Transcript Antibiotics

Antibiotics
‫מבנה דופן חיידק‬
‫סינתזת דופן החידק‬
Resistance mechanism
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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)
Resistance mechanism
Beta-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
Beta-lactamase
Resistance mechanism
Beta-lactamase
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 mechanismenterococci
• 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
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Penicillins
Beta-lactamase inhibitors
Cephalosporins
Cephamycins
Carbapenems
Monobactams
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)
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 penicillinaseproducing 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 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.
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
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
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 betalactamase, are resistant to these antibiotics
Beta-lactams
Cephalosporins
Spectrum of activity
• Third generation cefalosporins
– Less active against most gram-positive organisms than the firstgeneration 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 betalactamases , 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 broadspectrum, inducible, chromosomal beta-lactamase (Enterobacter, indolepositive 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 penicillinresistant S. pneumoniae
• It has in vitro activity similar to that of ceftazidime or
cefepime against Enterobacteriaceae; it also has activity
against enterococci
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, indolepositive 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 extendedspectrum 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-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
Beta-lactams
Carbapenems
• Meropenem
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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
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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- 15-20%
– Azithro, clarithro, telithro have enhanced gram negative activity
compared with erythromycin
Staphylococcus aureus
Erythromycin R
Clindamycin S
D test, induction of ribosomal
methylation (erm gene). Do
not use clindamycin.
No induction,
macrolide efflux
(msrA gene). Can
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 highlevel 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)
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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
vancomycin (glycopeptide)
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
vancomycin (glycopeptide)
Resistance
• Staphylococcus aureus: VISA, VRSA
• Enterococcus: VAN-A/B
New agents
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Streptogramins
Linezolide
Lipopeptides
Tigecycline
Doripenem
Glycolipopeptides
Ceftobiprole
Streptogramins- Quinpristin-dalfopristin (Synercid)
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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
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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 nonfermentative 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, microorganisms 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