Basics of Antimicrobial Therapy

(1)

Basics of Antimicrobial

Therapy

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Selective Toxicity – How is selective toxicity achieved?

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X X

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M M

P P

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Selective Toxicity – How is selective toxicity achieved?

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X X

A A

M M

P P

L L

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Classification

Mechanism of action

Narrow/broad spectrum Chemical structure

…

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Volume 31, Issue 11, p509–515, 2010

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ACQUIRED RESISTANCE TO ANTIMICROBIAL DRUGS

(8)

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(9)

(10)

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NOSOCOMIAL INFECTION

Nosocomial infections or healthcare

associated infections occur in patients under medical care that occurre within 48 hours of hospital admission, 3 days of discharge or 30 days of an operation

SUPRAINFECTION

(11)

How to delay emergence of resistance ?

Centers for Disease Control and Prevention (CDC)

launched its Campain to Prevent Antimicrobial Resistance

(12)

(13)

(14)

SELECTION OF ANTIBIOTICS SELECTION OF ANTIBIOTICS

 Identitity of infecting organism

 Drug sensitivity of the infecting organism

 Host factors

For any given infection, several drugs may be effective

However, one ^{drug is} superior

(greater efficacy, lower toxicity,

more narrow spectrum, etc. )…. First choice

(15)

Inability of the drug to penetrate to

the site of infection Unusual

susceptibility of the

patient

(16)

General Guidelines

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Do not treat colonization or contamination (S.epidermidis from a single blood culture should be carefully examined)

Use the most narrow-spectrum agent for the infection Use proper dose

Use the shortest effective duration

(17)

Beta-Lactams & Other

Cell Wall- Active Antibiotics

(18)

18

• All cause hypersensitivity rxn (mild rush→ drug fever → acute interstitial nephritis → anaphylaxis)

• Some cross-sensitivity

• Seizures at high doses

• check dose for renal function

• All inhibit transpeptidation Beta-Lactams & Other

Cell Wall- Active Antibiotics

(19)

All beta-lactams inhibit bacterial growth by interfering with the transpeptidation

reaction

Are they safe to

host?

(20)

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fT>MIC

Time-dependent killing

• [AB] > MIC for a spesific time during dosing interval

•Prototype β-lactams

fT>MIC Penicillins 50%

Cephalosporins 60-70* % Carbapenems 40%

(21)

They must bind to a protein, now called

PBP

(22)

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Despite thick peptidoglycan, penicillins easily reach PBS in Gram-positive ^bacteria

Despite thick peptidoglycan, penicillins easily

reach PBS in Gram + ^bacteria

(23)

MECHANISMS OF RESISTANCE MECHANISMS OF RESISTANCE

• inability to reach PBPs

• inactivation of penicillins (β- lactam ring) by bacterial

enzymes

• beta-lactamases that

(24)

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β-lactamases are enzymes that open the beta-lactam ring, inactivating the

antibiotic

The first plasmid-mediated β-lactamase in gram-negative bacteria was discovered in Greece in the 1960s

It was named TEM after the patient from whom it was isolated (Temoniera)

Subsequently, a closely related enzyme

was discovered and named TEM-2

(25)

Microorganisms with

Microorganisms with β β -lactamase -lactamase activity activity

… hundreds ^of ^β ^β 

-lactamases!!

Some are narrow in

specificity..prefer penicillins

(26)

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https://www.uptodate.com/contents/overview-of-carbapenemase-produci ng-gram-negative-bacilli

(27)

β-lactamase inhibitors

(28)

N êw D êlhi m etallo-beta- lactamase 1 îs

an enzyme that makes bacteria

resistant to a broad range of β

-lactam antibiotics

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(29)

Natural penicillins:

Penicillin G , Penicillin V Penicillin G (benzyl penicillin),

β-lactamase-, and acid-sensitive Penadur®

Penisilin V, more resistant to acid, oral use

Cliacil®, Pen-Os®

(30)

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P h a r m a c o k i n e t i c s

t

_1/2

<2 hrs

• Good distribution in body fluids

• Organic acids; renal tubular secretions

(31)

Treponema pallidum (T. pallidum)

What are they good for?

Syphilis

(32)

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What are they good for?

Syphilis

Susceptible streptococcal infections

(33)

Antistaphylococcal Penicillin(s):

nafcillin, oxacillin, dicloxacillin , methicillin, cloxacillin

flucloxacillin

• Short half-life (30-60’)

(34)

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What are they good for?

Infections caused by MSSA

Skin and soft tissue

infections caused by

MSSA

(35)

(Broad-Spectrum Penicillins) Ampicillin, Amoxicillin

Aminopenicillins:

• More water-soluble and pass through porin channels of some Gram -

• SUSCEPTIBLE to beta-lactamases

• Usually combined with beta-lactamase inhibitors

• High incidence of diarrhea when given orally

(36)

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Except for amoxicillin, absorption of penicillins is

impaired by food

(37)

Co-amoxiclav

(amoxicillin+clavulanic acid)

Sultamicillin

(ampicillin+sulbactam)

(38)

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What are they good for?

Infections caused by susceptible GNR

Strep throat

URT infections,

including strep throat

Otitis media

(39)

https://www.cdc.gov/antibiotic-

use/community/for-hcp/outpatient- hcp/adult-treatment-rec.html

http://www.idsociety.org/

PracticeGuidelines/?q=

The Infectious Diseases Society of America (IDSA)

Centers for Disease Control and Prevention

(40)

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Recommended treatment

course for all oral beta lactams is 10 days in adults and children

Remember low bioavailability of penicillin V

https://www.cdc.gov/groupastrep/diseases- hcp/strep-throat.html

(41)

•Amoxicillin remains first line

therapy for children who have not

received amoxicillin within the past

30 days

(42)

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(43)

Acute rhinosinusitis

•Amoxicillin or

amoxicillin/clavulanate is

the recommended first-line

therapy

(44)

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To achieve bactericidal activity against

enterococci ^, beta lactams ^have

to be combined with

aminoglycosides

(45)

Antipseudomonal Penicillins:

piperacillin, mezlocillin,*

carbenicillin, ticarcillin

(46)

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Pseudomonas aeruginosa

a common nosocomial pathogen

often resistant to multiple antibiotics

Serious Pseudomonas infections usually occur in people in the hospital and/or with weakened

immune systems

healthy people can also develop mild illnesses with Pseudomonas aeruginosa, especially after exposure to water: Ear infections ^,

especially in children, and more generalized skin rashes may occur after exposure to

inadequately chlorinated hot tubs or swimming pools

Eye infections occasionally in persons using

extended-wear contact lenses

(47)

Piperacillin ve tazobactam :

Tazeracin®

(48)

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What are they good for?

Infections caused by Pseudomonas and other susceptible GNR

E.Coli (another nosocomial cause) may be resistant

they are NO good for

MRSA, extended-spectrum beta-lactamase (ESBL)

producing GNRs

(49)

Adverse effects

• All cause hypersensitivity rxn (mild rush→ drug fever → acute interstitial nephritis → anaphylaxis)

• Diarrhea

• Drug-induced acute interstitial nephritis (DI-AIN)

(50)

Cephalosporins

cephalosporin penicillin

• Grouped into generations that largely correlate with their spectrum of activity

• All have some cross-allergenity with penicillins

• Usually more resistant to β-lactamases

• None of the current have useful activity against enterococci

(51)

Cephalosporins

1    4

(5th genera is unique)

• Increasing activity against gram – bacteria and anaerobes

• Increasing resistance to β-lactamases

(52)

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Good alternatives to antistaphylococcal penicillins

1st generation:

Cephazolin Cephalothin

Cephradine (PO) Cephalexin (PO) Cephadroxil (PO)

Similar to penicillin G

(53)

What are they good for?

1

^st

generation: Cephazolin (parenteral, DOES NOT penetrate to CNS)

•Surgical prophylaxis

•Staphylococcal or streptococcal infections in penicillin allergy

• For penicillin-allergic patients,

C

(54)

2nd generation: Cefuroxime, Cefoxitin (iv), Cefotetan, Cefprozil, Loracarbef, Cefaclor…

Cefoxitin, Cefotetan, Cefmetazole: CEPHAMYCINS (none in Turkey), also active against anaerobes

DO NOT penetrate to CNS

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Infections caused by susceptible GNR

Particularly active against Haemophilus

influenzae

(55)

(56)

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What are they good for?

Specific indications are limited

•Upper respiratory tract infections

•Community-acquired pneumonia

(caused by bacteria, viruses, or fungi

Bacterial pneumonia is the most common type in adults)

Gonorrhea [ceftriaxone (3rd genera, preferred)]

•Surgical prophylaxis

(57)

3rd generation Cefdinir (PO)

Cefdiroten(PO) Cefixime (PO)

Cefdibuten (PO)

Ceftazidime (parenteral)

Cefaperazone (parenteral)

Ceftriaxone (parenteral)

(58)

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Antibiotic-Resistant Gonorrhea

https://www.cdc.gov/std/gonorrhea/arg/default.htm

Gonorrhea can be cured with the right treatment

CDC recommends dual therapy, or using two drugs, to treat

gonorrhea –

a single dose of 250mg of

intramuscular ceftriaxone AND

1g of oral azithromycin

(59)

BROAD SPECTRUM OF ACTIVITY

More stable to common beta-

lactamases of gram-negative

bacilli , and these compounds are highly active ^against Enterobacteriaceae

They are the therapy of choice for gram- negative meningitis due to susceptible Enterobacteriaceae

Drugs of choice for meningitis

caused by enteric gram- bacilli

(60)

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NOSOCOMIAL infections caused by Gram – bacilli are indications for 3rd genera…

CAUTION for resistance!

SHO ULD NOT BE U SED

ROU TINE LY!

(61)

(62)

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(63)

CEFTRIAXONE - CALCIUM

(64)

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3rd generation is closely associated with Clostridium difficile-associated

diarrhea

(65)

Antibiotic-associated diarrhea

refers to diarrhea that develops in a person who is taking or recently took antibiotics

One of the most serious causes of antibiotic- associated diarrhea is infection with a

bacterium, Clostridium difficile

(66)

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Antibiotic treatment — Usually an oral antibiotic (most often vancomycin ^or fidaxomicin ^{) is}

used to treat people who are infected with C. difficile.

It is important to take each dose of the antibiotic on time and to finish the entire course of treatment

( usually 10 to 14 days ⁾

Probiotics — Probiotics are "healthy"

microorganisms (bacteria, yeast) that can be taken

by mouth. These probiotics do not by themselves

cure C. difficile infection, but they may be

beneficial in selected situations ^.

(67)

4th generation: Cefepime

• Good empiric choice for many nosocomial infections

• De-escalate therapy if possible

• Better Gram + activity compared to 3rd genera

• MAY INDUCE LESS RESISTANCE in GNRs than 3rd genera

(68)

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What is it good for?

Febrile neutropenia

Nosocomial infections Postsurgical meningitis

ANC<1500/µL

(69)

5th generation: Ceftaroline, Ceftolozane

Complicated skin and soft tissue infections and community-acquired

pneumonia

Gram – activity is LESS

THAN 4th genera

(70)

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Basics of Antimicrobial Therapy