• No results found

Biosynthesis of Peptidoglycan 30 enzymes M G M G M G. Three stages: 1) Precursor formation: Cytoplasm M G M G M G

N/A
N/A
Protected

Academic year: 2021

Share "Biosynthesis of Peptidoglycan 30 enzymes M G M G M G. Three stages: 1) Precursor formation: Cytoplasm M G M G M G"

Copied!
12
0
0

Loading.... (view fulltext now)

Full text

(1)

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)

(2)

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

(3)

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

(4)

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 Aextended spectrumlactamase; degrade Hydrolyse lactam ring of penicillin's

Class Aextended spectrum -lactamase; degrade penicillin, some cephalosporin's and carbapenems

Class Bdestroy all -lactums except aztreonam

Class Ccephalosporin's

(5)

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 V

Pen 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)

(6)

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)

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

(7)

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 penicillingreater 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 weight

Hapten

+

binding to protein or cell protein or cell Immune Response (IgE, IgG,IgM, Lymphocyte) Gell-Coombs

Classification 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

(8)

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 acids

44

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

(9)

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 CSFmeningitis

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;

(10)

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

(11)

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-lactamaseprevent 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

(12)

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 administrationflushing, 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

References

Related documents

• The extent to which the tests measure other performance relevant behaviors (e.g., cognitive or intrapersonal characteristics) as well as the five interpersonal dimensions of

And we also have the nature of Buddha’s mind, so that we see the potential and then we (are) working. Then “distinctive features of latter and acts which bring it about.”

Doing Energized Meditation or similar exercizes does not mean you will be a Perfectly Enlightened Being or a Guru in a few years, just that you will be a great deal happier and a

• Full cover for day-case procedures in the Mater Private, the Beacon hospital and Blackrock Clinic less €200 per claim on CompleteCare and less €125 per claim on Health Smart

Thus, they concluded that &#34;within the CMEA the Soviet Union has been 'subsidizing' certain East European countries by exporting 'hard goods' (fuels, nonfood raw

In our study, control subjects were well matched to 100% of case patients for the factors age, sex, and NNIS index, and we unable to find control subjects who underwent surgery in

That is—the plays under discussion are employed in shaping a sense of sympathy among the white audiences as they witness the horrible consequences of lynching on the entire lives

The time-dependent TWTA data at 0.03 Hz were used to construct a dose-response curve (Figure 2d), which will be used to assess the concentration of aspirin that has eluted from