Online Medical Tourism Agency Health Options
Worldwide (HOW) Discusses India's Resistant
Medical Travel "Super Bug“
Dolly Mehta
5-0236
dmehta@uic.edu
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,,
treatment.
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
Gram positive bacterial cell wall
Penicillins (PCN or PEN)
Proteoglycan (PG) (15-50 nm thick)
Plasma membrane
Cephalosporins
Clavulanate
Carbapenems
Bacterial
cell wall
Vancomycin
Gram negative bacterial cell wall
Lipopolysacharides
(LPS)
PG (2 nm thick)
Plasma membrane
periplasm
LPS: lipid A + core polysaccharides, O antigen
Gram negative bacterial cell wall
Peptidoglycan
N acetylmuramic acid (NAMA)
M
N acetylglucosamine (NAG) G
Penta peptide Glycine
1
Biosynthesis of Peptidoglycan
30 enzymes
M
G
M
G
M
G
Three stages:
1) Precursor formation: Cytoplasm
M
G
M
M
L-alanine
G
G
M
M
G
G
M
M
2) Binding with phospho-C55 lipid carrier
to form long polymer: Cell membrane
G
3) Cross-linking in cell wall
Penicillin: -Lactam antibiotics
CYTO
M UDP
racemase
D-alanine
synthetase
Drug of choice for a large number of diseases
M UDP
UMP
Discovered by Alexander Flemming 1928.
G UDP
UDP
Produced by penicillium
P-C55 lipid
M P-P-C55
G M P-P-C55
G M P-P-C55
MEMB
P-P-C55 lipid
P
G M
WALL
transglycolase
G M G M G M G
transpeptidase
-lactum ring
Thiazolidine ring
S
CH3
C CH3
R
C
CH
NH
CH
6APA
amidase
O =C
CH
COOH
N
=
O
Penicillinase/
-lactamase
R decides:
6-aminopenicillanic
p
acid
i.e. penicillin nucleus (required
for biological activities)
Classification
Spectrum
Natural Penicillins
Gram (+) cocci, hydrolyzed by
penicillinase so 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/
modern spectrum
Gram (-) e.g Hemophillus influenzae,
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
Penicillin subtype
Antibacterial activity
CH2OCH2-
OCH3
OCH3
R1
CH2-
NH2
CH-
COOR
resistance to -lactamase
stability for stomach acids
2
Mechanism of Inhibition
PBP domain structure
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

lactum antibodies
N
TG
Ser
TP
C
Transglycolase (TG) (insensitive to penicilin) formation
of linear glycan strands
Transpeptidase (TP) (sensitive to penicillin)cross-link
the peptide subunits)
Acylation of PBPs
serine residue (required for covalent bond formation) at the
active site is conserved in all members of the PBP family
.
Inhibition of PBPs
Structural irregularities
Cell lysis
high-molecular-weight (HMW) PBPs include
transpeptidase
M G M G M G
low-molecular-weight (LMW) PBPs
p of bacteria
mayy maintain shape
M G M G M G M
M G M G M G
PBP’s (40kD-91kD):
Number of PBPs varies within bacterial strain. i.e.
S aureus has 4 PBPs whereas E coli has 7
1
Apparent
molecular
weight
91000
Binding of
penicillin( %
total )
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
Protein
Affinity of PBPs to antibiotics is variable
Penicillin
Molecules/cell
Lytic PBP1
(leads to death
of bacterial cell)
Non-lytic (PBP2/3)
(affect holin-like proteins in
bacterial cell memb which alter
membrane potential)
3
Mechanisms of Penicilin Resistance
A. Elaboration of normal PBPs
A. Elaboration of PBPs
a) decreased affinity for -lactams
B. Inability of agent to penetrate to site of action
C. Increased expression of efflux pumps i.e E. coli
a1. formed by homologous recombination
between PBPs of different bacterial species
D. Production of -lactamase
a2 by transposans from unknown org
a2.
b) structural differences in PBPs
C. Increased expression of efflux pumps i.e E. coli
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 aeruginosa resistant to most antibiotics lacks
porins
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
Hydrolyse  lactam ring of penicillin's
d1. -lactamases class A-D:
Class A, C and D works by hydrolyzing serine ester
Class B (Zn-dependent)
Class A extended spectrum -lactamase;
 lactamase; degrade
penicillin, some cephalosporin's and
carbapenems
Class B destroy all -lactums except aztreonam
Class C cephalosporin's
Class D cloxacillin
4
General features of the Penicillins
d2. Site of liberation
Distribution
Gram (+),  lactamase is secreted extracellularly in large
amounts
Gram (-),  lactamase is located in the periplasmic space,
small amounts.
Primary mechanism of acquired resistance!
d3. Other factors:
surviving bacterial cell,
biofilms produce bacteria in prosthetics
Excretion
Eliminated by glomerular filtration. Higher urine
concentrations.
O
S
=
R
C
NH
CH
B
amidase
O
=C
A
N
O
CH
O
CH3
Do not penetrate phagocytic cells, very low conc in
prostatic fluids
fluids, brain tissue
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
Natural Penicillin
Penicillin G
Penicillin V
Pen V is superior to Pen G because of acid stability and
absorption
CH
COOH
Penicillanase
CH
=
R
CH + NH2
CH3
C
CH
widely distributed; concentration varies in diff tissues.
therapeutic concentrations is achieved readily in joint
fluid, pleural fluid, pericardial fluid, and bile
=C
CH
N
6-APA
OH
H
Penicilloic acid
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,
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% by
b glomerular
l
l filtration;
filt ti
90% by
b tubular
t b l secretion
ti
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)
lower in neonates and infants (3hrs in1wk old baby)
5
Renal dysfunction:
i.e Anuriaincreases the half life of Pencillin G
from 0.5 hr10hr 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)
Nafcillin
Very effective agnst S aureus
Inactivated in the acidic medium
Isoxazoyl penicillin (oxacillin, cloxacillin, dicloxacillin)
Temocillin
(dicloxacillin most active)
p
aeruginosa
g
or acinetobacter spp
pp
anti-pseudomonas
Relatively stable in an acid medium
Absorbed rapidly but incompletely (30-80%)
increases after empty stomach
Eliminated rapidly by kidney. Also hepatic
Aminopenicillins (Moderate spectrum)
Ampicillin (Principen)
Amoxicillin
Amocxicillin superior than ampicillin
acid stability, absroption, half life
Ampicillin (Principen)
Excretion
Appears in bile, undergo
enterohepatic circulation
and is excreated in feces
Amoxicillin
Eliminated in urine;
probenecid delays
excreation of drug;
Use Upper respiratory infections, UTI, Meningitis,
salmonella infections
Amoxicillin less effective than ampicillin for shigellosis
6
-lactamase sensitive
Carbenicillin Indanyl sodium (Geocillin)
only used for managing UTI caused by Proteus
Ticarcillin
2-4
2
4 times effective for P aeruginosa than
Carbenicillin, which is toxic
•Hypersensitivity: MOST common side effect (0.7%-4%)
Allergy to one penicillin greater risk to other penicillins
O
S
CH3
C CH3
R C NH CH CH
B
A
O =C
N
CH
COOH
amidase
Penicillanase
O
CH
=
Piperacillin (Pipracil)
extends the spectrum of ampicillin to include
most strains of P aeruginosa
VIII. Untoward Effects:
=
Antipseudomonal penicillins: (extended spectrum)
Carboxypenicillin and Ureidopenicillin
R
CH + NH2
CH
O
=C
CH
Haptens
N
6-APA
OH
H
IgE Abs
Penicilloic acid
Immunologic Classification of Hypersensitivity Reactions (Gell and Coombs)
Hapten
non-immunogenic
compound of low
molecular weight
Time of Onset
Mediator(s)
Clinical Signs
Type I
<1 h
IgE
Anaphylaxis:
urticaria,
angioedema,
wheezing, laryngeal
edema, hypotension
T
Type
II
>72 h
Immune cytopenia,
IgG/IgM
g g + comple
p
some organ
ment
inflammation
N
No
Type III
>72 h
Serum sickness,
IgG or IgM
drug fever,
immune complexes vasculitis, tissue
injury
No
Type IV
>72 h
T cells and
cytokines
Immunogenic
+
binding to
protein or cell
Immune
Response
(IgE, IgG,IgM,
Lymphocyte)
Skin Testing
Indicated
Gell-Coombs
Classification
Yes
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
Beta-Lactam Reactions Based on Time of Occurrence and Relation to IgE
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
Severe late reactions (>72 h), not IgE mediated
Hemolytic anemia
Neutropenia
Thrombocytopenia
Serum sickness
Interstitial nephritis
Hepatitis
Pulmonary infiltration
Eosinophilia
Vasculitis, Stevens-Johnson syndrome, Drug fever
•Decreased platelet aggregation (carbenicillin and
ticarcillin)
•Neutropenia (especially the -lactamase -resistant penicillins)
•Hypernatremia and hypokalemia (carbenicillin)
•Pseudomembranous
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
42
7
Cephalosporins
Drug-drug Interactions
R1
S
C
O
Carboxy- or Ureidopenicillins and aminoglycosides are
synergistic in their anti-pseudomonas activity.
CH2
NH
=
Chemically antagonize aminoglycosides. MUST NOT be
administered simultaneously through the same I.V. line;
should be staggered by about 1 to 2 hours.
CH CH
7ACP
O =C
N
R1 decides:
antibacterial activity
resistance to -lactamase
stability for stomach acids
C
C
C
=
R2 (effects
metabolism
and
pharmacokinetic)
O
OH
7ACP: 7-aminocephalosporanic acid
43
44
Cephalosporins
Acylation of PBPs
Classification: Best indicated by generation
based on antimicrobial activity
Inhibition of PBPs
M G M G M G
M G M G M G M
Inhibits cross linking
of peptidoglycan
M G M G M G
Structural irregularities
45
Cell lysis
Ist generation
Useful spectrum
Cefazolin (ANCEF,
ZOLICEF, others)
Cefadroxyl (DURACEF)
Cefalexin monohydrate
(KEFTAB)
Cefradine (VELOSEF)
good against Gram (+);
modest against Gram (-)
Streptococci (except penncillinresistant strains);
Staphylococcus aureus (except
Methicillin-resistant strain)
IInd generation
Cefuroxime (ZINACEF)
Cefuroxime axetil
(CEFTIN)
Cefprozil (CEFZIL)
Cefmatazole (ZEFAZONE)
Loracarbef (LORABID)
46
IIIrd generation
I
Increased
d activity
ti it against
i t
Gram (-) but much less
active than IIIrd generation
Gram (-) e.g., Enterobacter
sp, Klebsiella sp.,
haemophilus influenza; Not
active against gram + as Ist
generation
47
Cefotaxime (CLAFORAN)
Ceftriaxone (ROCEPHIN)
Cefdinir (OMNICEF)
Cefditoren pivoxil (SPECTRACEF)
Ceftizoxime (CEFIZOX)
Ceftibuten (CEDAX)
p
pproxetil (VANTIN)
(
)
Cefpodoxime
Cefoperazone (CEFOBID)
Ceftazidime (FORTAZ, others)
IV generation
Cefepime (MAXIPINE)
Useful spectrum
Less active than Ist
generation against Gram
(+) but more active
against Enterobactericeae
including
-lactamase producing
bacteria
Active agnst Pseudomonas
Extended spectrum of
activity than IIIrd generation
and have increased stability
against hydrolysis by lactamase
48
8
Ceftobiprole (Zeftera/Zevtera)
5th generation
Mechanism of Resistance:
active against MRSA (methicillin-resistant Staphylococcal
aureus, penicillin-resistant Streptococcus pneumoniae,
Pseudomonas aeruginosa
Same as penicillin's. i.e.Altered PBPs or lactamase
function
First generation cefazolin is more susceptible to lactamase from S aureaus than is Cephalothin
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.
Third generation: susceptible to hydrolysis by inducible
chromosomally encoded (Class 1 -lactamase)
Ceftobiprole inhibits the PBP. Ceftobiprole is resistant to
staphylococcal ‐lacatmase.]
Fourth generation: less susceptible
50
General features of the Cephalosporins
Excretion
Distribution
Primarily excreted by kidney
dosage should be adjusted in patients with
renal insufficiency
Cefoperazone (excreted in bile)
•absorbed readily after oral administration
•Several cephalosporins can penetrate into
CSFmeningitis
cefotaxime is deacelated in vivo; the metabolite
less active
•Can
C also
l cross placenta
l
t
•High concentrations also seen in synovial, bile and
pericardial fluids
•Penetration in aqueous humor of eye is high
51
52
IInd generation:
Specific Agents:
Cefoxitin
Ist generation:
Resistant to -lactamse produced by Gram (-) rods
For Gram (+) < active than Ist generation cephalosporins
More active than Ist or IInd generation agents agnst -fragalis
Cefazolin
Well-tolerated after either IM or IV
Conc in plasma after 1g IM administration reach to 64 ug/ml
E
Excreted
t db
by glomerular
l
l filt
filtration
ti and
d iis b
bound
d tto plasma
l
proteins (85%)
Conc in plasma after 1g IM administration reach to 22 ug/ml;
half life 40 min
Preferred among Ist generation as can be administered less
frequently due to longer half-life
53
54
9
IIIrd generation:
Cefotetan
Ceftazidime
Active agnst Gram (+) excellent for Pseudomonas and
Other Gram (-) bacteria
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 generation:
IIIrd
ti
half life 1.5 hrs; not metabolized
IVth generation:
ti
Cefotaxime
Cefepime
Resistant to many -lactamase and has a good activity
agnst most Gram (+) and (-) bacteria except B. fragilis
Active agnst many enterobact which are resistant to
other Cephalo
Half life in plasma 1 hr
Metabolized desacetylcefotaxime
Excellent penetration in CSF;
Conc in plasma after 2-g IV administration reach to
126-193 ug/ml; half life 2 hrs
55
56
Untoward Reaction:
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
cefotaxime or ceftriaxone: used to treat meningitis due to
pneumococci, meningococci, and Haemophillus influenza
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.
p
Nephrotoxic
Renal tubular necrosis i.e. cephaloridine (4g/day)
Hyperprothrombinemia, Platelet dysfunction
Thrombocytopenia
Fourth generation noscomal infections where
resistance to -lactum antibiotics is expected.
Disulfiram-like Effect: cefamandole, cefotetan,
moxalactam, cefoperazone.
57
58
OTHER -LACTAM Antibiotics
(Not penicillin or cephalosporins)
Drug-drug Interactions:
Concurrent administration of Cephalosporins or gentamicin
cause nephrotoxicity (in >60 yr old patients)
Carbapenems (fused -lactum ring and a 5-membered ring sys)
Imipenem, Meropenem, Ertapenem, Aztreonam
59
60
10
iii. Metabolism:
i. Mechanism of action: Binds to PBPs, disrupting cell wall
synthesis and is bactericidal.
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
ii. Spectrum: Broad-spectrum covers Gram (+) & Gram (-)
g Streptococci,
p
Enterococci.
e.g.
Resistant to most forms of -lactamase, including
that produced by staphylococcus.
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.
61
62
Seizures have been reported with high doses.
Aztreonam (AZACTAM)
A monocyclic -lactam (a monobactam).
iv. Therapeutic Use:
urinary tract and lower respiratory infections
intra-abdominal and gynecological infections
i. Mechanism of action: Interacts with PBPs and induces the
formation of long filamentous bacteria
effective against cephallosporin resistant bacteria
ii. Spectrum: It more closely resembles the spectrum of the
aminoglycosides. No activity against Gram (+) and
anaerobic bacteria are resistant.
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
Aztreonam is resistant to the -lactamase produced
by Gram (-) organisms.
iii. Side effects: well tolerated. Penicillin allergic patients do
not exhibit cross-reactions with aztreonam.
63
-Lactamase Inhibitors:
64
Mechanism of action:
i.
ii.
Inhibits -lactamaseprevent the destruction of lactun sensitive antibodies.
Very efficient against -lactamase that degrade
ceftazidine/cefotaxime.
However,
inactive
against
-lactamase
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
amoxacillin (Augmentum) or with ticaricillin (TIMENTIN)
65
66
11
Vancomycin
Complex tricyclic glycopeptide antibiotic
Antibacterial activity:
Gram (+)
Gram(–) are resistant because D-ala-D-ala (target) is
substituted with D-ala-D-ser or D-ala-D-lactate
Mechanism: Inhibits cell wall polymerization by binding to
terminal D-Ala-D-Ala terminus of incoming complex
attached to carrier
( G M )n
G M P-P-C55
+
G M
( G M )n
P-P-C55
Vancomycin
67
Absorption, Distribution and excretion:
68
Untoward Effects:
Oral absorption poor; slow IV is preferred, NEVER IM
(dose should be adjusted to maintainmdesirable trough
levels)
appears in body fluids and CSF
Hypersensitive Reacns (macular skin rashes, anaphylaxis,
Chills)
Rapid administrationflushing, tachycardia,
hypotension, erythematous or urticarial reacn
flushing “red-neck” or “red-man” syndrome by
di tl inducing
directly
i d i
toxicity
t i it in
i mastt cells
ll
90% excreted by glomerular filtration;
accumulates if renal function is impaired
(can be cleared by hemodialysis)
auditory impairment (ototoxicity) and nephrotoxicity;
caution with the use of aminoglycosides
69
70
12