Dolly Mehta 5-0236 dmehta@uic.edu
Online Medical Tourism Agency Health Options Worldwide (HOW) Discusses India's Resistant Medical Travel "Super Bug“
NDM-1 (New Delhi metallo-beta-lactamase bacteria) was found in British patients returning from Bangladesh, India, and Pakistan after medical treatment The NDM 1 is also being carried over by treatment. The NDM-1,, is also being carried over by patients in the United States and South Asia, who also have received surgical care in India.
"Scientists say it is highly resistant to antibiotics and is nearly impossible to treat," said David Goldstein, President of Health Options Worldwide
Penicillins (PCN or PEN) Cephalosporins Clavulanate Carbapenems Bacterial cell wall Carbapenems Vancomycin cell wall Proteoglycan (PG) (15-50 nm thick) Plasma membrane
Gram positive bacterial cell wall
PG (2 nm thick)
Plasma membrane
Lipopolysacharides (LPS)
periplasm
Gram negative bacterial cell wall
LPS: lipid A+ core polysaccharides, O antigen
Gram negative bacterial cell wall Peptidoglycan
M N acetylmuramic acid (NAMA)
G N acetylglucosamine (NAG) G N acetylglucosamine (NAG)
M G M G M G M G M G M G M M G M G M G Biosynthesis of Peptidoglycan 30 enzymes
1) Precursor formation: Cytoplasm 2) Binding with phospho-C55 lipid carrier
to form long polymer: Cell membrane Three stages:
to form long polymer: Cell membrane 3) Cross-linking in cell wall
M UDP
UDP M
UMP G UDPUDP
CYTO synthetase L-alanine D-alanine racemase P-C55 lipid M P-P-C55 P-P-C55 M G MEMB WALL P-P-C55 M G G M M G M G M G P-P-C55 lipid transglycolase P transpeptidase G
Penicillin: -Lactam antibiotics
Drug of choice for a large number of diseases Discovered by Alexander Flemming 1928. Produced by penicillium Produced by penicillium C CH COOH CH3 CH3 S CH N CH C
=
O NH C R=
O -lactum ring Thiazolidine ring
Penicillinase/ -lactamase 6APA 6-aminopenicillanic acid amidase R decides:
stability for stomach acids Antibacterial activity Penicillin subtype
resistance to -lactamase p
i.e. penicillin nucleus (required for biological activities)
Classification Spectrum
Natural Penicillins Gram (+) cocci, hydrolyzed by penicillinaseso ineffective against most strains of S. aureus
-lacatamse resistant Penicillin
Less active agnst bacteria sensitive to Penicillin G
First choice for S aureus and S epidermidis
Aminopenicillins/ Gram (-) e.g Hemophillus influenzae,
OCH2-CH2
-OCH3
OCH3
modern spectrum E.Coli, Neissaria sp.
Administered with -lactamse inhibitor such as clavanate to prevent hydrolysis Carboxypenicillin Gram (-) e.g. pseudomonas sp,
enterobacter sp. Inferior to ampicillin against Gram + cocci
Ureidopenicillins/ extended penicillin
Pseudomonas sp, 10 times more effective than carboxypenicillin CH2 -R1 NH2 CH-COOR
Mechanism of Inhibition
All -Lactam antibiotics binds penicillin binding proteins (PBP)belong to acyl serine transferases
PBPs: required for final stages of cell wall synthesis i.e. peptidoglycan (bind covalently)
-lactum antibodies Cell lysis Acylation of PBPs Inhibition of PBPs Structural irregularities lactum antibodies
Transglycolase(TG) (insensitive to penicilin) formation of linear glycan strands
Ser
N TG TP C
PBP domain structure
Transpeptidase(TP) (sensitive to penicillin)cross-link the peptide subunits)
serine residue (required for covalent bond formation) at the active site is conserved in all members of the PBP family . M G M G M G M G M G M G M M G M G M G high-molecular-weight (HMW) PBPs include transpeptidase low-molecular-weight (LMW) PBPs may maintain shape of bacteriay p
PBP’s (40kD-91kD):
Number of PBPs varies within bacterial strain. i.e. S aureushas 4 PBPs whereas E colihas 7
Protein Apparent molecular weight Binding of penicillin( % total ) Molecules/cell 1 91000 8.1 230 1 91000 8.1 230 2 66000 0.7 20 3 60000 1.9 50 4 49000 4.0 110 5 42000 64.7 1800 6 40000 20.6 570
Affinity of PBPs to antibiotics is variable Penicillin
Lytic PBP1 (leads to death
Non-lytic (PBP2/3) (affect holin-like proteins in (leads to death
Mechanisms of Penicilin Resistance A. Elaboration of normal PBPs
B. Inability of agent to penetrate to site of action C. Increased expression of efflux pumps i.e E. coli D. Production of -lactamase
A. Elaboration of PBPs
a) decreased affinity for -lactams
a2 by transposans from unknown org a1. formed by homologous recombination
between PBPs of different bacterial species a2. by transposans from unknown org
b) structural differences in PBPs
B. Inability of agent to penetrate to site of action
b1. Gram (-) bact outer layer of LPS
Small hydrophilic antibiotics can pass through channels porins i.e. amoxicillin, ampicillin>Penicillin G
P aeruginosaresistant to most antibiotics lacks P aeruginosaresistant to most antibiotics lacks porins
C. Increased expression of efflux pumps i.e E. coli
Major facilitator superfamily (MFS)
Adenosine triphosphate binding cassette (ABC) Small multidrug resistance (SMR)
Resistance nodulation cell division (RND)Gram (-) Multidrug and toxic compound extrusion (MATE)
D. Production of -lactamase
d1. -lactamases class A-D:
Class A, C and Dworks by hydrolyzing serine ester
Class B(Zn-dependent)
Class Aextended spectrumlactamase; degrade Hydrolyse lactam ring of penicillin's
Class Aextended spectrum -lactamase; degrade penicillin, some cephalosporin's and carbapenems
Class Bdestroy all -lactums except aztreonam
Class Ccephalosporin's
Gram (+), lactamase is secreted extracellularly in large amounts
Gram (-), lactamase is located in the periplasmic space, small amounts.
d2. Site of liberation
Primary mechanism of acquired resistance!
d3. Other factors:
surviving bacterial cell,
biofilms produce bacteria in prosthetics
Distribution
widely distributed; concentration varies in diff tissues. therapeutic concentrationsis achieved readily in joint fluid, pleural fluid, pericardial fluid, and bile
Do not penetrate phagocytic cells, very low conc in prostatic fluids brain tissue and intracular fluid General features of the Penicillins
prostatic fluids, brain tissue, and intracular fluid <1% in CSF when meninges are normal; ~5% when inflamed meningis
Active transport process pumps penicillin's from CSF to the bloodstream. This mechanism is blocked by Probenecid
Excretion
Eliminated by glomerular filtration. Higher urine concentrations. C CH COOH CH3 CH3 S CH N CH C
=
O NH C R=
O B A amidase CH N CH C=
O OH H Penicilloic acid NH2 + CH R=
O CH 6-APA Penicillanase amidase Natural Penicillin Penicillin G Penicillin VPen V is superior to Pen G because of acid stability and absorption
Repository Forms of Penicillin G:
Penicillin G procaine (Wycillin) (benzyl penicillin with local anasethetic agent procaine)
slowly absorbed after IM injection; Wycillin will maintain adequate plasma levels for 24 hours. Syphillis, RTI, anthrax
Penicillin G benzathine (Bicillin L A Permapen); slowest rate Penicillin G benzathine (Bicillin L-A, Permapen); slowest rate
of absorption after IM absorbtion. Can maintain adequate plasma levels for 10 days.
Distribution
bound with albumin
significant amount appear in liver, bile, kidney, semen, lymph, intestine Excretion
rapidly eliminated from the body by kidney
10% b l l filt ti 90% b t b l ti
10% by glomerular filtration; 90% by tubular secretion 60-90% urine within Ist hr after injection
rest metabolized to penicilloic acid
Renal clearance ~ total renal plasma flow ( 3 million u (1.8 g)/hr)
Renal dysfunction:
i.e Anuriaincreases the half life of Pencillin G from 0.5 hr10hr impairment of renal function 7-10% antibiotic may be inactivated by liver/hr
Therapeutic uses
Penicillin G: cellulitis, bacterial endocarditis,gonorrhea Pneumonia, Steptococcal infections, syphilis,
meningococcal infections
Penicillin V: tonsilitis, pharyngitis, skin infection, odontogenic infection
Prophylactic uses:
Affords protection agnst Steptococcal infections Rheumatic fever
-lactamase resistant Penicillin
narrow spectrum also called as anti-staphylococcal aureus penicillin)
Isoxazoyl penicillin (oxacillin, cloxacillin, dicloxacillin) (dicloxacillin most active)
Relatively stable in an acid medium Absorbed rapidly but incompletely (30-80%)
increases after empty stomach
Eliminated rapidly by kidney. Also hepatic
Nafcillin
Very effective agnst S aureus Inactivated in the acidic medium
anti-pseudomonas aeruginosa or acinetobacter spp Temocillin
p g pp
Aminopenicillins (Moderate spectrum) Ampicillin (Principen)
Amoxicillin
Amocxicillin superior than ampicillin acid stability, absroption, half life
Eliminated in urine; probenecid delays excreation of drug; Appears in bile, undergo
enterohepatic circulation and is excreated in feces
Ampicillin (Principen) Amoxicillin
Upper respiratory infections, UTI, Meningitis, salmonella infections
Excretion
Use
Ticarcillin
Antipseudomonal penicillins: (extended spectrum) Carboxypenicillin and Ureidopenicillin
-lactamase sensitive
2-4 times effective for P aeruginosa than Carbenicillin Indanyl sodium (Geocillin)
only used for managing UTI caused by Proteus
Piperacillin (Pipracil)
extends the spectrum of ampicillin to include most strains of P aeruginosa
2 4 times effective for P aeruginosa than Carbenicillin, which is toxic
VIII.Untoward Effects:
•Hypersensitivity:MOST commonside effect (0.7%-4%) Allergy to one penicillingreater risk to other penicillins
C CH COOH CH3 CH3 S CH N CH C
=
O NH C R=
O B A amidase CH N CH C=
O OH H Penicilloic acid NH2 + CH R=
O CH 6-APA Haptens IgE Abs Penicillanase amidase Immunogenic non-immunogenic compound of low molecular weightHapten
+
binding to protein or cell protein or cell Immune Response (IgE, IgG,IgM, Lymphocyte) Gell-CoombsClassification Time of Onset Mediator(s) Clinical Signs
Skin Testing Indicated Type I <1 h IgE Anaphylaxis: urticaria, angioedema, wheezing, laryngeal edema, hypotension Yes T II >72 h IgG/IgM + comple Immune cytopenia, N
Immunologic Classification of Hypersensitivity Reactions (Gell and Coombs)
Type II >72 h mentg g p some organ inflammation
No
Type III >72 h IgG or IgM immune complexes Serum sickness, drug fever, vasculitis, tissue injury No
Type IV >72 h T cells and cytokines Contact dermatitis, some organ inflammation No Ig = Immunoglobulin.
Beta-lactam antibiotics can cause all 4 types of hypersensitivity reactions.
Ann Yates, am J Med: 2008
Immediate (<1 h) and accelerated (1-72 h), IgE mediated Urticaria
Angioedema Laryngeal edema Bronchospasm Hypotension
Late reactions (>72 h), possibly IgE mediated Morbilliform rash
Urticaria
Beta-Lactam Reactions Based on Time of Occurrence and Relation to IgE
Urticaria
Severe late reactions (>72 h), not IgE mediated Hemolytic anemia Neutropenia Thrombocytopenia Serum sickness Interstitial nephritis Hepatitis Pulmonary infiltration
•Neutropenia (especially the -lactamase -resistant penicillins)
•Hypernatremia and hypokalemia (carbenicillin) •Pseudomembranous colitis: due to effect on microflora •Decreased platelet aggregation (carbenicillin and ticarcillin)
Pseudomembranous colitis: due to effect on microflora Management of patient potentially allergic to penicillin:
history
skin tests (not confirmatory) desensitization
achieved by administering gradually increasing dose of penicillin
Drug-drug Interactions
Chemically antagonize aminoglycosides.MUST NOT be
administered simultaneously through the same I.V. line; should be staggered by about 1 to 2 hours.
Carboxy- or Ureidopenicillins and aminoglycosides are synergistic in their anti-pseudomonas activity.
43 CH2 C S CH N CH C
=
O NH C R1=
O 7ACP R2 C (effects metabolism Cephalosporins C C=
O OH metabolism and pharmacokinetic) R1 decides: antibacterial activity resistance to -lactamase stability for stomach acids44
7ACP: 7-aminocephalosporanic acid
Acylation of PBPs Inhibition of PBPs
Cephalosporins
M G M G M G
Inhibits cross linking
Cell lysis Structural irregularities M G M G M G
M G M G M G M
Inhibits cross linking of peptidoglycan
45
Classification: Best indicated by generation based on antimicrobial activity
46 Cefazolin (ANCEF, ZOLICEF, others) Cefadroxyl (DURACEF) Cefalexin monohydrate (KEFTAB) Cefradine (VELOSEF) Ist generation
good against Gram (+); modest against Gram (-)
Streptococci (except penncillin-resistant strains);
Staphylococcus aureus (except Methicillin-resistant strain) Useful spectrum IIndgeneration I d ti it i t 47 Cefuroxime (ZINACEF) Cefuroxime axetil (CEFTIN) Cefprozil (CEFZIL) Cefmatazole (ZEFAZONE) Loracarbef (LORABID) II generation
Increased activity against Gram (-) but much less active than IIIrd generation
Gram (-) e.g., Enterobacter sp, Klebsiella sp., haemophilus influenza; Not active against gram + as Ist generation
Cefotaxime (CLAFORAN) Ceftriaxone (ROCEPHIN) Cefdinir (OMNICEF)
Cefditoren pivoxil (SPECTRACEF) Ceftizoxime (CEFIZOX) Ceftibuten (CEDAX)
Cefpodoxime proxetil (VANTIN) IIIrd generation
Less active than Ist generation against Gram (+) but more active against Enterobactericeae including -lactamase producing bacteria Useful spectrum p p ( ) Cefoperazone (CEFOBID) Ceftazidime (FORTAZ, others)
48
IV generation Cefepime (MAXIPINE)
Extended spectrum of activity than IIIrd generation and have increased stability against hydrolysis by -lactamase
Ceftobiprole(Zeftera/Zevtera) 5th generation
active against MRSA (methicillin-resistant Staphylococcal aureus, penicillin-resistant Streptococcus pneumoniae, Pseudomonas aeruginosa It has been shown to be statistically non‐inferior to the combination of vancomycin and ceftazidime for the treatment of skin and soft tissue infections. Ceftobiprole inhibits the PBP. Ceftobiprole is resistant to staphylococcal ‐lacatmase.] Mechanism of Resistance:
Same as penicillin's. i.e.Altered PBPs or lactamase function
First generationcefazolin is more susceptible to -lactamase from S aureaus than is Cephalothin Third generation:susceptible to hydrolysis by inducible
chromosomally encoded (Class 1 -lactamase) Fourth generation:less susceptible
50
Generalfeatures of the Cephalosporins
•absorbed readily after oral administration •Several cephalosporins can penetrate into CSFmeningitis
C l l t
Distribution
•Can also cross placenta
•High concentrations also seen in synovial, bile and pericardial fluids
•Penetration in aqueous humor of eye is high
51
Excretion
Primarily excreted by kidney
dosage should be adjusted in patients with renal insufficiency
Cefoperazone (excreted in bile)
cefotaxime is deacelated in vivo; the metabolite cefotaxime is deacelated in vivo; the metabolite less active
52
Specific Agents: Ist generation:
Cefazolin
Well-tolerated after either IM or IV
Conc in plasma after 1g IM administration reach to 64 ug/ml
E t d b l l filt ti d i b d t l
Excreted by glomerular filtration and is bound to plasma proteins (85%)
Preferred among Ist generation as can be administered less frequently due to longer half-life
IIndgeneration:
Cefoxitin
Resistant to -lactamse produced by Gram (-) rods For Gram (+) < active than Istgeneration cephalosporins
More active than Istor IIndgeneration agents agnst -fragalis
Conc in plasma after 1g IM administration reach to 22 ug/ml; Conc in plasma after 1g IM administration reach to 22 ug/ml;
Cefotetan
More active than Cefoxitin agnst Gram (-)
Conc in plasma after 1-g IM administration reach to 70 ug/ml; half life 3.3 hrs
III d ti
Resistant to many -lactamase and has a good activity agnst most Gram (+) and (-) bacteria except B. fragilis
IIIrd generation:
Cefotaxime
Half life in plasma 1 hr
Metabolized desacetylcefotaxime
55
IVth ti
Active agnst Gram (+) excellent for Pseudomonas and Other Gram (-) bacteria
IIIrd generation:
Ceftazidime
half life 1.5 hrs; not metabolized
Active agnst many enterobact which are resistant to other Cephalo
IVthgeneration:
Cefepime
Excellent penetration in CSF;
Conc in plasma after 2-g IV administration reach to 126-193 ug/ml; half life 2 hrs
56
Therapeutic Uses:
First generation: skin and soft tissue infections, surgical prophylaxis of wound infection.
Third generation:
infections caused by Klebsiella, Enterobacter, Proteus etc,
ceftriaxone: all forms of gonorrhea, severe lyme diseases
Fourth generationnoscomal infections where resistance to -lactum antibiotics is expected.
ceftriaxone: all forms of gonorrhea, severe lyme diseases
cefotaxime or ceftriaxone: used to treat meningitis due to pneumococci, meningococci, and Haemophillus influenza
57
Hypersensitivity:The frequency of cross-reactivity with penicillin-sensitive individuals is 5 to 15%.
CONTRAINDICATED in patients with a history of anaphylaxis to a penicillin.
Nephrotoxic Untoward Reaction:
p
Renal tubular necrosis i.e. cephaloridine (4g/day)
58
Hyperprothrombinemia, Platelet dysfunction Thrombocytopenia
Disulfiram-like Effect: cefamandole, cefotetan, moxalactam, cefoperazone.
Drug-drug Interactions:
Concurrent administration of Cephalosporins or gentamicin cause nephrotoxicity (in >60 yr old patients)
59
OTHER -LACTAM Antibiotics (Not penicillin or cephalosporins)
Carbapenems (fused -lactum ring and a 5-membered ring sys)
60
ii. Spectrum:Broad-spectrum covers Gram (+) & Gram (-) e.g. Streptococci, Enterococci.
i. Mechanism of action:Binds to PBPs, disrupting cell wall synthesis and is bactericidal.
g p
Resistant to most forms of -lactamase, including that produced by staphylococcus.
61
iii. Metabolism: not absorbed orally
Imepenem hydrolyzed by dipeptidase, so always administered with cilastatin, an inhibitor of dipeptidase Meropenem, Ertapenem (long half life) are resistant to dipeptidase
most of it is recovered in urine as the active drug; renal insufficiency
iv. Side effects:
patients allergic to the penicillins may demonstrate cross-reactivity with imipenem.
nausea and vomiting.
Seizures have been reported with high doses. 62
iv. Therapeutic Use:
urinary tract and lower respiratory infections intra-abdominal and gynecological infections effective against cephallosporin resistant bacteria prudent to use imipenem for empirical treatment of serious infections in hospitalized patients who have recvd other -lactums
should NOT be used as monotherapy against pseudomonas due to risk of resistance during therapy
63
Aztreonam (AZACTAM)
A monocyclic -lactam (a monobactam).
i.Mechanism of action:Interacts with PBPs and induces the formation of long filamentous bacteria
ii. Spectrum:It more closely resembles the spectrum of the aminoglycosides.No activity against Gram (+) and anaerobic bacteria are resistant.
anaerobic bacteria are resistant.
Aztreonam is resistant to the -lactamase produced by Gram (-) organisms.
iii. Side effects:well tolerated. Penicillin allergic patients do not exhibit cross-reactionswith aztreonam.
64
-Lactamase Inhibitors:
Mechanism of action:
i. Inhibits-lactamaseprevent the destruction of -lactun sensitive antibodies.
ii. Very efficient against -lactamase that degrade ceftazidine/cefotaxime.
However, inactive against -lactamase produced by treatment with IInd and IIIrd produced by treatment with IInd and IIIrd generation cephalosopirns.
iii. Poor antimicrobial activity, but binds irreversibly with -lactamase from both gram (+) or gram (-) bact so known as “SUICIDE"inhibitor of -lactamase
iii. well absorbed; included in combination with
Vancomycin
Mechanism: Inhibits cell wall polymerization by binding to Complex tricyclic glycopeptide antibiotic
Mechanism: Inhibits cell wall polymerization by binding to terminal D-Ala-D-Ala terminus of incoming complex attached to carrier P-P-C55 M G G M P-P-C55 M G ( )n + M G ( )n 67 Vancomycin Antibacterial activity: Gram (+)
Gram(–) are resistant because D-ala-D-ala (target) is substituted with D-ala-D-ser or D-ala-D-lactate
68
Absorption, Distribution and excretion:
Oral absorption poor; slow IV is preferred, NEVER IM (dose should be adjusted to maintainmdesirable trough levels)
appears in body fluids and CSF
69
90% excreted by glomerular filtration;
accumulates if renal function is impaired (can be cleared by hemodialysis)
Untoward Effects:
Hypersensitive Reacns (macular skin rashes, anaphylaxis, Chills)
Rapid administrationflushing, tachycardia, hypotension, erythematous or urticarial reacn
flushing “red-neck” or “red-man” syndrome by di tl i d i t i it i t ll
70
auditory impairment (ototoxicity) and nephrotoxicity; caution with the use of aminoglycosides