Antibiotics

Learning Objectives

Identify the major types of antibiotics by drug class. Know which auxiliary labels to use when dispensing major types of antibiotics. Define therapeutic effects, side effects, and administration routes of major antibiotics. Use antibiotic and general drug terminology correctly in written and oral communications.

Anti-Infective Agents
Antibiotics: Sulfonamides Penicillins Cephalosporins Tetracyclines

Aminoglycosides
Quinolones Macrolides

Antibiotics

Medications used to treat bacterial infections Ideally, before beginning antibiotic therapy, the suspected areas of infection should be cultured to identify the causative organism and potential antibiotic susceptibilities.

Antibiotics

Empiric therapy: treatment of an infection before specific culture information has been reported or obtained Prophylactic therapy: treatment with antibiotics to prevent an infection, as in intra-abdominal surgery

Antibiotics
Bactericidal:

kill bacteria Bacteriostatic: inhibit growth of susceptible bacteria, rather than killing them immediately; will eventually lead to bacterial death

Types of Bacteria
Aerobic

bacteria bacteria

needs oxygen to survive

Anaerobic

survives in the absence of oxygen

Bacteria Shapes

(a) Round cocci (b) Rod-like bacilli (c) Spiral-shaped spirochetes

Grams Stain Results and Related Diseases

Shape Grams Stain
rods gram-positive

Bacteria
Corynebacteria

Related Disease
endocarditis

gramnegative

E. Coli

UTI

Grams Stain Results and Related Diseases

Shape
cocci

Grams Stain Bacteria

gram-positive

Related Disease
toxic shock syndrome gonorrhea

Staphylococcus

gram-negative Neisseria

Grams Stain Results and Related Diseases

Shape
curved or spiral rods

Grams Stain Bacteria

gram-negative Campylobacter

Related Disease
septicemia syphilis

spirochetes gram-negative Treponema

palladium

How Antibiotics Work

Block protein formation

How Antibiotics Work

Block protein formation

Macrolides Tetracyclines Aminoglycosides

How Antibiotics Work

Block protein formation Inhibit cell wall formation Interfere with DNA formation

How Antibiotics Work

Block protein formation Inhibit cell wall formation Interfere with DNA formation
Nalidixic acid

How Antibiotics Work

Block protein formation Inhibit cell wall formation Interfere with DNA formation Prevent folic acid synthesis

How Antibiotics Work

Block protein formation Inhibit cell wall formation Interfere with DNA formation Prevent folic acid synthesis
Sulfonamides

Sulfonamides
One of the first groups of antibterial agents sulfadiazine sulfamethizole sulfamethoxazole sulfisoxazole

Sulfonamides: Mechanism of Action

Bacteriostatic action Prevent synthesis of folic acid required for synthesis of purines and nucleic acid Does not affect human cells or certain bacteriathey can use preformed folic acid

Structure of sulfonamides
para-Aminobenzoic acid sulfonamide

Classification of sulfonamides (accordingly to duration of action)

Short action: streptocid, sulfadimezine, aethazole, norsulfazole, urosulfan, sulfizoxazole, sulfacyl-sodium Medium duration of action: sulfamethoxazole (is a part of co-trimoxazole) Longlasting action: sulfadimethoxyn, sulfapirydazin, sulfamonomethoxyn Super longlasting action: sulfalen, sulfadoxyn (is a part of fansidar)

Sulfonamides: sulfamethoxazole Therapeutic Uses Azo-Gantanol

Combined

with phenazopyridine (an analgesic-anesthetic that affects the mucosa of the urinary tract). to treat urinary tract infections (UTIs) and to reduce the pain associated with UTIs. with trimethoprim.

Used

Bactrim
Combined

Used

to treat UTIs, Pneumocystis carinii pneumonia, ear infections, bronchitis, gonorrhea, etc.

Co-trimoxazole (Bactrim)

480 - for adults 960 - for adults 120 for children 240 for children Orally 2 times daily

Co-trimoxazole = Bactrim (trimethoprim + sulfamethoxazole)

Sulfonamides: sulfisoxazole Therapeutic Uses

Azo-Gantrisin

Combined with phenazopyridine Used for UTIs

Pediazole Combined with erythromycin Used to treat otitis media

Sulfonamides: Side Effects

Body System
Blood

Effect
Hemolytic and aplastic anemia,

thrombocytopenia Integumentary Photosensitivity, exfoliative dermatitis, StevensJohnson syndrome, epidermal necrolysis

Sulfonamides: Side Effects

Body System
GI vomiting, diarrhea, Other crystalluria,

Effect
Nausea, pancreatitis Convulsions, toxic nephrosis, peripheral neuritis,

headache, urticaria

Sulfonamides Dispensing Issues

Avoid the sun Maintain adequate fluid intake

Classes of Antibiotics

Sulfonamides Penicillins Cephalosporins Tetracyclines Macrolides

Ketolides Quinolones Streptogramins Aminoglycosides Cyclic Lipopetides

Antibiotics: Penicillins

Natural penicillins Penicillinase-resistant penicillins Aminopenicillins Extended-spectrum penicillins

Antibiotics: Penicillins
Natural penicillins

penicillin G, penicillin V potassium

Penicillinase-resistant penicillins

cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin

Antibiotics: Penicillins
Aminopenicillins

amoxicillin, ampicillin, bacampicillin

Extended-spectrum penicillins

piperacillin, ticarcillin, carbenicillin, mezlocillin

Antibiotics: Penicillins

First introduced in the 1940s Bactericidal: inhibit cell wall synthesis Kill a wide variety of bacteria Also called beta-lactams

S H2 N T CH3 CH3 L

O OH

Nucleus of penicillin molecule L beta-lactame ring, T thiazoline ring

Antibiotics: Penicillins

Bacteria produce enzymes capable of destroying penicillins.

These enzymes are known as beta-lactamases. As a result, the medication is not effective.

Antibiotics: Penicillins

Chemicals have been developed to inhibit these enzymes:

clavulanic acid tazobactam sulbactam

These chemicals bind with betalactamase and prevent the enzyme from breaking down the penicillin

Antibiotics: Penicillins

Penicillin-beta-lactamase inhibitor combination drugs: ampicillin + sulbactam = Unasyn amoxicillin + clavulanic acid = Augmentin ticarcillin + clavulanic acid = Timentin piperacillin + tazobactam = Zosyn

Unasyn (ampicillin/sulbactam)

Penicillins: Mechanism of Action

Penicillins enter the bacteria via the cell wall. Inside the cell, they bind to penicillin-binding protein. Once bound, normal cell wall synthesis is disrupted. Result: bacteria cells die from cell lysis. Penicillins do not kill other cells in the body.

Penicillins: Therapeutic Uses

Prevention and treatment of infections caused by susceptible bacteria, such as:

gram-positive bacteria Streptococcus, Enterococcus, Staphylococcus species

Penicillins: Adverse Effects

Allergic reactions occur in 0.7% 8% of treatments

urticaria, pruritus, angioedema

10% of allergic reactions are lifethreatening and 10% of these are fatal

Penicillins: Side Effects

Common side effects:

nausea, vomiting, diarrhea, abdominal pain

Other side effects are less common

Penicillins Dispensing Issues

Take on an empty stomach

Food slows absorption Acids in fruit juices or colas could deactivate the drug

Penicillin Resistance

Penicillinase-resistant penicillins work against gram-positive aerobes Extended-spectrum penicillins are more resistant to gramnegative bacteria Penicillin combinations improve effect

Antibiotics: Cephalosporins

First Generation Second Generation Third Generation Fourth Generation

S H2N
L D

CH2

CO

CH3

O
OH

Structure of cephalosporins L beta-lactame ring, D dihydrothiazine ring

Antibiotics: Cephalosporins

Semisynthetic derivatives from a fungus Structurally and pharmacologically related to penicillins Bactericidal action Broad spectrum Divided into groups according to their antimicrobial activity

Cephalosporins: First Generation

cefadroxil cephalexin cephradine cefazolin cephalothin cephapirin

Good gram-positive coverage Poor gram-negative coverage

Cephalosporins

First-generation
Similar to penicillinase-resistant penicillins with greater gram-negative coverage Used for
community-acquired infections mild to moderate infections

Cephalosporins: First Generation

cefazolin (Ancef and Kefzol) IV and PO cephalexin (Keflex and Keftab) PO

used for surgical prophylaxis, URIs, otitis media

Cephalosporins: Second Generation

cefaclor

cefonicid
cefprozil

ceforanide
cefamandole

cefmetazole
cefoxitin

cefotetan
cefuroxime

Cephalosporins

Second-generation
Increased activity, especially against

Haemophilus influenzae
Otitis media in children Respiratory infections UTIs

Used for

Cephalosporins: Second Generation

Cefoxitin (Mefoxin) Ceftin) IV and IM Used prophylactically for prophylaxis abdominal or colorectal surgeries Also kills anaerobes cefuroxime (Kefurox and PO Surgical Does not kill anaerobes

Cephalosporins: Third Generation

cefixime cefpodoxime cefoperazone

proxetil

cefotaxime

ceftizoxime
ceftriaxone ceftazidime

moxalactam

Most potent group against gram-negative Less active against gram-positive

Cephalosporins

Third-generation
Active against a wide spectrum of gramnegative organisms Long half-life, so once-a-day dosing for some Used for
Ambulatory patients Children (dosing before or after school)

Cephalosporins: Third Generation

cefixime (Suprax)

Only oral third-generation agent Best of available oral cephalosporins against gram-negative Tablet and suspension

ceftriaxone (Rocephin) IV and IM, long half-life, once-a-day dosing

Easily passes meninges and diffused into CSF to treat CNS infections

Cephalosporins: Third Generation

ceftazidime (Ceptaz, Fortaz, Tazidime, Tazicef)

IV and IM
Excellent gram-negative coverage

Used for difficult-to-treat organisms such as Pseudomonas spp.

Eliminated renally instead of biliary route

Excellent spectrum of coverage

Cephalosporins: Fourth Generation

cefepime (Maxipime)

Newest cephalosporin agents. Broader spectrum of antibacterial activity than third generation, especially against gram-positive bacteria.

Antimicrobial spectrum of cephalosporins

Generation of cephalosporin s Active towards Stability towards beta-lactamase

Grampositive bacteria
V

GramStaphylo Gramnegative cocci negative bacteria bacteria

+++
++ + ++

+/+ +++ +++

++
++ + ++

+/+ ++

Cephalosporins
Warning!
Alert the Pharmacist if a patient allergic to penicillins is receiving a cephalosporin prescription.

Cephalosporins Side Effects

Share side effects of penicillin Few may initiate unique toxic reactions Lower frequency of toxicity than many other antibiotics

Complications, caused by cephalosporins

Irritation of mucous membrane of digestive tract, infiltrates after intromuscular introduction , phlebitis after inrtavenous introduction Disbacteriosis, superinfection Allergic reactions, including cross allergy with penicillins Granulocytopenia (in case of treatment during more than 2 weeks) Hemorrhages (inhibition of synthesis of factors of blood coagulation in liver) cephalosporins Nephrotoxicity (accumulation in epithilial cells of kidney canalicules) Encephalopathy (hyperreflexia, , coma)

Cephalosporins
Warning!
All of the cephalosporins look alike when written in the generic form. Watch for dosing and indications for use.

Antibiotics: Tetracyclines

demeclocycline (Declomycin) oxytetracycline tetracycline doxycycline (Doryx, Doxy-Caps, Vibramycin) minocycline

Antibiotics: Tetracyclines

Natural and semi-synthetic Obtained from cultures of Streptomyces Bacteriostaticinhibit bacterial growth Inhibit protein synthesis Stop many essential functions of the bacteria

Antibiotics: Tetracyclines

Bind to Ca2+ and Mg2+ and Al3+ ions to form insoluble complexes Thus, dairy products, antacids, and iron salts reduce absorption of tetracyclines

Tetracyclines: Therapeutic Uses

Wide spectrum:
gram-negative, gram-positive, protozoa, Mycoplasma, Rickettsia, Chlamydia, syphilis, Lyme disease

Demeclocycline is also used to treat SIADH, and pleural and pericardial effusions

Therapeutic Uses of Tetracyclines

Acne Chronic bronchitis Lyme disease

Mycoplasma pneumoniae infection Rickettsia infection

Some venereal diseases, such as Chlamydia infection Travelers diarrhea

Tetracyclines: Side Effects

Strong affinity for calcium

Discoloration of permanent teeth and tooth enamel in fetuses and children May retard fetal skeletal development if taken during pregnancy

Tetracyclines: Side Effects

Alteration in intestinal flora may result in:

Superinfection (overgrowth of nonsusceptible organisms such as Candida) Diarrhea Pseudomembranous colitis

Tetracyclines: Side Effects

May also cause:

Vaginal moniliasis Gastric upset Enterocolitis Maculopapular rash

Tetracyclines Dispensing Issues

Avoid antacids to avoid chelation with minerals Photosensitization To be avoided by pregnant women and children Expired drugs are dangerous

Antibiotics: Aminoglycosides

gentamicin (Garamycin) kanamycin neomycin streptomycin tobramycin amikacin (Amikin) netilmicin

Aminoglycosides

Natural and semi-synthetic Produced from Streptomyces Poor oral absorption; no PO forms Very potent antibiotics with serious toxicities Bactericidal Kill mostly gram-negative; some gram-positive also

Aminoglycosides

Used to kill gram-negative bacteria such as Pseudomonas spp., E. coli, Proteus spp., Klebsiella spp., Serratia spp. Often used in combination with other antibiotics for synergistic effect.

Aminoglycosides

Three most common (systemic): gentamicin, tobramycin, amikacin

Cause serious toxicities:

Nephrotoxicity (renal failure)

Ototoxicity (auditory impairment and vestibular [eighth cranial nerve])

Must monitor drug levels to prevent toxicities

Aminoglycosides: Side Effects

Ototoxicity and nephrotoxicity are the most significant Headache Paresthesia Neuromuscular blockade Dizziness Vertigo Skin rash Fever Superinfections

Antibiotics: Quinolones

ciprofloxacin (Cipro) enoxacin (Penetrex) lomefloxacin (Maxaquin) norfloxacin (Noroxin) ofloxacin (Floxin)

Quinolones

Excellent oral absorption Absorption reduced by antacids First oral antibiotics effective against gram-negative bacteria

Quinolones: Mechanism of Action

Bactericidal Effective against gram-negative organisms and some gram-positive organisms Alter DNA of bacteria, causing death Do not affect human DNA

Quinolones: Therapeutic Uses

Lower respiratory tract infections Bone and joint infections Infectious diarrhea Urinary tract infections Skin infections Sexually transmitted diseases

Quinolones: Side Effects

Body System
CNS fatigue, restlessness GI diarrhea, thrush, liver function

Effects
headache, dizziness, depression, nausea, vomiting, constipation, increased studies

Quinolones: Side Effects

Body System
Integumentary

Effects
rash, pruritus, urticaria, flushing, photosensitivity (with lomefloxacin) fever, chills, blurred tinnitus

Other vision,

Quinolones Dispensing Issues

Not to be given with theophylline Antacids interfere with absorption Avoid exposure to sun

Antibiotics: Macrolides

erythromycin azithromycin (Zithromax) clarithromycin (Biaxin) dirithromycin troleandomycin

bactericidal action

Erythromycin Formulations

Macrolides: Therapeutic Uses

Strep infections Streptococcus pyogenes (group A beta-hemolytic streptococci) Mild to moderate URI Haemophilus influenzae Spirochetal infections Syphilis and Lyme disease Gonorrhea, Chlamydia, Mycoplasma

Macrolides: Side Effects

GI effects, primarily with erythromycin:

nausea, vomiting, diarrhea, hepatotoxicity, flatulence, jaundice, anorexia Newer agents, azithromycin and clarithromycin: fewer side effects, longer duration of action, better efficacy, better tissue penetration

Macrolides Dispensing Issues

Although most antibiotics should be taken on an empty stomach, erythromycins usually cause severe GI distress, so should be taken with food

Antibiotic Dispensing Issues

Warning!

Mix exactly as directed by manufacturer Swab counting tray with alcohol between drugs to prevent crosscontamination

Antibiotic Side Effects

Most antibiotics should be taken on an empty stomach to attain faster absorption Examples of exceptions
nitrofurantoin (Macrobid, Macrodantin) cefuroxime (Ceftin, Zinacef)

Antibiotics: Nursing Implications

Before beginning therapy, assess drug allergies; hepatic, liver, and cardiac function; and other lab studies. Be sure to obtain thorough patient health history, including immune status. Assess for conditions that may be contraindications to antibiotic use, or that may indicate cautious use. Assess for potential drug interactions.

Antibiotics: Nursing Implications

It is ESSENTIAL to obtain cultures from appropriate sites BEFORE beginning antibiotic therapy.

Antibiotics: Nursing Implications

Patients should be instructed to take antibiotics exactly as prescribed and for the length of time prescribed; they should not stop taking the medication early when they feel better. Assess for signs and symptoms of superinfection: fever, perineal itching, cough, lethargy, or any unusual discharge.

Antibiotics: Nursing Implications

For safety reasons, check the name of the medication carefully since there are many agents that sound alike or have similar spellings.

Antibiotics: Nursing Implications

Each class of antibiotics has specific side effects and drug interactions that must be carefully assessed and monitored. The most common side effects of antibiotics are nausea, vomiting, and diarrhea.

All oral antibiotics are absorbed better if taken with at least 6 to 8 ounces of water.

Antibiotics: Nursing Implications

Sulfonamides

Should be taken with at least 2400 mL of fluid per day, unless contraindicated. Due to photosensitivity, avoid sunlight and tanning beds. These agents reduce the effectiveness of oral contraceptives.

Antibiotics: Nursing Implications

Penicillins

Any patient taking a penicillin should be carefully monitored for an allergic reaction for at least 30 minutes after its administration. The effectiveness of oral penicillins is decreased when taken with caffeine, citrus fruit, cola beverages, fruit juices, or tomato juice.

Antibiotics: Nursing Implications

Cephalosporins

Orally administered forms should be given with food to decrease GI upset, even though this will delay absorption.

Some of these agents may cause an Antabuse-like reaction when taken with alcohol.

Antibiotics: Nursing Implications

Tetracyclines

Milk products, iron preparations, antacids, and other dairy products should be avoided because of the chelation and drug-binding that occurs. All medications should be taken with 6 to 8 ounces of fluid, preferably water. Due to photosensitivity, avoid sunlight and tanning beds.

Antibiotics: Nursing Implications

Aminoglycosides

Monitor peak and trough blood levels of these agents to prevent nephrotoxicity and ototoxicity. Symptoms of ototoxicity include dizziness, tinnitus, and hearing loss. Symptoms of nephrotoxicity include urinary casts, proteinuria, and increased BUN and serum creatinine levels.

Antibiotics: Nursing Implications

Quinolones

Should be taken with at least 3 L of fluid per day, unless otherwise specified

Antibiotics: Nursing Implications

Macrolides

These agents are highly protein-bound and will cause severe interactions with other protein-bound drugs. The absorption of oral erythromycin is enhanced when taken on an empty stomach, but because of the high incidence of GI upset, many agents are taken after a meal or snack.

Antibiotics: Nursing Implications

Monitor for therapeutic effects: Disappearance of fever, lethargy, drainage, and redness

The ABCs of Antibiotics

Lourdes Irizarry, MD Associate Professor of Medicine Albuquerque VAMC & UNM SOM

Principles of Antimicrobial Therapy

Site of action Individual patient Ecology of the institution Efficacy Toxicity Cost

Classes of Antibiotics

Beta lactams Monobactams Carbapenems Macrolides/Azalides/Lincosamides Aminoglycosides Fluoroquinolones Oxazolidinones

Antibiotic brands

50 penicillins 71 cephalosporins 12 tetracyclines 8 aminoglycosides 1 monobactam 3 carbapenems

9 macrolides 2 streptogramins 3 dihydrofolate reductase inhibitors 1 oxazolidinone 5.5 quinolones

Inhibition of Cell Cell Wall Synthesis Vancomycin, teicoplanin Beta-lactams Monobactams Carbapenems

Inhibition of Protein Synthesis

50 S inhibitors macrolides chloramphenicol

clindamycin

30 S inhibitors tetracycline aminoglycosides

oxazolidinones

Interference with basic cell functions

quinolones DNA gyrase

Folic acid metabolism

trimethoprim

sulfonamides

Antibiotic Inactivation

Destruction or modification
Ex: Beta-lactamase production

Alteration of the antibiotic target site(s)

Ex: Abnormal PBPs

Prevention of access to target

Ex: Efflux pump & Deletions of porins

Antibiotic Essentials
Antibiotic Gram (+) + Gram. (-) Anaerobes CNS

PCN

Strep. A, N.meingitidis Listeria, Eikenella Enterococcus Pasteurella

(Not Staph. Not PRSTP)

+/-

+ Neurosyphilis

N. meningitidis
+

Nafcillin

MSSA

Ampicillin

+ Enterococcus
(Not S. pyogenes, Not Sthaph.)

E.coli, Proteus
B-lactamase neg. H.flu, Moraxella

+/-

+/-

Listeria

Antibiotic Essentials (2)

Antibiotic Gram. (+) + i.e. PCN
Not Enterococcus

Gram. (-) +++

Anaerobes

CNS

Ticarcillin

P.aeruginosa
(Not Acitenobacter)

+/-

Piperacillin

E. faecalis
Mezlocillin + i.e. PCN Enterococcus +++ + +/-

+ i.e. PCN

+++

+/-

Antibiotic Essentials (3)

Antibiotic Gram. (+) +++ MSSA, MSSE
Not PRSTP

Gram. (-) +

Anaerobes

CNS

Ampicillin/ Sulbactam

i.e.

+++

Few Klebsiella

H. flu, Moraxella
+++
No increased activity for

Ampicillin

Ticarcillin/ +++ Clavulanic MSSA, MSSE Not Enterococcus acid Piperacillin/ +++ Tazobactam MSSA, MSSE, Enterococcus

+++

Pseudomonas

+++
Pseudomonas
No increased activity for

+++

Antibiotic Essentials (4)

Antibiotic Gram. (+) Gram. (-) Anaerobes CNS

1st gen. Cephalosporins

+ MSSA, MSSE
Not STP Not Enterococcus

+/Not Blactamase producers

Antibiotic Essentials (5)

3rd Gen Cephalosporin

Gram. (+) -

Gram. (-) +++

Antipseudomonal

Anaerobes -

CNS +++ +++

Ceftazidime Ceftriaxone

+++ ++ Not antiMSSA, MSSE, pseudomonal PRSTP

Not Enterococcus

Cefotaxime

+++

Ceftizoxime

Not ideal for Staph. Not Enterococcus

Not antipseudomonal Not antipseudomonal

++

++

+++

++

++

++

+++

Not ideal for Staph. Not Enterococcus

Antibiotic Essentials (6)

4th Generation Cephalosporin Gram. (+) Gram. (-) Anaerobes CNS

Cefepeme

+++ MSSA, MSSE Not Enterococcus

+++ Antipseudomonal

+++

Antibiotic Essentials: (7)

Antibiotic Gram. (+) Gram. (-) Anaerobes CNS

Meropenem Imipenem

+++
Not MRSA, Not Enterococcus

+++
Not. Sternothrophomon as

+++

Aztreonam

+++

+/-

Antibiotic Essentials: (9)

Antibiotic Gram. (+) Gram. (-) Anaerobes CNS

Azithromycin Clarithromy

+
Not Enterococcus +/- SAU

H. Flu Moraxella
+/- H. flu & Moraxella

Erythromycin

+
Not Enterococcus +/-SAU

Macrolides

Erythromycin and Clarithromycin have hepatic metabolism via cytochrome p-450 (Increase levels of
theophylline, warfarin, triazolam, bromocriptine, carbamazepine and cyclosporin)

Erythromycin iv from causes phlebitis, not Azithromycin, no IV Clarithromycin (too venous toxic)

Classification of Fuoroquinolones

First generation
nalidixic acid

Third generation**
gatifloxacin

Second generation
norfloxacin ciprofloxacin* ofloxacin levofloxacin

(sparfloxacin, grepafloxacin)

Fourth generation***
moxifloxacin trovafloxacin,
(clinafloxacin)

Activity of Fluoroquinolones Against Gram Positive Bacteria

Species

Cipro.

Gati.

Levo.

Moxi.
0.06 4 0.13 1 1-4 0.120.25

Trova
0.06 4

Oflox
0.125-1

MSSA MRSA S. epi

0.5-.078 0.1-0.13 0.25 3.13-32 0.39-1 0.2-16 16

0.2-0.25 0.5-1 0.78-2 1.56-4 0.5 1-3.13 3.13-8 1-3.13

0.015-4 0.125-1 0.12-2 0.25-8 0.120.5 1-8 1-4 1-2

E. 1.56-4 faecalis E. 3.13-16 faecium S. 1.56-4 pneumo

Activity of Fluoroquinolones for Gram Negative Bacteria

Species Cipro
E.cloac
E.coli Amp.-R Kleb. Cefz.-R Pseudo.

Gati

Levo

Moxi
0.06 0.008 8 0.13 8 32

Trova
0.06 0.03-0.5 32 0.13-0.5 16 2-32

Oflox
0.030.12

0.03-0.1 0.06-0.2 0.06 0.0160.5 16 0.060.39 8 0.78-8 0.0160.1 8 0.03 16

0.1-0.39 0.13 4 3.13-32 16 32

0.25-32

Activity of Fluoroquinolones Against Anaerobes

Species Cipro Gati Levo Moxi Trova

B. frag

2-128

0.25-1 1-2 1

2 8 3.13>4

0.12 2

0.25-2 1-2-16 0.25-0.5

C.difficile 16-32 Peptostre 0.5-8

Susceptibility of S.pneumoniae to Fluoroquinolones

5
Pneumococci With Reduced Susceptibility to Fluoroquinolones (%)
Ages 15-64 Age 65 and older

6 5 4 3 2 1 0 88 89 90 91 92 93 94 95 96 97 98
No. of Prescriptions per 100

4 3 2 1 0

Year
Chen DK, et al. N Engl J Med. 1999;341:233-239.

Activity of New Fluoroquinolones Against MRSA, VRE and PRSP

MRSA
Levofloxacin
Gatifloxacin Moxifloxacin Gemifloxacin Ciprofloxacin

VRE PRSP QTc change

+/+/+/+/+/---

+/+/+/+/+/---

++
++++ ++++ ++++ +/---

4.6 msc
2.9 msc 6 msc 5 msc ?

Quinupristin/Dalfopristin

S. pneumoniae S.aureus (MRSA)

E. faecium (VRE)
No activity against E. faecalis

Others...

Metronidazole anaerobic drug with excellent CNS penetration Clindamycin: good for Gram.(+) and anaerobes. Always include in the treatment of Strep. skin & soft tissue infections. Great for lung abscesses. (No CNS penetration)

Vancomycin: Inferior to B-lactams against SAU

Other highlights...

Cross allergic reaction between Penicillins, Cephalosporins and Carbapenems. Not Aztreonam. Aztreonam cross allergy with Ceftazidime Cephalosporins and Metronidazole: Disulfiram reaction Ticarcillin: bleeding in uremic patients

Drugs Under Development

PRSP, MRSA,VISA,VRE

Lipopetides (Daptomycin: narrow therapeutic index) Glycyclines Glycopeptides (Vancomycin analogues) Fluoroquinolones Macrolides/Ketolides Evernimicin (trials on hold)

Antibiotics With Immunomodulating Effects

Macrolides Fluoroquinolones Quinupristin/dalfopristin

Future Directions on the Treatment of Infections

Usage of immunomudalating agents Usage of non-antibiotics as adjuvant therapy New approaches to rational drug design
mapping binding genomics

A collection of anecdotes is not data.

Anonymous

You have to run towards where the ball is going to be.

Yogi Berra

Prediction is very

difficult, particularly about the future.

Neils Bohr

ABT-492

4th generation fluororoquinolone Trovafloxacin like activity Levofloxacin safety profile Little CNS or CV activity Iv & po Phase I trials 2,000

ABT-723

Ketolide
ketone added to erythromycin quinoline ring increases activity

Phase II trials Phase III Fall 2,000 S. pneumoniae activity 2-3x higher than clarithromycin

Macrolides

Inhibits RNA dependent protein synthesis, causing dissociation of peptidyl transfer (tRNA) from the ribosome during elongation phase

Fluoroquinolones
Mechanism of Action

Inhibit the activities of DNA gyrase (an essential adenosine triphosphatehydrolizing topoisomerase) which in turn inhibits bacterial DNA peplication and transcription. Leading to bacterial death.

Mechanism of Action of Quinolones (2)

To accommodate within bacterial cell, organisms DNA helix is coiled and twisted in a direction opposite to the double helix (negative supercoil). DNA gyrase catalyzes the entry of these negative supercoils into circular chromosomal DNA and plasmid DNA

Mechanism of Action Quinolone (3)

DNA gyrase consists of 2A and 2B subunits. A interrupts supercoiling. After fixing the negative supercoils in place, A reseals the break. Quinolones trap the complex after strand breakage preventing A from resealing the breaks. DNA sythesis is halted.

Mechanisms of Resistance

Spontaneous mutations in bacterial chromosomes

Mutations in A subunit of bacterial DNA gyrase that lowers affinity of drug at gyrase complex Mutations of chromosomally mediated drug influx and efflux systems Selection for resistance dependent on quinolone and organism