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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
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
antibiotic
Disease
6. Patient factors
7. Drug-related factors
1. Site of infection
Koda-Kimble M.A. et al, Applied Therapeutics , The Clinical Use of Drugs (Lippincott Williams & Wilkin, 9th ed.), 2009
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
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
3. Severity of infections
abscess in lung / brain/ liver/ pelvis/ intra-abdominal; meningitis/ endocarditis/ pneumonias / pyelonephritis / puerperal sepsis;
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:
Elderly
In the elderly, achlorhydria may affect absorption of anticbacterial agents; drug elimination is slower, requiring dose adjustments & ototoxicity of aminoglycosides may be increased.
streptomycin
clarithromycin Safe in pregnancy penicillins cephalosporins erythromycin isoniazid ethambutol
chloramphenicol
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
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
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.
- 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
- IV 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.
Route of administration.cont
However, some drugs are not available for parental use (eg. Most macrolides, sulpha drugs, tetracyclines) 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.
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
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:
4) To overcome resistance:
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
Which one of the following patients is least likely to require antimicrobial treatment tailored to the individuals condition?
A. Patient undergoing cancer chemotherapy B. Patient with kidney disease C. Elderly patient D. Patient with hypertension E. Patient with liver disease
C. Elderly patient
- Renal & hepatic function are often decreased among the elderly
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
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
Tetracycline
Erythromycin Vancomycin Methicillin Ampicillin Cephalosporins
1948
1952 1956 1960 1961 1964
1953
1988 1988 1961 1973 late 1960s
Antibiotic Resistance
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.
- widespread inappropriate use: up to 50% of prescriptions in developing countries are for viral infections that cannot respond
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
The four main mechanisms by which microorganisms exhibit resistance to antibiotics are:
e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of -lactamases.
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.
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
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.
Inactivation
Impermeability
(reduced drug accumulation)
Efflux
A
By-pass
B
Altered target
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)
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
transformation
transduction
DNA Most resistance genes are plasmid mediated Plasmid may enter cells by processes such as conjugation, transduction (phage mediated) & transformation
Diffusion
test
Serial
dilution
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
A pregnant woman was hospitalized and chatheterized with a catheter. She developed a urinary tract infection caused by Pseudomonas aeruginosa and was treated with gentamicin. Which of the following adverse effects was arisk to the fetus when the woman was on gentamicin? A. Skeletal deformity B. Hearing loss C. Teratogenesis D. Blindness E. Mental retardation
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
Definitions
Antibiotics acting only on a single or a limited group of microorganisms Eg.- isoniazid active only against mycobacteria
Extended-spectrum antibiotics
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
Broad Spectrum
Amoxycillin
Aminoglycoside Ciprofloxacin Chloramphenicol Imipenam Tetracycline Vancomycin Carbenicillin 3rd generation cephalosporins
Bacteriostatic agents inhibit growth but dont kill. They rely on body defenses to clear the infection.
Mechanism of action
Antimetabolites
2) Cephalosporins
3) Monobactams 4) Carbapenems
2. Glycopeptides
1) Vancomycin
3. Beta-lactamase inhibitors
1) Clavulanic acid 2) Sulbactam
2. Glycopeptide
Vancomycin Teicoplanin
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).
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
Penicillins - indication
Penicillinase-resistant penicillins Staph infection Impetigo Abcess Extended spectrum penicillin Gram +ve & Gram ve Pneumonia, otitis media
Cephalosporins
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
Glycopeptides
Vancomycin, teicoplanin Active against Gm +ve esp staph Not active against Gm ve Use in MRSA infection Nephrotoxicity, red man syndrome
Aminoglycosides
Bactericidal From various Streptomyces species
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
Aminoglycosides pharmacokinetic
Polar substance
Adjust dosage with renal impairment Can be calculated based on creatinine clearance
Aminoglycosides: PK-PD
Ototoxic
Aminoglycosides: toxicity
Auditory damage Vestibular damage Potentiated by other nephrotoxic drugs
Nephrotoxic
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
Staphylococci
Resistance
rapidly developed
Pseudomonas, klebsiella
Requires TDM
Poor penetration
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
Rarely nephrotoxic
Macrolides
azithromycin
erythromycin
clarithromycin
Macrolides
Streptomycin obtained from Streptomyces
erythreus
MOA Bind reversibly to the 50S subunit Inhibit elongation of the protein
Erythromycin- spectrum
Gram +ve
Atypical organism
Mycobacteria
Gram ve
Erythromycin - pharmacokinetics
Food interferes absorption t1/2 = 1.5 hours Well distributed except CSF Excreted in biles
Erythromycin- uses
Corynebacterial infection
Diphteria
Penicillin allergy
Erythromycin- ADR
GIT
Nausea, vomiting,diarrhoea
Liver toxicity
Cholestatic jaundice
Drug interaction
Clarithromycin
Improved acid stability Better absorption Longer t1/2
BD dosing
Metabolised by liver More active against Mycobacterium avian complex More expensive
Azithromycin
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
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
Tetracyclines - ADR
GIT
Hepatic injury
Due to Ca2+ chelating property Yellow discolouration Contraindicated in children < 8 years old
Nephrotoxicity Photosensitization
Chloramphenicol
Binds to 50 S ribosomal subunit Mainly bacteriostatic Bactericidal
H. influenza N. meningitidis
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
ANTIMETABOLITES 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)
Sulfonamides - effect
Bacteriostatic Active against
Both Gram +ve & -ve E. coli, Klebsiella, Salmonella Clamydia Some protozoa
Pneumocystis
carinii
Sulfonamides Pharmacokinetics
Preparation available
Topical Oral
Well
Sulfonamides - uses
Topical
Systemic
Use in combination
Sulfonamides - ADR
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
TMP
Combination is bactericidal
co-trimoxazole pkinetics
TMP:SFX = 1:5 Available in IV and oral Oral
Penetrates well into CSF, prostate Excreted in urine Usually given BD dose
co-trimoxazole - uses
Infection caused by
UTI
Shigella Salmonela
Treatment prophylaxis
Treatment prophylaxis
Co-trimoxazole - ADR
Sulfonamides ADR Megaloblastic anaemia Leukopenia Granulocytopenia
Fluoroquinolones
Synthetic fluorinated analogs of nalidixic acid Inhibit bacterial DNA synthesis Inhibit DNA gyrase & topoisomerase Examples
Fluoroquinolones
Spectrum depend on drugs Earlier fluoroquinolones (ciprofloxacin)
Also useful in
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 able to serve as an electron acceptor, forming reduced cytotoxic compounds that bind to proteins and DNA, resulting in cell death.
Metronidazole - anaerobes
Side Effects
Nausea & vomiting
Peripheral neuropathy Convulsions, headaches Hepatitis
PK
A patient with degenerative joint disease is to undergo insertion of a hip prosthesis. To avoid complication due to postoperative infection, the surgeon will pretreat this patient with an antibiotic. This hospital has a significant problem with MRSA. Which of the following antibiotics should the surgeon select?
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