- Augmentin-S, Cefotaxime-R, Ceftazidime-R,
    cefamycin-S
  • Most of them also resistance to AG, resprim and
    quinolones, and beta lactaminhibitor
  • 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

13
Resistance mechanismBeta-lactamase
14
Resistance mechanismBeta-lactamase
15
Resistance mechanism Staphylococcus aureus
  • Beta lactamase- resistance to penicillin
  • Low affinity to PBP2a (mecA gene)- resistance to
    methicillin (MRSA)
  • VISA
  • VRSA- VANA from enterococcus

16
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

17
Beta lactams
  • Penicillins
  • Beta-lactamase inhibitors
  • Cephalosporins
  • Cephamycins
  • Carbapenems
  • Monobactams

Bactericidal
18
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)

19
Penicillin G- spectrum of activity
Beta-lactams
  • Penicillin G is highly active against
  • Gram-positive cocci (except penicillinase-producin
    g 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)

20
Penicillin G- spectrum of activity
Beta-lactams
  • 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.

21
Antistaphylococcal penicillins nafcillin,
oxacillin, cloxacillin and dicloxacillin
Beta-lactams
  • 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.

22
Broad spectrum penicillins(2nd, 3rd, 4th
generations)
Beta-lactams
  • 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.

23
Broad spectrum penicillins(2nd, 3rd, 4th
generations)
Beta-lactams
  • 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.

24
Broad spectrum penicillins(2nd, 3rd, 4th
generations)
Beta-lactams
  • 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

25
Penicillins- pharmacology
Beta-lactams
  • 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

26
Beta lactamase inhibitors
Beta-lactams
  • 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

27
Beta lactamase inhibitors
Beta-lactams
  • 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-tazobacta
    m (timentin and tazocin)
  • Beta lactamase producing SA, HI, NG,
    enterobacteriacea and anaerobes
  • Not effective for ticracillin or piperacillin
    resistant strains of PA

28
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)

29
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

30
Spectrum of activity
Cephalosporins
Beta-lactams
  • 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.

31
CephalosporinsSpectrum of activity
Beta-lactams
  • 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

32
CephalosporinsSpectrum of activity
Beta-lactams
  • 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

33
CephalosporinsSpectrum of activity
Beta-lactams
  • 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

34
CephalosporinsSpectrum of activity
Beta-lactams
  • 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

35
CephalosporinsSpectrum of activity
Beta-lactams
  • 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

36
CephalosporinsSpectrum of activity
Beta-lactams
  • 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-intermed
    iate 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?

37
CephalosporinsSpectrum of activity
Beta-lactams
  • 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

38
CephalosporinsTreatment indicators for 3rd or
4th generation drugs
Beta-lactams
  • 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

39
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)

40
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 lt5 mL/min should generally
    not receive imipenem

41
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

42
Monobactams
  • Aztreonam
  • Gram negative bacteria including PA
  • No activity against anaerobes or gram positive
    bacteria
  • Similar to AG
  • Absence of cross allergenicity

43
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

44
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.
45
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

46
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)

47
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

48
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

49
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

50
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
    gt2,000)

51
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.

52
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.

53
Aminoglycosides Toxicity
  • Nephrotoxicity
  • 10-20 (highly variable)
  • Mostly reversible
  • Ototoxicity
  • Vestibular or cochlear
  • Neuromuscular blockadge
  • MG

54
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

55
vancomycin (glycopeptide)
  • 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 MIC2mcg/ml

56
Adverse events
vancomycin (glycopeptide)
  • 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 gt1, trough 15-20
  • MIC2, daptomycin
  • Whom to monitor
  • Therapy longer than 3 days

57
Resistance
vancomycin (glycopeptide)
  • Staphylococcus aureus VISA, VRSA
  • Enterococcus VAN-A/B

58
New agents
  • Streptogramins
  • Linezolide
  • Lipopeptides
  • Tigecycline
  • Doripenem
  • Glycolipopeptides
  • Ceftobiprole

59
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)

60
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

61
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

62
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

63
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

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colistin
  • Reintroduced to clinical practice
  • Gram negative pathogens
  • AB, PA

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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

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

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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
    lt18y
  • 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

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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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