Beta lactam & other cell wall- & membrane-active antibiotics

Beta-Lactam & Other Cell Wall &

Membrane-Active Antibiotics

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

M.H.FarjooM.H.Farjoo

Beta-Lactam & Other Cell Wall Antibiotics

General Considerations Introduction to beta lactams Penicillins Cephalosporins Other beta-lactam drugs Miscellaneous Drugs of choice based on:

Disease or Pathogen Site of infection

Drug Pictures

Escherichia Coli

Staphylococcus_aureus


Introduction

β-lactam drugs have a β-lactam ring and consist of: Penicillins Cephalosporins Other beta-lactam drugs Miscellaneous

They have similar: Mechanism of action. Pharmacologic effects. Mechanism of bacterial resistance.

Core structures of four β-Lactam antibiotic families. The ring marked B in each structure is the β-lactam ring. The penicillins are susceptible to bacterial metabolism and inactivation by amidases and lactamases at the points shown. Note that the carbapenems have a different stereochemical configuration in the lactam ring that apparently imparts resistance to β-lactamases.


Introduction (Cont’d)

β-lactam antibiotics, inhibit bacterial growth by interfering with bacterial cell wall synthesis.

They covalently bind to the active site of PBPs inhibiting the transpeptidation.

This halts peptidoglycan synthesis, and the cell dies.

Penicillins and cephalosporins kill bacteria only when they are actively growing and synthesizing cell wall.

The transpeptidation reaction in Staphylococcus aureus that is inhibited by β-lactam antibiotics. The cell wall of gram-positive bacteria is made up of long peptidoglycan polymer chains consisting of the alternating aminohexoses N-acetylglucosamine (G) and N-acetylmuramic acid (M) with pentapeptide side chains linked (in S aureus) by pentaglycine bridges. The exact composition of the side chains varies among species. The diagram illustrates small segments of two such polymer chains and their amino acid side chains. These linear polymers must be cross-linked by transpeptidation of the side chains at the points indicated by the asterisk to achieve the strength necessary for cell viability.

A highly simplified diagram of the cell envelope of a gram-negative bacterium. The outer membrane, a lipid bilayer, is present in gram-negative but not gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic access to the cytoplasmic membrane. The peptidoglycan layer is unique to bacteria and is much thicker in gram-positive organisms than in gram-negative ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins (PBPs) are membrane proteins that cross-link peptidoglycan. β-Lactamases, if present, reside in the periplasmic space or on the outer surface of the cytoplasmic membrane, where they may destroy β-lactam antibiotics that penetrate the outer membrane.


فکر نمي کنم آمپول پني سيلين در هيچ جاي دنيا بهاندازه ايران عاشق سينه چاک داشته باشد. انگار

ايراني ها همانقدر که مردم دنيا شکالت دوست دارند آمپول پني سلين دوست دارند.

يکي از مشکالت عمده پزشکان کنار آمدن با اين مدلمريض هاست.

مريض هايي که وقتي از علت مراجعه شان مي پرسي سرماخورده ام و تا پني سيلين نزنم مي گويند : دکتر من

خوب نمي شوم. ک تر هستند مي گويند آمده ام برايم پني بعضي هم که ر=

سيلين بنويسيد. تازه اينها غير از افرادي هستند که پني سيلين از داروخانه خودشان تعداد عجيب و غريبي

تهيه کرده اند و براي تزريق مراجعه مي کنند. پزشکان بيچاره هم اين وسط گير افتاده اند. تجربه

که سعي در توجيه بيماران بي فايده است می دهد نشان چون آنها براي نظر شخصي خود ارزش بيشتري از نظر

ايل هستند.قپزشک


Penicillins

Penicillins are divided into three groups: Penicillin salts Extended-spectrum Antistaphylococcal

In each group gastric acid resistant penicillins for oral use exist.


Penicillin Salts

Penicillin G Salts consist of: Na+ & K+ salts of penicillin G Benzathine Procaine

Penicillin V is the oral form of this group. All of them are hydrolyzed by β-lactamases. Benzathine and procaine have delayed

absorption resulting in prolonged blood concentrations.


Penicillin Salts (Cont’d)

An IM injection of benzathine penicillin, 1.2 million units, treats streptococcal pharyngitis for 10 days.

It is enough to prevent streptococcal infection for 3 weeks.

An IM injection of 600,000 unit of procaine penicillin is useful for 12-24 hrs.

Penicillin V is used only in minor infections. Amoxicillin is often used instead.


Extended-spectrum Penicillins

Extended-spectrum penicillins consist of: Aminopenicillins:

Ampicillin Amoxicillin

Carboxypenicillins: Ticarcillin

Ureidopenicillins: Piperacillin Mezlocillin Azlocillin

They are relatively susceptible to hydrolysis by β-lactamases.


Antistaphylococcal Penicillins

Antistaphylococcal Penicillins consist of: Methicillin Nafcillin Isoxazolyl Penicillins:

Oxacillin Cloxacillin Dicloxacillin

They are resistant to β-lactamases produced by staphylococci.


Pharmacokinetics of penicillins

Ampicillin, and amoxicillin are acid-stable and well absorbed.

Ampicillin and amoxicillin, have identical activity, but amoxicillin is better absorbed orally.

Anti staphylococcal penicillins are acid-stable and have reasonable bioavailability.

Food impairs absorption of oral penicillins (except amoxicillin) and they should be taken 1-2 hr before or after a meal.


Pharmacokinetics of penicillins (Cont’d)

For parenteral use, IV administration is preferred to the IM route because of irritation and pain from large doses.

Penetration into the eye, the prostate, and the central nervous system is poor.

In meninges therapeutic penicillin concentrations can be achieved with a daily parenteral dose of 18-24 million units.

Nafcillin, Oxacillin, cloxacillin, and dicloxacillin are also cleared by biliary excretion.


Pharmacokinetics of penicillins (Cont’d)

Blood levels of all penicillins can be raised by simultaneous administration of probenecid.

Probenecid impairs renal secretion of β-lactams.

The half-life of penicillin G is 30 min., in renal failure it increases to 10 hrs.

Depending on the severity of infection, doses range between 4 and 24 million units/day.

Extended-spectrum penicillins are inactivated by β-lactamases.


Resistance to penicillins

Resistance is due to one of four mechanisms: Inactivation by β-lactamase (the most common

mechanism). Modification of target PBPs. Impaired penetration of drug to target PBPs. Efflux.

Some β-lactamases prefer penicillins to cephalosporins others hydrolyze both of them.

Only in gram-negatives because of their impermeable outer cell wall membrane


Adverse Reactions to penicillins The penicillins are nontoxic. Most adverse effects are

due to hypersensitivity. All penicillins are cross-sensitizing and cross-

reacting. 5-8% of people claim a penicillin reaction but it is not

true. < 1% of persons who have received penicillin without

incident will have an allergic reaction when given penicillin.

Penicillin should be administered with caution if there is a history of penicillin allergy.


Adverse Reactions to penicillins Cont’d

The incidence of allergic reactions in small children is negligible.

Allergic reactions include: Anaphylactic shock (0.05%)

Serum sickness

A variety of skin rashes.

In renal failure, high dose penicillin can cause seizures.

Urticaria, fever, joint swelling, intense pruritus, respiratory embarrassment occurring 7-12 days after exposure


Adverse Reactions to penicillins Cont’d

Nafcillin is associated with neutropenia.

Oxacillin can cause hepatitis.

Large doses of oral penicillins may lead to vomiting and diarrhea.

Ampicillin has been associated with vaginal candidiasis and pseudomembranous colitis.

Ampicillin and amoxicillin can cause skin rashes that are not allergic in nature.


Penicillin Units

Penicillin G contains 1600 units per mg, 1 million units = 0.6 g).

In dry form, penicillins are stable for years at 4 °C.

Solutions lose their activity rapidly (24 hours at 20 °C) and must be prepared fresh.


Cephalosporins

Cephalosporins are similar to penicillins but: More stable to bacterial β-lactamases.

Have a broader spectrum of activity.

They are grouped into 4 generations.


First-generation Cephalosporins

First-generation include

Probenecid, increases serum levels substantially.

In patients with impaired renal function, dosage must be reduced.

First-generation cephalosporins are rarely the drug of choice for any infection.

Oral cephalosporins should not be relied on in serious systemic infections.

Cephalexin CephalothinCefazolinCefadroxilCephapirinCephradine


Second-generation Cephalosporins

Second-generation include

They have extended gram-negative coverage compared to first generation.

The oral second-generation cephalosporins are active against β-lactamase.

Because of their activity against anaerobes (including B fragilis), can be used to treat such infections (peritonitis or diverticulitis).

CefaclorCefamandoleCefonicidCefuroximeCefprozilLoracarbefCeforanide CefoxitinCefmetazoleCefotetan


Third-generation Cephalosporins Third-generation agents include They have expanded gram-negative coverage. They can treat infections resistant to most other

drugs. Parenteral cephalosporins (except cefoperazone)

achieve sufficient levels in the CSF. The excretion of cefoperazone and ceftriaxone is

mainly through the biliary tract. The others are excreted by the kidney.

CefoperazoneCefotaximeCeftazidimeCeftizoximeCeftriaxoneCefiximeCefpodoxime ProxetilCefdinirCefditoren pivoxilCeftibutenMoxalactam


Fourth-generation Cephalosporins

Cefepime is a fourth-generation cephalosporin.

It is useful in the treatment of enterobacter infections.

Otherwise, its clinical role is similar to that of third-generation agents.


Adverse Effects of Cephalosporins

Cephalosporins elicit hypersensitivity reactions identical to penicillins.

Some individuals with a history of penicillin allergy may tolerate cephalosporins.

Cephalosporins with methylthiotetrazole group (cefamandole, cefmetazole, cefotetan, cefoperazone) cause two problems: Bleeding disorders due to hypoprothrombinemia which can

be prevented by vitamin K1. Severe disulfiram-like reactions (alcohol and alcohol-

containing medications must be avoided).


Other beta-lactam drugs

Other beta-lactam drugs consist of:

Monobactams

Carbapenems

Aztreonam

ErtapenemImipenem Meropenem


Monobactams

Monobactams: are drugs with a monocyclic β-lactam ring.

They are resistant to β-lactamases and active against gram-negative rods.

They have no activity against gram-positive bacteria or anaerobes.

Penicillin-allergic patients tolerate aztreonam without reaction.


Carbapenems

Imipenem has good activity against gram-negative, gram-positive and anaerobe organisms.

Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations.

It is administered with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use.

Meropenem and ertapenem are not degraded by renal dehydropeptidase.


Carbapenems (Cont’d)

IM ertapenem is irritating, so it is formulated with 1% lidocaine.

A carbapenem is used for P aeruginosa resistant to other drugs and mixed aerobic and anaerobic infections.


Miscellaneous

Miscellaneous drugs related to β-lactams are: Beta-lactamase inhibitors

Other cell wall ormembrane-active agents

Clavulanic AcidSulbactamTazobactam

VancomycinDaptomycinFosfomycinBacitracinCycloserine


Beta-lactamase Inhibitors

They are inhibitors of many but not all bacterial β-lactamases.

Penicillin-β-lactamase inhibitor are used in empirical therapy of a wide range of pathogens.


Vancomycin

Vancomycin is active against gram-positives bacteria, particularly staphylococci.

β-lactamase producing staphylococci and those resistant to nafcillin and methicillin are killed.

Vancomycin kills staphylococci slowly and only if cells are actively dividing.


Vancomycin (Cont’d)

Vancomycin is poorly absorbed from the GI tract.

It is used orally only for antibiotic-associated enterocolitis caused by C difficile.

Metronidazole is preferred as initial therapy and vancomycin is reserved for refractory cases.

Parenteral vancomycin is ised in sepsis caused by methicillin-resistant staphylococci.


Vancomycin (Cont’d)

Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection.

A common reaction is "red man" or "red neck" syndrome.

This infusion-related flushing is caused by release of histamine.

It can be largely prevented by prolonging the infusion period to 1-2 hours or increasing the dosing interval.


Daptomycin

It is similar to vancomycin but is active against vancomycin-resistant enterococci and S aureus.

it appears to bind to and depolarize the cell membrane, causing potassium efflux and rapid cell death.

It can cause myopathy, and creatine phosphokinase levels should be monitored.


Fosfomycin It inhibits the cytoplasmic enzyme, enolpyruvate

transferase. The drug is transported into the bacterial cell by

glycerophosphate or glucose 6-phosphate transport systems.

Resistance is due to inadequate transport of drug into the cell.

Fosfomycin is active against both gram-positive and gram-negative organisms.

Fosfomycin is used for treatment of uncomplicated lower urinary tract infections in women.

The drug appears to be safe for use in pregnancy.


Bacitracin

There is no cross-resistance between bacitracin and other antimicrobial drugs.

Systemic bacitracin is highly nephrotoxic and is only used topically.

Bacitracin (with polymyxin or neomycin), is used for mixed bacterial flora in surface lesions of the skin or mucous membranes.


Cycloserine

Cycloserine is used only to treat tuberculosis resistant to first-line agents.

Cycloserine causes serious CNS toxicity with headaches, tremors, acute psychosis, and convulsions.


PenicillinTreponema species

PenicillinLeptospira species

Spirochetes

Penicillin Gram-positive (clostridia, Peptococcus, Actinomyces, Peptostreptococcus)

Anaerobic bacteria

Penicillin ± aminoglycosideEnterococcus species

PenicillinBeta-lactamase-negative

Staphylococcus aureus

PenicillinViridans streptococci

Penicillin (+ aminoglycoside?)Streptococcus agalactiae (group B)

PenicillinStreptococcus pyogenes (group A)

PenicillinStreptococcus pneumoniae

Gram-positive cocci (aerobic)

PenicillinNeisseria meningitidis

Gram-negative cocci (aerobic)

First ChoiceDisease or Pathogen


AmoxicillinEarly

Borrelia Burgdorferi

Spirochetes

Ampicillin (± Aminoglycoside)Listeria Species

Gram-positive Rods (Aerobic)

Penicillinase-resistant PenicillinBeta-lactamase-positive

Staphylococcus Aureus

Gram-positive Cocci (Aerobic)

Antipseudomonal Penicillin + Aminoglycoside

Pseudomonas Aeruginosa

Gram-negative Rods (Aerobic)

First ChoiceDisease Or Pathogen


CeftriaxoneLate

Borrelia Burgdorferi

Spirochetes

Cephalosporin (Third-generation)Salmonella

Cephalosporin (First- Or Second-generation)

E Coli, Klebsiella, Proteus


Ceftriaxone, CefpodoximeNeisseria Gonorrhoeae

Cephalosporin (Second- Or Third-generation)

Moraxella (Branhamella) Catarrhalis

Gram-negative Cocci (Aerobic)



VancomycinBacillus Species (Non-anthracis)

Gram-positive Rods (Aerobic)

VancomycinMethicillin-resistant

Staphylococcus Aureus

Gram-positive Cocci (Aerobic)

CarbapenemEnterobacter, Citrobacter, Serratia




First ChoiceSite Of Infection

Outpatient: AmoxicillinAdult (Community-acquired)

Pneumonia

Piperacillin-tazobactamPeritonitis Due To Ruptured Viscus

Ampicillin + Cephalosporin (Third-generation)

Neonate

Meningitis

Penicillinase-resistant PenicillinCellulitis

AmoxicillinAcute Otitis Media, Sinusitis

Vancomycin + GentamicinAcute

Bacterial Endocarditis

Penicillin + GentamicinSubacute


Septic arthritis

Vancomycin + Cephalosporin (Third-generation)

Septicemia

Inpatient: Macrolide + Cephalosporin (Third-generation)

Adult (Community-acquired)

Ceftriaxone, Cefuroxime, CefotaximeChild

Pneumonia

Metronidazole + Cephalosporin (Third-generation)

Peritonitis Due To Ruptured Viscus

Ceftriaxone, CefotaximeAdult

Ceftriaxone Or Cefotaxime ± Vancomycin

Child

Ampicillin + Cephalosporin (Third-generation)

Neonate

Meningitis

Cephalosporin (First-generation)Cellulitis

CefazolinAdult

CeftriaxoneChild

Saayeh khosh formations in Southern Iran

SummaryIn English

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Health & Medicine

Beta lactam & other cell wall- & membrane-active antibiotics