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