Penicillinase-resistant Penicillins Penicillinase-resistant Penicillins

Presented by

Abdulaziz M. Al - Saad

Developed because of the increasing resistance of staphylococci to natural penicillins

Alexander Fleming: Discover Penicillin on September 15, 1928

Resistance

1. Methicillin (1960)

2. Cloxacillin (1962)

3. Flucloxacillin (1970)

In 1959, acylase was discovered

in resistant bacteria

History

They are B-lactam acetylated with ( Bulky group ) , which give protection against ( penicillinase enz. ) by providing steric hindrance . They are fit into 3 chemical

groups :

1- Phenyl Penicillins : 2- Isoxazoyl Penicillins :

3- Naphthyl Penicillin : - Oxacillin ( Staphcillin R )

- Cloxacillin ( Cloxapen R )

- Dicloxacillin ( Dynapen R )

- Flucloxacillin ( Floxapen R )

- Nafcillin ( Unipen R )

-Methicillin ( Staphcillin R )

Chemistry

Treatment of infections such as :

Osteomyelitis , Septicemia , Endocarditis , pneumonia , skin and soft tissue infection

, CNS infection caused by staphylococci species ( Penicillinase producing ) .

1- Staphylococci species 2- Staphylococcus aureus3- Streptococcus pneumonia4- Strep. Faecalis & viridance ( Nafcillin ) .

Note : Temocillin is effective against G –ve except pseudomonas aeruginosa.

- Nafcillin + Gentamycin ------ Endocarditis .

- Nafcillin + Rifampin --------- DOC for chronic staph. Osteomyelitis .

- Nafcillin ---------------------- More effective than vancomycin for MSSA .

Mechanism of action 2 :

Inhibit cell wall synthesis by binding to PBPs --- Inhibit final

transpeptidation --- No peptidoglycan .

Therapeutic Indications

1- Methicllin :

- Not used in general therapy ------- ( Why ? ) .

- Higher incidence of nephrotoxicity & hypersensitivity > other pen.

- MRSA ( intrinsic resistance ) ----------- explain .

2- Nafcillin :

- Higher activity than ( methicillin & isoxazoyl pen. ) against pneumococci & hemolytic strept. cocci .

- Acid stable but not recommended orally ( why? ) .

3- Isoxazoyl penicillins ( oxa , diclo , clo , flu. ) :

Isoxazoyl group leads to -------- 1- Resistance to b- lactamase . 2- Resistance to gastic acid .

3- Effective anti-staphylococcal .

A. Oxacillin : Constricted for treatment of staph. Resistance to Pen G ( Why? ) .

B. Cloxacillin : - CL at ortho position ----- Enhance activity over Oxacillin ( Why? ) - More potent than Methicillin .

C. Dicloxacillin : - 2 CL at ortho position ------------ Enhance stability & activity - More potent than Cloxacillin .

Major features of each member

Generally, Penicillin cause Hypersensetivity , GIT disturbance , Fever .

Methicllin :

1. Nephrotoxicity ( large IV dose ) >>> ( symp. & sign ) , treatment ?

2. Leukopenia : Decrease neutrophils & lymphocyte ( < 500/mm3)

Isoxazoylyl Pen. :

1. Hepatotoxicity : Rapid disappear after stop medication .

2. Neurotoxicty ( large IV dose ) : Especially in patient with RF .

3. Hematological : Neutopenia ( especially with Oxacillin 200mg /kg dailly) .

Note : flucloxacillin increase risk of juandice .

Naficillin :

1. Nephrotoxicity ( large IV dose ) .

2. Hypokalemia & alkalosis : ( why ? )

3. Hematological : Neutopenia , Platelet dysfunction ( abnormal bleeding time ) .

Adverse Reactions

Drug F distribution

Protein binding

Vd (L/Kg)

Elemination

T1/2 T max

( hr )

Cmax

Orally

Methicillin - Wide 40 % 0.36 Mainly unchanged

urine

0.3-1

hr

0.5-1

(IM)

12

Nafcillin Erratic , poor

Wide

BBB Poor

90 % 1.1 Hepatic

60-70 %

0.5-1.5

hr

1-2 orally

0.5-1( IM)

7-6

Oxacillin 30-35 % Wide

peritonial , pericardial

90-94 % 0.4 Mainly unchanged

urine

23 – 60 min

0.5-1(IM&orally)

5-7

Dicloxcillin 35 – 50 % High conc. In kidney & liver

95-98 % 0.08 Mainly unchanged

urine

0.6 – 0.8 hr

0.5 -1 4.7

Cloxacillin 50 % Wide ,

poor BBB

bone , eyes

95 % 0.11 Mainly unchanged

urine

0.5 – 1.5 hr

1 – 2 8

Flucloxacillin

30-50 % 94 % Mainly unchanged

urine

0.7-1.3

hr

1 6-10

Pharmacokinetics

– Not removed by hemodialysis – No dose reduction in renal impairment ( except sever cases )

( oxa , cloxa, diclo, fluclo ) but methicillin need. – Naficillin : Dose reduction in liver dysfunction .

Drug-drug Interactions 2 :

Naficillin is strong inducer of CYP 3A4 , But Dicloxacillin is weak

1. B-lactam( penicillin ) + Aminoglycoside ------- Chemical incompatibility

2. Probenecid + Pen. ------------------------------------ Increase level of Pen.

3. Penicillins ------------------------------------- Increase exposure to Methotrexate

4. Chloramphenicol + Pen. --------------------- Decrease efficacy of naficillin .

5. Naficillin + Cyclosporin -------------------Subtherapeutic levl of cyclosporin .

Pregnancy 2 :

Pregnancy risk factor B .Cross placentaEnter breast milk ( Use with caution ) .

Contraindications 2:

• Hypersensitivity to Penicillin .

• Elder people : Not treated with Methicillin , but use Naficillin .

Sodium content 3 :

Must be considered in patients on restricted Na+ intake ( e.g.. HTN ) .

Mode of administration 3 :

• Dicloxacillin ( orally )• Oxacillin , Cloxacillin , Fluoxacillin ( Orally , Parentrally ) .• Methicillin & Temocillin ( Only inject able )

Drug Forms & Conc. Dose

Methicillin IV & IM ( 1,4,6,10 gm ) IM or IV 1gm Q 6 hr

Nafcillin Infusion [ 1gm (50ml) ,2gm ( 100 ml) ].

Injection ( Powder ) [ 1 , 2, 10 gm ] .

Child [ IM 25 mg/kg bid ] ,

[ IV 50-100 mg/kg/day divided Q6hr (IV) ]

Adult [ IM 500 mg/4-6hr ] ,

[ IV 500-2000 mg/4-6hr ]

Oxacillin Infusion [ 1gm (50ml) ,2gm ( 50 ml) ].

Injection ( Powder ) [ 1 , 2, 10 gm ] .

Capsule [ 250 , 500 mg ] .

Child [ 150-200mg/kg/day divided Q6hr ]

Adult [ 250mg Q4-6hr ] IV & IM

Dicloxcillin Capsule [ 125 ,250 ,500 mg ] Child [ >40 kg 125-250mg Q6hr ]

Adult [ 125-250mg Q 6hr ]

Cloxacillin Capsule [ 250 -500mg ]

Powder (for suspension) 125mg/5ml ( 100. 200 ml )

Child [ >20 kg 250-500mg Q6hr ]

Adult [ 250-500mg Q 6hr ]

Flucloxacillin

Capsule [ 250- 500mg ]

Injection ( powder ) [ 250-500mg ]

Solution [125mg/5ml ( 100ml ) ]

Orally : Child [ 125-250mg Q6-8hr ]

Adult [250-500mg Q6-8hr ]

IM & IV : Child [ 125-250mg Q6hr ]

Adult [250-500mg Q6hr ]

Dosage Forms

– Take all medication , don’t skip doses , – Take it 1 hr befor or 2 hr after meals [ Enhance F ] .

– Missed dose- take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage :

• Keep out of the reach of children.

• Store away from heat and direct light.

• Do not store the capsule or tablet form of penicillins in the bathroom. Heat or

moisture may cause the medicine to break down.

• Store the oral liquid form of penicillins in the refrigerator because heat will

cause this medicine to break down. However, keep the medicine from freezing.

Follow the directions on the label.

• Do not keep outdated medicine or medicine no longer needed. Be sure that any

discarded medicine is out of the reach of children.

Patient Informations

1. Methicillin : - Sensetive to moisture --- Loss ½ of its activity after 5 days at RT . - Solution for parental ad. May kept for 24 hr ----- [ at 5oC ] .

2. Nafcillin , Oxacillin :

Parentral sol. Stable for 3 days at RT. ( 96 hr if ref. ) .

3. Dicloxcillin :

Parentral sol. Stable for 7 days at RT ( 14 day if ref. ).

4. Cloxacillin :

Parentral sol. Stable for 14 days ( ref. ) .

5- Flucloxacillin :

Parentral sol. Stable for 7 days ( ref. )

Storage :

Store between 15 – 30oC

Stability

References :

1. Web site e.g. www. .com .

2. Drug Information Handbook 12th Edition 2004 – 2005 pages ( 452 ,

642 , 1062 , 1137 ).

3. USP DI Edition 1999 , pages ( 2251, 2252, 2253, 2254, 2255,

2256, 2262 ) .

4. Principle of Medicinal Chemistry 4th Edition page 778-779 .

Temocillin is a beta-lactamase-stable penicillin with a selective. Gram-negative spectrum of activity and a long half-life The urinary excretion by 12 h was 70.58% of the administered