Cell Wall Synthesis Inhibitors 4c1y5r

Cell wall synthesis inhibitors

1

Cell wall synthesis inhibitors 

Cell wall is presents in bacterial cells only.



It is the important cellular structure by which selective toxicity is achieved. 

Penicillin, Cephalosporin, Monobactams (with lactam ring)



Others with out -lactam ring Bacitracin

,cyclocerine ,Vancomycine 2

Beta-Lactam Antibiotics

3

The Penicillin's Mechanism of Action 

Penicillins inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis.



The bacterial cell wall is composed of a complex cross linked polymer - peptidoglycan.



The cross-linked peptidoglycan strands give structural integrity to cell walls and permit bacteria to survive environments that do not match the organism’s internal osmotic pressure. 4



Peptidoglycan is composed of glycan chains, which are linear strands of -1,4 linked two alternating amino sugars (Nacetylglucosamine and N-acetylmuramic acid) that are crosslinked by peptide chains.



A five-amino-acid peptide, which terminates in D-alanyl-Dalanine residue. is linked to the N-acetylmuramic acid sugar.



The -lactam antibiotics structurally resemble the terminal Dalanyl-D-alanine (D-Ala-D-Ala) in the pentapeptides on peptidoglycan. 

They covalently bind to the active serine site on transpeptidases and blocks further enzyme function. 5



In addition to transpeptidases, -lactam antibiotics interact with other enzymes termed penicillin binding proteins (PBPs).



PBPs are enzymes involved in both the elongation

of glycan strands (transglycosylation) and the formation of cross-links between the peptides (transpeptidation) of PG.

6

7

Mechanisms of Bacterial Resistance 

There are four major mechanisms of resistance to penicillins 1.

Inactivation of the -lactam ring Many bacteria possess -lactamases (penicillinases and cephalosporinases) that hydrolyze penicillins and cephalosporins.

2.

Alteration of PBPs 

Resistant bacteria, usually gram-positive organisms, produce PBPs with low affinity for -lactam antibiotics.



The mutations of PBPs involved in Streptococcus, pneumoniae, Enterococcus faecium, and MRSA 8

3.

Efflux pumps —

Some gram-negative organisms, For example, strains of P.

aeruginosa produce xenobiotic efflux pumps to eject antibiotics. 4.

Reduction of antibiotic access to PBPs 

Gram-positive organisms have an exposed peptidoglycan

layer easily accessible to -lactam antibiotics. 

In contrast, gram-negative organisms have an outer membrane surrounding the peptidoglycan layer. The gramnegative outer membrane hinders penetration of large molecules and helps bacteria resist the actions of antibiotics.

9

Interplay of -lactam antibiotics with G-ve and G+ve bacteria

10

Classification of the Penicillins 

Penicillins may be classified by their chemical structure and spectrum of activity into four groups:

Natural penicillins

1. 

Penicillin G, penicillin V,

Antistaphylococcal (penicillinase resistant)

2. 

Methicillin, Nafacillin, Oxacillin, Cloxacillin, Dicloxacillin,

Flucloxacillin

Aminopenicillins

3. 

Ampicillin, Amoxicillin

Extended-Spectrum Penicillins (Antipseudomonal

4.

penicillins) 

Ticarcillin, Piperacillin, Mezlocillin, Carbenicillin

11

Natural penicillins 

Penicillin G (benzylpenicillin) has the greatest antimicrobial activity and is the one most commonly used

clinically. 

Penicillin V has also similar spectrum of activity and may be used orally instead of Penicillin G



Have the greatest activity against gram-positive organisms, and non -lactamase-producing anaerobes.



Most streptococci are sensitive.



Most of the staphylococci including MSSA and MRSA have developed resistance 12



Penicillin G is an acid-labile compound. Consequently, most appropriate for IM or IV therapy



Penicillin does not readily enter the CSF when the meninges are normal. However, when the meninges are acutely inflamed, penicillin penetrates into the CSF more easily.



Penicillin G is excreted by the kidneys, with 90% of renal elimination occurring via tubular secretion and 10% by glomerular filtration.



Probenecid blocks tubular secretion and has been used to increase the serum concentration and prolong the half-life of penicillin G and other penicillins. 13



Penicillin Units: activity of penicillin G was originally defined in units (1 unit = 0.6 g; 1 million units of penicillin = 0.6 g).



Dose : 6 - 20 mllion unit per day divided on 4 - 6 doses for

adults and 100 - 250,000 u per kg per day divided on 4-6 doses for children 

Depot intramuscular formulations of penicillin G, including

procaine penicillin and benzathine penicillin have decreased solubility, delayed absorption, and a prolonged half-life.

14



procaine penicillin G



It is slowly released from the site of injection to produce relatively low but persistent concentrations in the blood.



Given only i.m. as 600,000 units once or twice per day.



Fortified procaine penicillin (PPF)



it consist of 300,000 units of procaine penicillin and 100,000 units of benzyl penicillin given once daily intramuscularly



Benzathine penicillin



produce low blood levels lasting from few days to 4 weeks



Is given only deep i.m. as 1.2 million unit every 2 - 4 weeks (4.8 million unit may be used as a single dose for treatment of syphilis and tonsillitis).

15

Clinical uses 

Penicillin G is a drug of choice for syphilis



It is also a drug of choice in streptococcal infection such as endocarditis caused by S. viridans (or

Streptococcus bovis), pharyngitis (S. pyogenes), and cat bite cellulites (Pasteurella multocida) 

Penicillin G is also the drug of choice for meningococcal infections

16

The Penicillinase - Resistant Penicillins 

Are resistant to hydrolysis by staphylococcal penicillinase.



But are much less active than is penicillin G against other penicillin-sensitive microorganisms, including non-

penicillinase-producing staphylococci. 

The clinical role of these agents has declined due to emgergence of resistant strains- esp. MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE).

17

18



The term “methicillin-resistant” denotes resistance of these bacteria to all the penicillinase-resistant penicillins and cephalosporins



Nafcillin is inactivated in the acidic medium of the gastric contents and its oral absorption is irregular  injectable preparations should be used.



Oxacillin, Cloxacillin, and Dicloxacillin are absorbed rapidly but incompletely (30% to 80%) from the GIT. Absorption is more efficient when they are taken on an empty stomach preferably they are istered 1 hour before or 2 hours after meals. 19

Aminopenicillins 

Have similar but more broader spectrum of activity than natural and penicillinase resistant penicillins.



They all are destroyed by -lactamase



Food decreases the bioavailability of Ampicillin but not Amoxicillin  oral doses of Ampicillin should be given on an empty stomach or pro-drugs (bacampicillin) can be used



Ampicillin achieves therapeutic concentrations in the cerebrospinal fluid only during inflammation  is effective treatment for meningitis caused by Listeria monocytogenes.



Amoxicillin does not reach adequate concentrations in the CSF and is not appropriate for meningitis

20

Clinical use 1.

Respiratory tract infection 

Ampicillin and amoxicillin are active against S. pyogenes and many strains of S. pneumoniae and H. influenzae, which are major upper respiratory bacterial pathogens.



Used in sinusitis, otitis media, acute exacerbations of chronic bronchitis, and epiglottitis.

2.

Urinary Tract Infections 

Ampicillin is effective in uncomplicated urinary tract infections often caused by Enterobacteriaceae, and E. coli.

3.

Meningitis 

Ampicillin has excellent activity against L. monocytogenes, a cause of meningitis in immunocompromised persons

21

Antipseudomonal Penicillins 

These drugs retain the antibacterial spectrum of penicillin and

have improved activity against gram -ve organisms. 

They are sensitive to destruction by -lactamases



Unlike other penicillins, no coverage against Staph.



Are active against P. aeruginosa which is resistant to other penicllins.



The ureidopenicillins, mezlocillin and piperacillin, have superior activity against P. aeruginosa compared with carbenicillin and ticarcillin (the carboxypenicillins). 22



Mezlocillin, piperacillin, and ticarcillin are parenteral antibiotics formulated as sodium salts  the sodium content in patients with congestive heart failure



Antipseudomonal penicillins achieve only low concentrations in the CSF  are not among the drugs of first choice for meningitis therapy.

23

Clinical use 

They are important agents for the treatment of serious infections caused by gram-negative bacteria.

24

-Lactamase Inhibitor 



Agents include:

Clavulanic acid,



Sulbactam and



Tazobactam

These substances resemble -lactam molecules but themselves have very weak/no antibacterial action.



Irreversibly binds -lactamases produced by a wide range of gram +ve and gram-ve microorganisms.



Given in combination with penicillins they provide protection against -Lactamases

25



They do not provide protection against all -Lactamases. 

most active against plasmid-encoded -lactamases



not good inhibitors of some chromosomally encoded -

lactamases. 

For example, they do not increase activity against P.

aeruginosa because resistance is due to either chromosomal -lactamases or decreased permeability of piperacillin into the per-plasmic space. 

The common combination used include 

Amoxicillin–clavulanic acid (agumentin)



Ampicillin-sulbactam



Ticarcillin-clavulanic acid



Piperacillin- tazobactam

26

Adverse Effect of Penicillins 

Hypersensitivity reactions are the most common ADR



Manifestations of allergy to penicillins include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis.



Allergic reactions to penicillin are immediate immunoglobulin (Ig) E–mediated type I immune responses.



The most serious hypersensitivity reactions produced by the penicillins are angioedema and anaphylaxis.



Other rare and minor ADRs include bone marrow depression, granulocytopenia, and hepatitis.

27

Cephalosporins and Cephamycins

28

Cephalosporins and Cephamycins

Mechanism of action 

similar with that of Penicillins

Mechanism of resistance 

Similar to penicillins



The penicillinases inactivate some cephalosporins but are much less efficient than are the cephalosporinases (lactamases specific for the cephalosporins)

29

Classification 

The cephalosporins are classified into generation according to their general features of antimicrobial activity. 1.

First Generation Cephalosporins 

Cephazolin, Cephalexin, Cefadroxil, Cephalothin, Cephradine

2.

Second Generation 

Cefaclor, Cefonicid, Cefuroxome, loracarbef, cefprozil, Cefixime, Cefamycins

30

3.

Third Generation 

Cefotaxime, Ceftriaxone, Ceftazidime, Cefpodoxime, Cefoperazone, Cefdinir, Ceftibuten, Cefpodoxime proxetil

4.

Fourth Generation 

Cefepime, Cefpirome

31

Spectrum of Activity 

As a general rule, first-generation compounds have better activity against gram-positive organisms and the later generations exhibit improved activity against gram-negative aerobic organisms.

1.

First Generation 

Gram Positive: active against streptococci spp. and methicillinsensitive S. aureus, but not against enterococcus



Gram Negative: limited activity including N. gonorrhoeae, Klebsiella spp.

32

2.

Second-Generation



Have a broader spectrum than do the first-generation agents and also have greater stability against lactamase inactivation 

Gram Positive: Streptococci spp., S. aureus



Gram Negative: improved activity including E.coli, Hemophilus I, Klebsiella spp., N. gonorrhoeae,

N.Menigitidis, Citrobater spp., Providentia spp., etc… but no activity against P. aeruginosa.

33

3.

Third Generation



Are less active than first-generation agents against grampositive cocci ( esp staphylococci), but they are much more active against the Enterobacteriaceae, including blactamase-producing strains



Have a broader spectrum of action against many common gram-negative bacteria and anaerobes



A subset of third-generation agents (ceftazidime and

cefoperazone) also is active against P. aeruginosa but less active than other third-generation agents against gram-positive cocci

34

4.

Fourth Generation



Have similar activity to 3rd generation drugs but with superior gram negative activity



None of the cephalosporins adequately treats infections caused by Enterococcus faecalis, E. faecium, MRSA, MRSE, penicillin-resistant S. pneumoniae, or L. monocytogenes

35

Clinical Uses 

Cephalosporins are effective as both therapeutic and prophylactic agents in a wide array of infection. 

Surgical prophylaxis 

The first-generation cephalosporins are activity against most of the bacterial pathogens that colonize skin and

soft tissue infections owing to S. aureus and S.

pyogenes.

36



The second-generation cephalosporins generally have been displaced by third-generation agents but, in some cases, may be used to treat infections caused by susceptible organisms. 

For. eg. cefoxitin and cefotetan are used in the treatment of lower abdominal and gynecological infection owing to their anaerobic activity.



Cefuroxime is used in sinusitis.

37



Third-generation cephalosporins have broad spectrum of antibacterial activity :

Ceftriaxone is the therapy of choice for all forms of

gonorrhea. 

Cefotaxime or ceftriaxone are used for the initial treatment of meningitis in non immunocompromised adults and children older than 3 months; they are also excellent for the treatment of community-acquired pneumonia



Ceftazidime plus an aminoglycoside is the treatment of choice for Pseudomonas meningitis

38



The fourth-generation cephalosporins 

are indicated for the empirical treatment of nosocomial infections where antibiotic resistance owing to extendedspectrum -lactamases or chromosomally induced lactamases is anticipated.

39

Adverse Effects 

Hypersensitivity reactions similar to penicillins may occur.



Cross-reactivity occurs between cephalosporins and

penicillins  caution when prescribing cephalosporins to patients with penicillin allergy. 

If a patient had anaphylaxis, angioedema, or urticaria

following penicillin use, cephalosporins should be avoided. 

Bleeding is an uncommon but serious side effect of some cephalosporins.

40



Other Beta Lactam Antibiotic 

Carbapenems 



Drugs include Ertapenem, Imipenem, and Meropenem

Monobactams: 

Aztreonam

41

Other Cell wall synthesis inhibitors Vancomycin 

Vancomycin is a glycopeptide antibiotic produced by

Streptococcus orientalis. Spectrum of activity 

It is primarily active against gram-positive bacteria; 

Because of its large size and complex structure, vancomycin does not penetrate the outer membrane of gram-negative organisms.



Active against S. aureus and S. epidermidis, including strains resistant to methicillin

42



S. pyogenes, S. pneumoniae, and viridans streptococci are highly susceptible.



Essentially all species of gram-negative bacilli and mycobacteria are resistant to vancomycin

43

Mechanism of Action 

Vancomycin interrupts cell wall synthesis by forming a complex with the C-terminal D-alanine residues of peptidoglycan precursors.



Complex formation at the outer surface of the cytoplasmic membrane prevents the transfer of the precursors from a lipid carrier to the growing peptidoglycan wall by transglycosidases.



Biochemical reactions in the cell wall catalyzed by transpeptidases and D,D-carboxypeptidases are also inhibited by vancomycin and other glycopeptide antimicrobials.

44

Mechanism of Resistance 

Modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate  loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target

45

Clinical Uses 

The main indication for parenteral vancomycin is sepsis or endocarditis caused by methicillin resistant staphylococci.



However, it is not as effective as antistaphylococcal penicillin for treatment of serious infections such as endocarditis caused

by methicillin-susceptible strains.

46



Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a highly penicillinresistant strain of pneumococcus.



Can be istered orally to patients with pseudomembranous colitis but metronidazole is strongly preferred as initial therapy and vancomycin should be reserved for treatment of refractory cases  because of the emergence of vancomycin-resistant enterococci

47

ADR 

Vancomycin is irritating to tissue at the site of injection.



Chills fever and rash may occur



Rapid intravenous infusion may cause erythematous or urticarial reactions, flushing, tachycardia, and hypotension.



The extreme flushing that can occur is sometimes called "redneck" or "red-man" syndrome. This is not an allergic reaction but a direct toxic effect of vancomycin on mast cells, causing them to release histamine.



Ototoxicity is rare and nephrotoxicity uncommon with current preparations. 48