Beta lactam antibiotic cephalosporin

Beta Lactam AntibioticCephalosporin

Dr Lokendra Sharma Professor

Beta Lactam Antibiotic ? Major Penicillins CephalosporinsMinor Monobactum Carbapenum

An ideal antibiotics ?

• Broad-spectrum ? Narrow ?• Did not induce resistance• Selective toxicity, low side effects• Preserve normal microbial flora

For lecture only

CEPHALOSPORINS ?

• Cephalosporium fungus• Dihydrothiazine ring + B lactum• Semisynthetic B-lactams derived from

chemical side chains added to 7-aminocephalosporanic acid.

• 4 generations CS add 5th• Generally more resistant to B-lactamases.

.

SPECTRUM1ST GENERATION gram(+). cefazolin (used as prophylactic following surgery)2ND GENERATION: gram (+) & gram (-)3RD GENERATION: good against gram (-) aerobessome cross into CNS readily e.g. cefotaxime ! used totreat meningitis4TH GENERATION: like 3rd gen but more resistant to betalactamases5th GENERATION

Fifth Generation Ceftobiprole and ceftaroline both parentalInhibit Bind to Penicillin binding protein -2a

produce by MRSA resistance S Pneumonia

Ceftaroline 2010 for MRSA Ceftobiprole – post antibiotic effect on

MRSA

Ceftolozane 5 GN

??• All CEF = 1 GN (Except cefaclor 2GN)• Pi = 4 GN (CefPime, CefPirome)• ME end =3 rd generation (Exept

CefuroxiME)• ROL (CeftibipRole,CeftaRoline) 5 GN• ME,ONE,TEN (3 GN)• OR oral (CefacLOr,)• T Injectable (CefoTetan)

. Bactericidal

Less susceptible to β-lactamases.

Disrupt the synthesis of the peptidoglycan .

The peptidoglycan layer =important structural integrity.

The final transpeptidation step in the synthesis of the peptidoglycan

Facilitated by transpeptidases known as penicillin-binding proteins (PBPs).

PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan

precursors) to crosslink the peptidoglycan.

Beta-lactam antibiotics mimic the D-Ala-D-Ala site

Irreversibly inhibiting PBP crosslinking of peptidoglycan.

1. drugs that affect the bacterial cell wall Inhibit Transpeptidase &Carboxipeptidase

.Pharmacokinetics

• 7 aminocephalosporinic acid = active nucleous

• New modification at position 3 & 7• Modification position 3 PK & toxicity• Modification position 7 Antibacterial

Spectrum

.

• Conc dependent killing(CDK)= FQ,Aminog• Time dependent killing(TDK)= beta lactum• postantibiotic effects(PAE)• MIC

Cephalosporins Antibacterial Spectrum 

First Generation        Second Generation     Third Generation       Fourth Generation

+Cocci Ө Cocci Ө Cocci Ө Cocci

  Ө Bacclli   Ө Bacclli   Ө Bacclli   Ө Bacclli

Anaerobes Anaerobes Resistance 3GN

LESS LESS LESS LESS

  + Bacclli +Cocci +Cocci  

  Ө Cocci   + Bacclli + Bacclli   +Cocci

Cephalosporins  

First Generation        Second Generation     Third Generation       Fourth Generation

                    * Oral Agent

CEFADROXIL *(tissue)   CEFACLOR * CEFDINIR CEFEPIME

(100% renal)

  CEFAZOLIN(surgical

prophylaxis)   CEFAMANDOLE  CEFOPERAXONE 

CEFPIROME

Cefalidin 

  CEFELIXIN *(bile)   CEFONICID  CEFOTAXIME

(prototype)   

  CEPHALOTHIN(prototype) 

(IM pain)  CEFORANIDE CEFTAZIDIME

(Thrombocytopeni)  

  CEPHAPRIN    CEFOTETAN(anaerobics) CEFTIBUTEN  

  CEPHRADINE *(diarrhoea)

  CEFOXITIN(prototype )  CEFTIZOXIME  

   CEFUROXIME

(BBB)MOXALACTAM

CEFTRIAXONE(MDR Typhoid)

First generation cephalosporins:

CEPHALOTHIN, CEFAZOLIN, CEFALEXIN. (Streptococcus, pneumococcus but not or methicillin-resistant Staphylococcus).

+ Cocci > - Bacilli > + Bacilli > - Cocci > Anaerobics

Do not cross blood-brain barrier. Primarily excreted = kidney Ineffective Pseudomonas aeruginosa,

Enterobacter, and indole-positive Proteus species

Second generation cephalosporins:

CEFUROXIME, CEFAMANDOLE, CEFOXITIN, CEFACLOR. - Cocci

>+ Cocci > +Bacilli - Bacilli Cefuroxime cross BBB ,Resistant to beta-

lactamase Do not achieve adequate levels in the CSF.

Cephalosporins Third generation

cefotaxime cefixime cefpodoxime ceftazidime cefdinir Fourth generation (cefilidin,cefoselin,cefluprenam) cefe Pime cef PiromeFifth GN - CeftobipRole - ceftaRoline

Third generation cephalosporins:

MOXALACTAM, CEFAPERAZONE, CEFTAZIDIRNE, CEFTRIAXONE.

Extended Gram negative coverage, resistant to non-Staphylococcus b-lactamase, Cross the blood-brain barrier. Enterobacter, Pseudomonas (ceftazidime and

cefaperazone only), Serratia, b-lactamase producing Haemophillus influenza and Neisseria species.

Ceftizoxime and moxalactam retain good activity against Bacteroides fragilis.

- cocci & Bacilli & Anaerobes > + Cocci & Bacilli

Fourth generation CEFEPIME ,CEFPIROME . Comparable to third-generation but more

resistant to some beta lactamases. - Cocci & Bacilli (Resistant to 3rd Gn) & > +

Cocci & + Bacilli & Anaerobes ----NO

Fifth Generation

CeftobipRole and ceftaRoline both parental

Inhibit Bind to Penicillin binding protein -2a produce by MRSA resistance S Pneumonia

CeftaRoline 2010 for MRSA CeftobipRole – post antibiotic effect on

MRSA

Pharmacokinetics

Some orally most parenterally (IM or IV). widely distributed . CEFOPERAZONE, CEFOTAXIME,

CEFUROXIME, CEFTRIAXONE, AND CEFTAZIDIME (third generation) also cross the blood-brain barrier

Drugs of choice for meningitis due to Gram-negative intestinal bacteria.

.

Almost all eliminated via the kidneys and actively secreted by renal tubules.

CEFAPERAZONE AND CEFTRIAXONE eliminated through biliary tract----Q.

Nephrotoxicity increase with loop diurtics …..Q

ADVERSE EFFECTS Hypersensitivity reactions =similar

penicillins. Nephrotoxicity =CEPHALORIDINE----Q Intolerance to alcohol (disulfiram like

reaction)(Q----cefamandole, cefotetan, moxalactam, cefoperazone=MTT group)

Diarrhea= oral forms. cephaloridine ,third cefoperazone,cefixime

Superinfection. resistant organisms , fungi, often proliferate

ADVERSE EFFECTSBLEEDING Hyperprothrombinemia= (Q-----MTT group=

cefamandole, cefotetan, moxalactam, cefoperazone)

Thrombocytopenia, Platelet dysfunction. Administration of vitamin K (10mg) twice a week can prevent this.

Neutropenia=Rare

Serum sickness=cefaclor ----- Q

Coinfection and Superinfection ?

CEPHALOSPORINS• Adverse reactions.

– 5-10% cross-sensitivity with pcn allergic pts.

– 1-2% hypersensitivity reactions in non-pcn allergic pts.

– Broader spectrum leads to opportunistic infections (candidiasis, C. difficile colitis).

CEPHALOSPORINS1. Identify this manifestation ?2. What is Opportunistic infection ?3. What is the treatment and

Preventive Majors ?4. Spectrum of Bacteria ?

Identify ?

Cause ?

Biliary sludging

syndrome ?

USES: A cephalosporin with or without aminoglycoside 1st Trt Klebsiella pneumococci. First GN surgical prophylaxis (Cefazolin) of wound

infection. Third GN meningitis due to, meningococci, and

Haemophillus influenza. CEFTRIAXONE = TOC beta-lactamase producing

Neisseria gonorrhea. E coli (G1), Salmonella Typhoid,Parathyphoid = CEFTRIAXONE H .Ducreyi = CEFTRIAXONE Pseudo Pseudomalli = CEFTRIAXONE

1.Antimicrobial agent acting by inhibition of cell wall synthesis isa.Erythromycinb.Tetracyclinec.Lomefloxacind.Cefepime

(d)2.Which one of the following drugs is an antipseu-domonal penicillin?

a.Cephalexinb.Cloxacillinc.Piperacillind.Dicloxacillin

(c)

3.All of the following drugs can cause renal failure EXCEPTa.Cephaloridine b.Amphotericin Bc.Cefoperazoned.Gentamicin(c)4.Which of the following drug is NOT used for the treatment of methicillin

resistant staphylococcus aureus (MRSA)?a.Cefaclorb. Cotrimoxazolec.Ciprofloxacind.Vancomycin(a)

5. Which of the following is a fourth generation cephalosporin?a.Ceftriaxoneb.Cefaclorc.Cefepimed.Cefuroxime(c)6. All of the following cephalosporins have good activity against pseudomonas

aeruginosa EXCEPTa.Cephadroxilb.Cefepimec.Cefoperazoned.Ceftazidime(a)7. Treatment of penicillin producing Neisseria gonorrhoeae is /area.Amoxicillinb.Ciprofloxacinc.Cefotaximed.Doxycyclinee.Azithromycin(b) (c)

8.Which of these antibiotics are safe in renal failure?

a.Cephalexinb.Tetracyclinec.Nitrofurantiond.Gentamicine.Doxycycline

(a)

9. Which of the following statement are true regarding cefepimea.It is a fourth generation cephalosporinb.Once a day dose is sufficientc.It possess antipseudomonal actiond.Its dose should not be reduced in renal pathologye.It is a prodrug(a)10.The mechanism of antibacterial action of cephalosporins involvesa.Inhibition of the synthesis of precursors of peptidoglycanb.Interference with the synthesis of ergosterolc.Inhibition of transpeptidation reactiond.Inhibition of beta lactamase(c)

11.Second generation cephalosporin that can be used orally isa.Cefepimeb.Cefalothinc.Cefaclord.Cefadroxil(b)12.Third generation cephalosporin that can be given orally isa.Cefiximeb.Cefpiromec.CefaclorD.Cefadroxil(a)

13. The antibiotic which can be given safely in a pregnant women is

a.Ciprofloxacinb.Cefuroximec.Metronidazoled.Chloramphenicol(b)14. Linezolid is best used fora.MRSAb.VRSAc,.K.pneumoniaed.E.coli(b)

15.Which one of the following is a fourth generation cephalosporin?a.Cefuroximeb.Ceftazidimec.Cefepimed.Cefamandole(c)

16.Neutropenia is associated witha.Nafcillin b.Methicillin c.Carbencillin d.Ampicillin(a)

17.Which of the following antimicrobials has antipseudomonal action?

(a)Cefopodoxime(b)Cephradine(c)Cefotetan(d)Cefoperazone

(d)

18.Treatment of penicillinase producing neisseria gonarrhoeae is/are

(a)Amoxycillin (b)Ciprofloxacin(c)Cefotaxime(d)Doxycycline(e)Azithromycin(b)*(c)

19.Which of the following antimicrobials has antipseudomonal action?

(a)Cefopodoxime(b)Cephradine(c)Cefotetan(d)Cefoperazone

(d)

20.All are first generation cephalosporins except

a.Cefadroxilb.Cefazolinc.Cephalexind.Cefaclor D

21.A patient develops an infection of methicillin resistant Staphylococcus aureus.All of the following can be used to treat this infection except.

a.Cotrimoxazoleb.Cefaclorc.Ciprofloxacind.Vancomycin

(b)

22.All are true about cephalosporins,EXCEPTa.Ceftazidime is a 3rd generation cephalosporin.b.Cefoperazone has got antipseudomonal

effect.c.Cefoxitin has got no activity against

anaerobes.d.Cephalosporins act by inhibiting cell wall

synthesis.(c)

23.Which of the following cephalosporins can be used in patients with low GFR?

a.Cefuroximeb.Cefiximec.Ceftazidime d.Cefoperazone

(d)

24.Cephalosporin that does not require dose reduction in patient with any degree of renal impairment is

a.Cefuoxime b.Cefoperazonec.Ceftazidimed.Cefotaxime

(b)

25.Which of the following drugs is not used for MRSA?

a.Cefaclor b.Cotrimoxazolec.Ciprofloxacind.Vancomycin

(a)

Cephalosporin vs Penicillin

• Cephalosporin advantages– cover staphylococci– better vs. Klebsiella, enteric gram-neg. bacilli, gonococci• Cephalsporin disadvantages– cost– poor distribution to CSF (1st & 2nd gen)– not cover enterococcus

Learning objective achieved ?

• Classification • ABS• Mechanism of Action • AE• Use

Thank You

Dr Lokendra Sharma