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Antibiotics

Outline of the lecture


1) Indications for antibacterial therapy definitive, empiric & prophylaxis 2) Selection of antimicrobial agents 3) Methods of administration of antimicrobials 4) Antibiotics Resistance 5) Classification of antibacterial agents

Indications for antibacterial therapy:


1. Definitive therapy
This is for proven bacterial infections Attempts should be made to confirm the bacterial infection by means of staining of secretions/fluids/exudates, culture & sensitivity, serological tests & other tests

Based on the reports, a narrow spectrum, least toxic, easy to administer & cheap drug should be prescribed.

2. Empirical therapy
Empirical antibacterial therapy should be restricted to critical cases, when time is inadequate for identification & isolation of the bacteria & reasonably strong doubt of bacterial infection exists:
- septicemic shock/sepsis syndrome - immunocompromised patients with severe systemic infection - hectic temperature - neutropenic patient (reduction in neutrophils)

In such situations, drugs that cover the most probable infective agent/s should be used.
Empiric antibiotic is antibiotic therapy that is begun before a specific pathogen is identified

3. Prophylactic therapy
Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections.

In all these situations, only narrow spectrum & specific drugs are used

The duration of prophylaxis is dictated by the duration of the risk of infection.


eg.

1. Prevention for persons from non-malarious areas who visit areas endemic for malaria.
2. Treatment prior to certain surgical procedures to prevent infections

Bacteria vs Host

Bacteria Pathogen Vs non pathogen Virulence

Host Host defence

antibiotic

Disease

Selection of antimicrobial agents

Factors should be considered before prescribing antibacterial agent


1. Site of infection
2. Type of infection 3. Severity of infection 4. Isolate & its sensitivity 5. Source of infection

6. Patient factors
7. Drug-related factors

1. Site of infection
Infection above the diaphragm: URTI eg pharyngitis, tonsilitis, sinusitis, otitis, epiglottitis etc. - commonly caused by organism like Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci (rarely Mycoplasma, H. influenzae) - Can be treated with drugs like penicillins

macrolides
cephalosporins

1. Site of infectioncont
Lower respiratory tract infections:
Eg. Bronchitis, pneumonitis, pneumonia, lung abscess etc -generally caused by the organisms Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci, Staph aureus (rarely Mycoplasma, H. influenzae, Moraxella, Klebsiella) etc. - can be treated penicillins, cephalosporins, macrolides & tetracylines

1. Site of infection . cont


Infection below the diaphragm:
Eg UTI, intra-abdominal sepsis, pelvic infections etc --these are caused by the organisms like E. coli, Klebsiella, Proteus, Pseudomonas, Bacteroides etc. Quinolones, aminoglycosides, 3rd generation cephalosporins & metronidazole alone or in combination are useful in these infections. Rule of the thumb
Infections above the diaphragm Infections below the diaphragm Cocci & Gram +ve organisms Bacilli & Gram -ve organisms

1. Site of infection . cont


There are certain sites where the infection tends to be difficult for treatment : - meningitis (impenetrable BBB),

- chronic prostatitis (non-fenestrated capillaris),


- intra-ocular infections (non-fenestrated capillaries), - abscesses (thick wall, acidic pH, hydrolizing enzymes etc.), - cardiac & intravascular vegetations (poor reach & penetration), - osteomyelitis (avascular sequestrum) etc

In such cases:Higher & more frequent dose Longer duration of therapy Combinations Lipophilic drugs may have to be used

2. Type of infection
Infections can be localised/extensive; mild/severe; superficial/deep-seated; acute/sub acute/chronic & extracellular/intracellular. For extensive, severe, deep-seated, chronic & intracellular infections Higher & more frequent dose Longer duration of therapy Combinations Lipophilic drugs

may have to be used

3. Severity of infections
Bacteremia / sepsis syndrome / septic shock; abscess in lung / brain/ liver/ pelvis/ intra-abdominal; meningitis/ endocarditis/ pneumonias / pyelonephritis / puerperal sepsis; Severe soft tissue infections / gangrene & hospital acquired infections For severe infections only IV route - to ensure adequate blood levels. only bacterial drugs - to ensure faster clearance of the infection. dose should be higher & more frequent.
- If the site is unknown, attempt should be made to cover all possible organisms, including drug resistant Staphylococcus, Pseudomonas, & anaerobes. - A combinations of Penicillins / 3rd generation cephalosporins, aminoglycosides & metronidazole may be used.

4. Isolate & sensitivity


Ideal management of any significant bacterial infection requires culture & sensitivity (C&S) study of the specimen. If the situation permits, antibacterials can be started only after the sensitivity report is available. Narrow spectrum, least toxic, easy to administer & cheapest of the effective drugs should be chosen.
If the patient is responding to the drug that has already been started, it should not be changed even if the in vitro report says otherwise

5. Source of infection
Community-acquired infections are less likely to be resistant whereas Hospital-acquired infections are likely to be resistant & more difficult to treat (eg. Pseudomonas, MRSA etc)

6. Patient factors
Factors should be considered in choosing the antibacterial agent:

- Age of the patient


- immune status - pregnancy & lactation

- associated conditions like renal failure, hepatic failure, epilepsy etc.


In infants, chloramphenicol (can cause grey baby) & sulpha drugs (can cause kernicterus) are contraindicated

Patient factors.cont Children


- Tetracycline are contraindicated < 8 years because they discolour the teeth - < 18 years ALL fluoroquinolones are contraindicated because they cause arthropathy by damaging the growing cartilage.

Elderly
In the elderly, achlorhydria may affect absorption of anticbacterial agents; drug elimination is slower, requiring dose adjustments & ototoxicity of aminoglycosides may be increased.

Patient factors.cont Patients with compromised immune status


In patients with likelihood of compromised immune status, like extremes of age, HIV infection, diabetes mellitus, neutropenia, splenectomy, using corticosteroids or immunosuppresants, patients with cancers/blood dyscrasias, ONLY bactericidal drugs should be used.

Patient factors.in pregnancy


Contraindicated in all trimesters tetracylines quinolones Contraindicated in the last trimesters sulpha drug nitrofurantoin

streptomycin
clarithromycin Safe in pregnancy penicillins cephalosporins erythromycin isoniazid ethambutol

chloramphenicol

Contraindicated in lactating mothers sulpha drug tetracylines nitrofurantoin quinolones metronidazole

Drugs with limited data on safety like aminoglycoside, azithromycin, clindamycin, vancomycin, metronidazole, trimethoprim, rifampicin & pyrazinamide should be used with caution when benefits overweigh the risks

Patient factors.in patients with renal failure


Absolutely contraindicated Relatively contraindicated Aminoglycoside Cephalosporins Fluoroquinolones Relatively safe Penicillins Sulpha drug

tetracycline

Macrolides
Vancomycin Metronidazole Isoniazid Ethambutol Rifampicin

It is better to avoid combinations of cephalosporins & aminoglycosides in these patients because both classes can cause nephrotoxicity

Patient factors.in patients with hepatic failure


No drugs are absolutely contraindicated. Relatively contraindicated
Chloramphenicol Erythromycin estolate Fluoroquinolones Pyrazinamide Rifampicin

Safe
Penicillins

Cephalosporins
Ethambutol Aminoglycosides

Isoniazid
Metronidazole

7. Drug factors

1. Hypersensitivity:
If the patient has prior history of hypersensitivity the antibacterial agent should be avoided. It is therefore important to elicit this history in all patients (common with penicillin)

2. Adverse reactions:
Certain ADRs warrant discontinuation of therapy & the doctor should adequately educate the patients on these adverse effects.

7. Drug factors

3. Cost:
It should always be remembered that just because as particular drug is expensive, it need not be superior than the cheaper ones. Eg. Cheaper drug like doxycycline or co-trimoxazole are as effective as the costlier clarithromycin or cephalosporins in the management of lower RTI.

7. Drug factors.cont
4. Interactions:
Interactions with food & other concomitant drugs should be considered before instituting antibacterial therapy so as to maximize efficacy & minimize toxicity. a) Interactions include enhanced nephrotoxicity or ototoxicity when aminoglycosides are given with loop diuretics, vancomycin or cisplatin. b) Rifampicin, a strong inducer of hepatic drug-metabolizing enzymes, decreases the effects of digoxin, ketoconazole, oral contraceptives, propranolol, quinidine & warfarin. c) Erythromycin inhibits the hepatic metabolism of a number of drugs, including phenytoin, terfenadine, theophylline & warfarin.

Methods of administration of antimicrobials


Route of administration The route of administration depends on the site, type & severity of the infection & the availability of a suitable drug - Oral route is the most preferred, easy & cheap, but may not be reliable in all circumstances, esp. in patients with severe infections, non-compliant patients, in the presence of vomiting etc.

Certain drugs like the aminoglycosides & most 3rd generations cephalosporins are not available for oral administration.

- IM route should generally be restricted for the administration of procaine & benzathine penicillin. The absorption is not very reliable & it is painful & dislike by the patients.

Route of administration.cont route is the best for the management of severe & deep-seated infections since it ensures adequate serum drug levels. Procaine penicillin & benzathine penicillin should never be given IV.
- IV

However, some drugs are not available for parental use (eg. Most macrolides, sulpha drugs, tetracyclines)

Chloramphenicol, the fluoroquinolones & trimethoprimsulphamethoxazole (TMP-SMZ) are also available orally.
Antibacterials are also used topically

Dosage
- Dosage depends on patients age, weight, associated conditions like pregnancy, renal & hepatic failure & site, type & severity of infection. - Generally the dose should be higher in cases of severe, deep-seated infections & lower in cases of renal-failure.

- Unnecessary overdosage only adds to the cost & adverse effects.

Frequency of administration
The drug should be administered 4-5x the plasma half-life to maintain adequate therapeutic concentrations in the serum throughout the day. Frequency can be:- increased in cases of severe, deep seated & sequestrated infections - reduced in cases of renal & hepatic failure.

Duration
Duration of therapy depends on the site 1) Tonsilitis 10 days 2) Bronchitis 5-7 days 3) UTI single shot to 21 days 4) Lung abscess- 2-4 weeks 5) Tuberculosis 6-24 months

Longer courses of therapy are usually required for infections due to fungi or mycobacteria Endocarditis & osteomyelitis require longer duration of treatment

Combinations
1) For synergistic effect:
eg: combination of 2 bacteriostatic drugs such as

trimethoprim + sulfamethoxazole =

Co-Trimoxazole (bacterim)
Therapeutic advantage of sulphonamide + trimethoprim 1) Synergistic effects 2) Bactericidal activity 3) Decrease resistance

4) Bigger spectrum of activity


5) Reduced toxicity

Combinations.cont
2) Treatment of infections with multiple organisms: Mixed infections in lung abcess, peritonitis, soiled wounds etc naturally require multiple antibiotics for complete clearance of the infection penicillins (for Gram +ve & certain anaerobes) & aminoglycosides (for Gram ve); metronidazole for bacteroides. penicillins + aminoglycosides + metronidazole

Combinations.cont
Use of combination is a well known method of preventing drug resistance. The classic example is the antiTB therapy,

3) To prevent resistance:

Eg isoniazid + ethambutol + rifampicin

4) To overcome resistance:

Combination of specific drugs can be useful in overcoming that resistant infections, eg

Penicillins + -lactamase inhibitors (Co-amoxiclav/augmentin)

The following combinations are irrational, not useful or even harmful:


1) Bactericidal with bacteriostatic eg. Penicillins (bactericidal) with tetracyclines ( bacteriostatic)
Bactericidal a/b (kill bacteria) tend to be used in combination with one another Bateriostatic a/b (prevent bacterias reproduction) tend to be used on its own

2) Combinations of drugs with similar toxicity eg. Chloramphenicol & sulpha drug 3) Combining drugs for non-existing mixed infections eg. Tablets of ciprofloxacin + metronidazole/tinidazole

Clinical failure of antimicrobial therapy

Failure of an antibiotic regimen (1)


Inadequate clinical or microbiological response to antimicrobial therapy can result from multiple causes, including; 1) Drug factors
incorrect choice, poor tissue penetration inadequate dose

pH low pH reduces effectiveness of aminoglycosides, erythromycin, clindamycin

Failure of an antibiotic regimen (2)


2) Host factors poor host defense, age renal & liver function

pre-existing dysfunction of other organs

3) Pathogen factors resistance superinfection

Antibiotic Resistance

Penicillin Era

1942-1950 available without a prescription Public demand followed by production of throat sprays, cough lozenges, mouthwashes, soaps and other products containing penicillin Alexander Fleming Warned that excessive use could result in antimicrobial resistance the microbes are educated to resist penicillin and

a host of penicillin-fast organisms is bred out which can be passed to other individuals and from them to others until they reach someone who gets a pneumonia or septicemia which penicillin cannot save. The New York Times 1945

Flemings words proved to be correct....

The Problem of Antibiotic Resistance

Penicillin resistance first identified in 1940s Since then, antibiotic resistance has developed faster than new drugs Estimated cost of infections: $4-5 million per year Antibiotic resistance previously concentrated in hospitals, especially ICUs MRSA recently estimated to kill 18,000 Americans yearly

History
DRUG Penicillin
Streptomycin

INTRODUCTION 1943
1945

APPEARANCE OF RESISTANCE 1946 1959

Tetracycline
Erythromycin Vancomycin Methicillin Ampicillin Cephalosporins

1948
1952 1956 1960 1961 1964

1953
1988 1988 1961 1973 late 1960s

Antibiotic Resistance

Relative or complete lack of effect of antimicrobial against a previously susceptible microbe

Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not stop their growth.

What Factors Promote Antimicrobial Resistance?


What causes the rapid occurrence of widespread resistance?

(1) Incomplete treatment:


- people fail to finish the full course of their medication - 25% of previously-treated tuberculosis patients relapsed with drug resistant strains; most had failed to complete their initial course

What Factors Promote Antimicrobial Resistance?


(2) Mis-prescription:
- patients demand antibiotics for cold

- widespread inappropriate use: up to 50% of prescriptions in developing countries are for viral infections that cannot respond

(3) Exposure to microbes carrying resistance genes

Inappropriate Antibiotic Use



Prescription not taken correctly Antibiotics for viral infections Antibiotics sold without medical supervision Spread of resistant microbes in hospitals due to lack of hygiene
Lack of quality control in manufacture or outdated antimicrobial Use of broad-spectrum agents when a narrowspectrum drug would suffice

(eg, use of third-generation cephalosporins for communityacquired pneumonia)

Mechanisms of Antibiotic Resistance (1)

The four main mechanisms by which microorganisms exhibit resistance to antibiotics are:

(1) Drug inactivation or modification:

e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of -lactamases.

(2) Alteration of target site:

e.g. alteration of PBPthe binding target site of penicillinsin MRSA and other penicillin-resistant bacteria resulting in decreased binding of the antibiotic to its target.

Mechanisms of Antibiotic Resistance (2)


(3) Alteration of metabolic pathway:
e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, they turn to utilizing preformed folic acid.

(4) Reduced drug accumulation:


by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.

Resistance: -lactamase Enzymes


-Lactam antibiotics act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.

Bacteria produce -lactamase enzymes to hydrolyze the -lactam ring before drugs can reach inner membrane where PG synthesis occurs A cell may produce 100,000 - lactamase enzymes, each of which can destroy 1,000 penicillins per second 100 million molecules of drug destroyed per second

-lactamases

Enzymes produced by bacteria which destroy -lactam antibiotics Many different types

Penicillinases, cephalosporinases, carbapenemases

Most are plasmid mediated

Overcoming -lactam Resistance


slow to hydrolyze

As a response to bacterial resistance to -lactam drugs, there are drugs, such as Augmentin, which are designed to disable the lactamase enzyme.
Augmentin is made of amoxicillin, a -lactam antibiotic, and clavulanic acid, a -lactamase inhibitor. The clavulanic acid is designed to overwhelm all -lactamase enzymes, bind irreversibly to them, and effectively serve as an antagonist so that the amoxicillin is not affected by the lactamase enzymes.

Overcoming -lactam Resistance


Amoxicillin (-lactam antibiotic)

+ clavulanic acid (a -lactamase inhibitor)


= Co-amoxiclav (Augmentin)

Ampicillin (-lactam antibiotic) + sulbactam (a -lactamase inhibitor) = Unasyn

Resistance in Simpler Terms


(reduced drug accumulation)

Inactivation

Impermeability
(reduced drug accumulation)

Efflux

A
By-pass

B
Altered target

(alteration of metabolic pathway)

Genetic alterations in drug resistance

Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic information.

1.

2.

Resistance develops due to the ability of DNA:To undergo spontaneous mutation To move from one organism to another (DNA/gene transfer)

Spontaneous mutation of DNA

Stable and heritable genetic change Not induced by antimicrobial agents Resistance variant will proliferate Eg. The emergence of rifampicin-resistant M.tuberculosis when rifampicin is used as a single antibiotic

DNA/Gene transfer of drug resistant


conjugation

transformation

transduction

DNA Most resistance genes are plasmid mediated Plasmid may enter cells by processes such as conjugation, transduction (phage mediated) & transformation

Measuring Antimicrobial Sensitivity


Disk
E-

Diffusion

(antimicrobial gradient method)

test

Serial

dilution

Measuring Antimicrobial Sensitivity


MIC

increase in the case of resistance

(Minimal inhibitory concentration)

- important in diagnostic laboratories to confirm resistance of microorganisms to an antimicrobial agent

Consequences of Antimicrobial Resistance


Infections

resistant to available antibiotics cost of treatment

Increased

Prevention of resistance
Speed development of new antibiotics Track resistance data nationwide Restrict antimicrobial use Narrow spectrum Combination in long term use (TB) Direct observed dosing (TB) Appropriate dose and duration Use more narrow spectrum antibiotics Use antimicrobial cocktails

Classification of antibacterial agents

Classification of antibacterial agents


Chemical structure Mechanism of action Spectrum of activity Broad, extended, narrow Types of actions Bactericidal, bacteriostatic

Chemical structure

Sulfonamides sulfadiazines Diaminopyrimidines Trimethoprim Quinolones Nalidixic acid, ciprofloxacin b-lactam antibiotics Penicillins, cephalosporins, carbapenems, monobactams Tetracyclines Tetracycline, doxycycline

Nitrobenzene derivatives Chloramphenicol Aminoglycosides Gentamicin Macrolides Erythromycin Nitrofuran derivatives Nitrofurantoin Glycopeptide Vancomycin Nitroimidazoles Metronidazoles

Spectrum of activity
Terms
Narrow-spectrum antibiotics Extended-spectrum antibiotics

Definitions
Antibiotics acting only on a single or a limited group of microorganisms Eg.- isoniazid active only against mycobacteria Antibiotics that are effective against gram +ve organisms & also against a significant no. of gram -ve organisms. Eg.- ampicillin acts against gram +ve organisms (Listeria monocytogenes) & some gram -ve organisms (E. coli). Antibiotics affect a wide variety of microbial species Eg.- tetracycline active against chlamydia, mycoplasma, actinomyces, anaerobic organisms, gram ve rods (E. coli)

Broad-spectrum antibiotics

Spectrum of activity

Summary of antibiotics spectrum


Narrow Spectrum
Aztreonam Benzylpenicillin Cloxacillin Phenoxymethylpenicillin Cephalexin

Broad Spectrum
Amoxycillin
Aminoglycoside Ciprofloxacin Chloramphenicol Imipenam Tetracycline Vancomycin Carbenicillin 3rd generation cephalosporins

Bactericidal vs. bacteriostatic


Bactericidal agents outright kill bacteria.
Penicillins Cephalosporins Macrolides Tetracyclines

Bacteriostatic agents inhibit growth but dont kill. They rely on body defenses to clear the infection.

Mechanism of actions
Mechanism of action
Inhibition of cell wall synthesis

Antibacterial agent
Penicillin Cephalosporins Monobactams Vancomycin Quinolones Rifampicin Aminoglycosides Tetracyclines Chloramphenicol Macrolides Trimethoprim Sulfonamides

Inhibition of DNA gyrase, RNA polymerase Inhibition of protein synthesis

Inhibition of folic acid metabolism

A. Cell wall Inhibitors


1. Beta-lactam antibiotics
1) Penicillin derivatives

2) Cephalosporins
3) Monobactams 4) Carbapenems

2. Glycopeptides
1) Vancomycin

1) Penicillin 2) Cephalosporins -lactam ring in red

3. Beta-lactamase inhibitors
1) Clavulanic acid 2) Sulbactam

Cell wall inhibitors


1. -lactam antibiotics
Penicillins Cephalosporins Carbapenems Monobactams

2. Glycopeptide
Vancomycin Teicoplanin

Penicillin core structure. "R" is variable group.

Bacterial cell wall

-lactam antibiotics inhibit transpeptidases enzymes that form these crosslinkages

Glycopeptides bind D-alanine and prevent crosslinkage

A schematic of peptidoglycans structure. The NAM and NAG sugars are shown as green and blue spheres respectively. The tetrapeptides linked to NAM are cross-linked by a pentaglycine peptide, shown as red lines linking the D-glutamine (L) to the Dalanine (A).

Glycopeptides bind D-alanine and prevent crosslinkage

-lactam antibiotics inhibit transpeptidases enzymes that form these crosslinkages

Penicillins - structure

Penicillins - classifications

Penicillin G like drugs Penicillin G (Benzylpenicillin) Penicillin V Procaine penicillin G Benzathine penicillin G Penicillinase- resistant penicillins (anti staph) Cloxacillin Flucloxacillin Methicillin Extended spectrum penicillin Ampicillin-like drugs Ampicillin Amoxicillin Broad-spectrum (antipseudomonal) penicillins Carbenicillin Piperacillin

Penicillins - pharmacokinetics
Given parenterally well distributed Crosses inflamed biological barrier Mainly excreted via kidney

Inhibited by probenecid

Penicillin G Gram +ve infection Streptococci Meningococci Pneumococci Clostridium Syphilis

Penicillins - indication

Penicillinase-resistant penicillins Staph infection Impetigo Abcess Extended spectrum penicillin Gram +ve & Gram ve Pneumonia, otitis media

Penicillins adverse reaction


Relatively

non-toxic Allergic reaction Anaphylaxis


- will occur in approximately in
0.01% patients
A rash on the back of a person with anaphylaxis

Cephalosporins

1. 1st generation cephalosporins


- best for Gram +ve - eg. Cephalexin, Cephazoline

2. 2nd generation cephalosporins


-best for Gram +ve & -ve -Extended Gram ve coverage - eg. Cefuroxime, Cefaclor

3. 3rd generation cephalosporins


-best for Gram ve -antipseudomonas - eg. Ceftazidime, Ceftriaxone, Cefotaxime, Cefoperazone

4. 4th generation cephalosporins


-Good coverage for both Gram +ve & -ve - antipseudomonal activity -Eg. Cefipime

Cephalosporins adverse reactions


Fairly

safe Allergic reaction Cross reaction with penicillin Superinfection


(an infection following a previous infection, esp. when caused by microorganisms that have become resistant to the antibiotics used earlier)

Carbapenem

Examples Imipenem Meropenem Wide spectrum Resistant against -lactamase Good activity against both Gram +ve & -ve Active against pseudomonas Use in resistant organisms Hospital acquired infection

Monobactam

Example Aztreonam Resistant against -lactamase Antipseudomonal activity Inactive against Gram +ve GIT side effects diarrhea, nausea & vomiting IV poorly absorbed when given via oral route.

- lactamase inhibitors
Resemble -lactam molecules No antibacterial activity Inhibits bacterial -lactamase Use in combination with penicillins

Ampicillinsulbactam Piperacillin-tazobactam Amoxycillin-clavulanate (clavulanic acid)

Glycopeptides
Vancomycin, teicoplanin Active against Gm +ve esp staph Not active against Gm ve Use in MRSA infection Nephrotoxicity, red man syndrome

B. PROTEIN SYNTHESIS INHIBITOR


1) Aminoglycosides 2) Tetracyclines 3) Chloramphenicol 4) Macrolides 5) Fusidic Acid

Aminoglycosides
Bactericidal From various Streptomyces species

Streptomycin Neomycin Amikacin Gentamicin Tobramycin Netilmicin

Aminoglycosides physical properties


Water

soluble (polar) Poorly absorbed from gut Given parenterally Less able to cross biological barrier More active at alkaline pH

Aminoglycosides - MOA

Irreversible inhibitor of protein synthesis Passive diffusion via porin channels of outer membrane Actively transport into cytoplasm

Bind to 30S subunit ribosome


Interfere with synthesis of protein

Aminoglycoside: clinical use


Use against Gram ve infection Usually combined with -lactam antibiotic

Better coverage Synergistic effect

No activity against anaerobe

Aminoglycosides pharmacokinetic

Polar substance

Given i.m. or i.v. Poorly penetrate CSF or eye


20% blood level in inflamed meninges May be given intrathecal

t1/2 = 2-3 hours Excreted unchanged by the kidneys


Adjust dosage with renal impairment Can be calculated based on creatinine clearance

Aminoglycosides: PK-PD

Concentration dependent killing

Post antibiotic effect

Rate of killing depend on concentration


Antibacterial activity persist after the level reduce to below MIC

Can be given single daily dose


Same efficacy Reduce risk of toxicity convenience

Ototoxic

Aminoglycosides: toxicity
Auditory damage Vestibular damage Potentiated by other nephrotoxic drugs

Nephrotoxic

Need to measure level (TDM)

Peak and trough Block neuromuscular junction

High dose

Streptomycin

Mainly use in the treatment of TB Combine with other anti TB Resistance easily developed without combination Side effect Fever, rashes Impair vestibular function Contraindicated in pregnancy Deafness in newborn

Gentamicin

Active both in Gram +ve & -ve

Staphylococci
Resistance

rapidly developed

Pseudomonas, klebsiella

No activity against streptococci and enterococci

But can enhance the effect of -lactam or vancomycin

Gentamicin clinical uses


Combine with cell wall inhibitor in severe infection With penicillin G in Strept viridans endocarditis Should not be used alone for pneumonia

Requires TDM

Poor penetration

If use more than 5 days Renal impairment

Amikacin
Semi synthetic aminoglycoside More resistant than genta towards inactivating enzymes Active against MDR M. tuberculosis Usually use as second line antibiotic

Spectinomycin
Structure related to aminoglycoside but lack of amino sugars Given i.m. Only use as an alternative to penicillin in gonorrhoea therapy

Penicillin sensitivity Resistant gonococcal

Rarely nephrotoxic

Macrolides

azithromycin

erythromycin

clarithromycin

Macrolides
Streptomycin obtained from Streptomyces

erythreus

Clarythromycin & azithromycin are semisynthetic

MOA Bind reversibly to the 50S subunit Inhibit elongation of the protein

Erythromycin- spectrum

Gram +ve

Pneumococci, streptococci, staph


Mycoplasma, clamydia M. kansasii

Atypical organism

Mycobacteria

Gram ve

Treponema pallidum (syphilis)

Neiserria sp, B pertussis, Corynebacteria

Erythromycin - pharmacokinetics

Destroyed by stomach acid

Enteric coated tablet

Food interferes absorption t1/2 = 1.5 hours Well distributed except CSF Excreted in biles

Erythromycin- uses

Corynebacterial infection

Diphteria

Clamydial infection Community acquired pneumonia Pertussis Syphilis

Penicillin allergy

Erythromycin- ADR

GIT

Nausea, vomiting,diarrhoea

Liver toxicity

Cholestatic jaundice

Drug interaction

Inhibit cytochrome P450

Clarithromycin
Improved acid stability Better absorption Longer t1/2

BD dosing

Metabolised by liver More active against Mycobacterium avian complex More expensive

Azithromycin

More active against


M avian complex Toxoplasma gondii

Penetrates well into tissues


Concentration > 10 100 times serum

Tissue t1/2 = 2-4 days


Single daily dose Short courses

Tetracyclines

Tetracyclines - MOA

Bind reversibly to the 30S subunit Misalignment of anticodons of the charged tRNAs with the codons of the mRNA. Failure of protein synthesis

Tetracyclines

Introduced in 1948 (chlortetracycline) Bacteriostatic Coverage

Gram +ve & -ve Atypical bacteria


Rickettsiae Chlamydia mycoplasma

Protozoa

Amoebas

Tetracyclines Pkinetics

GI absorption tetracycline (60-80%), doxycycline (95%), minocycline (100%) Impaired by food (esp with Mg2+, Ca2+) Ditributed widely except into CSF Crosses placenta Excreted both thru bile and urine T1/2 Short acting (6 hrs) Tetracycline Intermediate (12 hrs) demeclocycline Long (18 hrs) doxycycline, minocycline

Tetracyclines - uses

Drug of choice in atypical bacteria infection Ricketsiae Used in combination to treat gastric or duodenal ulcer

To eradicate H. Pylori

Cholera Acne Lyme disease (Borelia burgdorferi)

Tetracyclines - ADR

GIT

Hepatic injury

Nausea, vomiting, diarrhoea


Increased during pregnancy

Damage growing bone & teeth


Due to Ca2+ chelating property Yellow discolouration Contraindicated in children < 8 years old

Nephrotoxicity Photosensitization

Severe sunburn ; doxy/demeclocycline

Chloramphenicol
Binds to 50 S ribosomal subunit Mainly bacteriostatic Bactericidal

H. influenza N. meningitidis

Broad spectrum (including rickettsiae)

Chloramphenicol Pkinetics
IV (prodrug) or orally Complete oral absorption Excretion depends on conversion in liver to glucuronide, then secretion in kidney Slow excretion in liver impairment

Chloramphenicol - uses
Staph brain abscess Typhus As an alternative in meningitis Conjunctivitis eye preparation

Chloramphenicol - ADR

Blood dyscrasias

Idiosyncratic aplastic anemia

Gray baby syndrome

Neonates if doses not adjusted

D. FOLIC ACID METABOLISM INHIBITOR 1) Trimethoprim


2) Sulfonamides

Sulphonamide - MOA

Bacteria cannot transport folate into cells Tetrahydrofolate is a DNA precursor p-aminobenzoic acid (PABA) is a precursor for folate synthesis Sulfonamides are structurally similar to PABA Inhibits synthesis of dihydropteroate sythase (DHPS)

DHPS & DHFR absent in mammalian cells

Sulfonamides - effect
Bacteriostatic Active against

Both Gram +ve & -ve E. coli, Klebsiella, Salmonella Clamydia Some protozoa

Pneumocystis

carinii

Not active against rickettsiae

Sulfonamides Pharmacokinetics

Preparation available
Topical Oral

Well

absorbed from gut

Distributed widely including CSF Metabolized in liver Excreted via kidney

Sulfonamides - uses

Topical

Sulfacetamide ophthalmic solution


Conjunctivitis Trachoma

Silver sulfadiazine (SSD)


burns

Systemic

Use in combination

Sulfonamides - ADR

Fever Skin rash Exfoliative dermatitis Steven Johnson syndrome Crystalluria

Sulfonamides - combination

Sulfadiazine + pyrimethamine Pyrimethamine inhibit protozoan DHFR Synergistic Penetrates CSF 1st line for acute toxoplasmosis Sulfadoxin + pyrimethamine (Fansidar) Long acting Prophylaxis & treatment for malaria

Trimethoprim + sulfamethoxazole (TMP + SFX = co-trimoxazole)

TMP

Inhibit DHFR Synergistic when combined with SFX

Combination is bactericidal

co-trimoxazole pkinetics
TMP:SFX = 1:5 Available in IV and oral Oral

Well absorbed T1/2 = 10 hrs (both)

Penetrates well into CSF, prostate Excreted in urine Usually given BD dose

co-trimoxazole - uses

Infection caused by

UTI

Shigella Salmonela

Community acquired pneumonia PCP pneumonia (P. jiroveci)


Treatment prophylaxis

Treatment prophylaxis

Co-trimoxazole - ADR
Sulfonamides ADR Megaloblastic anaemia Leukopenia Granulocytopenia

C. DNA gyrase / RNA polymerase (Nucleic Acid Synthesis) INHIBITOR 1) Quinolones


Fluoroquinolones
Essential structure of all quinolone antibiotics

2) Metronidazole

Fluoroquinolones
Synthetic fluorinated analogs of nalidixic acid Inhibit bacterial DNA synthesis Inhibit DNA gyrase & topoisomerase Examples

Ciprofloxacin Norfloxacin Perfloxacin

Inhibition of topoisomerase IV prevents separation of replicated DNA

Required for normal transcription and replication

Fluoroquinolones
Spectrum depend on drugs Earlier fluoroquinolones (ciprofloxacin)

Later drug (gatifloxacin)

Mainly cover Gram ve

Also useful in

Better coverage for Gram +ve

Atypical pneumonia TB, M. avian

Fluoroquinolones - uses
Usually used in multidrug resistant infection UTI Bacterial AGE Gonorrhea Eradication of meningococci from carriers

Fluoroquinolones - ADR
Usually well tolerated GIT upset Allergic reaction May damage growing cartilage (rat)

Metronidazole - anaerobes
- It is used mainly in the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. - It is used to treat ameobic dysentry, giardiasis, gangrene, pseudomonas coitis & various abdominal infections, lung abscess & dental sepsis.

Mechanism of actions
- The nitro group of metronidazole is chemically reduced by ferredoxin (or a ferredoxin-linked metabolic process) and the products are responsible for disrupting the DNA helical structure, thus inhibiting nucleic acid synthesis.

Metronidazole - anaerobes
Side Effects Nausea & vomiting Peripheral neuropathy Convulsions, headaches Hepatitis

PK It is well absorbed after oral or rectal administration

Pathogen Gram +ve cocci


Pneumococcus Streptococcus (common) Staphylococcus (penicillase-producing) Staphylococcus (methicillin resistance) Enterococcus

Drug (s) of first choice


Penicillin G, Ampicillin Penicillin G Augmentin, Unasyn, Cloxacillin, Methicillin, Nafcillin, Timentin Vancomycin Penicillin G plus gentamicin

Alternative Drug (s)


Erythromycin, Cephalosporin Erythromycin, Cephalosporin Cephalosporin TMZ-SMZ Vancomycin plus gentamicin

Gram -ve cocci


Gonococcus Meningococcus Cetrriaxone Penicillin G, Ampicillin Penicillin G, Ampicillin, Spectinomycin Cefotaxime, Cefuroxime, Chloramphenicol

Gram -ve rods


E.coli, Proteus, Klebsiella Shigella Enterobacter, Citrobacter, Serratia Hemophilus spp Pseudomonas aeruginosa Bacteroides fragillis Aminoglycosides, 3rd generation cephalosporin Fluoroquinolone Imipenam, Fluoroquinolone Cefuroxime or 3rd generation cephalosporin Aminoglycosides plus extended spectrum penicillin Metronidazole, Clindamycin TMZ-SMZ, Fluoroquinolone, extended spectrum penicillin TMZ-SMZ, Ampicillin TMZ-SMZ, extended spectrum penicillin TMZ-SMZ, Ampicillin, Chloramphenicol Ceftazidime, Aztreonam, Imipenam Imipenam, Chloramphenicol, Ampicillin/sulbactam

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