Principles of Antibiotics

Mae Tao Clinic June 2011

Antibiotics: Introduction / General Concepts

General points for all antibiotics: The primary goal of antibiotic therapy is to

kill the infecting organisms or inhibit their growth

Antibiotics don’t treat the common cold! Complete the entire prescribed treatment

course, timing of antibiotics matters. Usually takes 2-3 days to see the effects of

the antibiotic on the infection Timing matters! (try to stick to the

prescribed interval)

Antibiotics: Introduction / General Concepts

Empiric (initial) therapy should be selected to target the most likely causative pathogen(s) of the infection…

Whenever possible, therapy should be narrowed to target the specific organism(s) that are causing the infection

What is a pathogen?

“Principle pathogens”: regularly cause disease in a certain

proportion of susceptible individuals with apparently healthy host defenses

“Opportunistic pathogens” only affect obviously compromised patients

e.g., Pseudomonas aeruginosa

How is Appropriate Antibiotic Therapy Selected?

Is there an infection? What is the identity of the pathogen(s)?

Predicted vs. definitive What is the pathogen’s antibiotic susceptibility

pattern? Predicted vs. definitive

What host factors might influence selection? Related/unrelated to the infection:

immunity, infection site, pharmacokinetics, etc….

What should be monitored for response/toxicity?

Common Signs/Symptoms of Infection

Fever (temp > 98.60F (370C)): circadian fluctuations influence of route of evaluation

rectal/axillary temp. ~1.0 0F (0.60C) higher/lower

sensitivity/specificity: fever also occurs in:

autoimmune disorders drug fever (beta-lactams, anticonvulsants, allopurinol,

hydralazine, sulfas, phenothiazines, methyldopa) Fever may be absent:

antipyretic therapy, elderly patients

Common Signs/Symptoms of Infection

Respiratory Rate: Increased (sometimes….)

Heart Rate/Blood Pressure: Increased/Decreased

beware confounding factors (medications, etc.)

Lung exam: productive cough rales, rhonchi, egophony, …. On auscultation

Physical appearance: “shake & bake” – slang for shaking chills & fever dehydration

Mental status

Common Signs/Symptoms of Infection

Pain Inflammation Erythema Swelling Tenderness Purulent drainage

Antibiotics: Introduction / General Concepts

All antibiotics can be generally classified as:

Bacteriostatic Prevent organisms from reproducing

Bactericidal kills organisms

Be aware that: antibiotics may be “cidal” versus certain organisms

but “static” versus others… antibiotics may be “cidal” above a certain threshold

concentration but only “static” below it…

Antibiotics: Introduction / General Concepts

For most infections, bacteriostatic activity is sufficient

Exceptions: Immune-deficient patients, Endocarditis (heart-valve infections)

Main concern for bacteriostatic antibiotics:

Possible increased chance for development of antibiotic resistance (not a problem if bacteriocidal: dead bacteria can’t develop resistance!)

Antibiotics: Introduction / General Concepts

The majority of human bacteria will be either: Aerobic Gram-positive:

Examples: Streptococci, Staphylococci, Enterococci

Aerobic Gram-negative: Examples: Haemophilus, E. coli, Klebsiella, Pseudomonas

Anaerobes (gram-positive or gram-negative): Examples: Bacteroides, Clostridium

“Atypical” bacteria: Examples: Chlamydia, Mycoplasma, Legionella

Gram Stain of a Blood Sample

Antibiotic Resistance Resistant infections adversely affect:

Duration of illness Treatment costs Mortality Disease spread

Resistance can be: Inherent: pathogen never susceptible to the

antibiotic Acquired: was susceptible once, but

developed resistance

How to prevent antibiotic resistance

1. Prevent infection Vaccinate Get the catheter out – no more than 48hr

Catheters are #1 cause of clinic or hospital-acquired infections

2. Target the pathogen Correct drug/dose/timing/route saves lives

3. Use local data to know resistance patterns of antibiotics

UTI Sensitivity (>85% E.Coli)

(2011 data, SMRU)

UTI Sensitivity (>85% E.Coli)

(2011 data, SMRU)

UTI Summary

Most E Coli resistant to: Amoxicillin Co-trimoxazole

Most E Coli sensitive to: Nitrofurantoin Cephalosporins Quinolones

Cost of antibioticsCost of antibiotics

Drug Cost

(per tablet/vial)

Cost

(per treatment course)

Nitrofurantoin 0.5 baht per 100mg tablet

14 baht

(100mg QID for 7d)

Cephalexin 4 baht per 500mg tablet

56 baht

(500mg BID for 7d)

Ciprofloxacin 2 baht per 250mg tablet

28 baht

(500mg BID for 7d)

Ceftriaxone (IV) 90 baht per

1g vial

1260 baht

(1g OD for 14d)

Recommendations

UTI treatment guidelines should reflect antibiotic sensitivity data Amoxicillin and co-trimoxazole are not

appropriate empiric choices First line drugs to consider are

nitrofurantoin, then cephalexin, (then ciprofloxacin)

Ceftriaxone should be kept in reserve for unwell pyelonephritis and resistant infections

Streptococcus pneumoniae

(SMRU MS Hospital data)

Recommendations

Significant resistance found in Streptococcus pneumoniae isolates: Co-trimoxazole and tetracycline would not be

appropriate empiric choices for ARI Penicillin still active (enough) for ARI but not for

meningitis Is chloramphenicol still appropriate for empiric

treatment of meningitis? Erythromycin useful for uncomplicated ARI Ceftriaxone in reserve for complicated ARI

and meningitis

Classification of Antibiotics Penicillins Cephalosporins Macrolides Tetracyclines Aminoglycosides Quinolones Sulfonamides Other (Nitrofurantoin, Metronidazole,

Chloramphenicol)

Penicillins (PCNs): General Considerations

In general, PCNs are bactericidal against the pathogens that they target

No activity against atypical pathogens GI upset, diarrhea, allergic rash are most

common adverse effects Rarely can cause neutropenia

“Risk factors” of neutropenia: maximal doses and long (>4 week) treatment courses

Most PCNs need dose reductions in patients with moderate-to-severe renal dysfunction

Classification of PCNs

Natural Penicillins: PCN V, PCN G

Anti-staphylococcal (Penicillinase-resistant): Cloxacillin (use here, in BBG), dicloxacillin,

nafcillin, oxacillin Aminopenicillins:

Ampicillin, amoxicillin Antipseudomonal (Extended spectrum) PCNs:

Carbenicillin, piperacillin, ticarcillin PCN/Beta-lactamase enzyme inhibitor

combinations: Amoxicillin/clavulanate(in BBG),

ampicillin/sulbactam, piperacillin/tazobactam

Natural Penicillins

Available agents: Penicillin V: oral Penicillin G: IV Procaine PCN G: IM Benzathine PCN G: IM Procaine PCN G / Benzathine PCN G: IM

Spectrum of Activity:

NARROW… limited to: Gram-positive aerobes (Streptococci, Enterococci)

Resistance in S. pneumoniae now ~40-50% Resistance in Staphylococci >95%

Some anaerobes Treponema palladium (syphilis) POOR against Gram-negatives

Natural Penicillins (cont.)

Current Uses:

Treatment of streptococcal infections with documented susceptibility to PCN (may not be 1st line)

E.g.: pharyngitis, otitis, meningitis, upper respiratory tract infections (RTIs), endocarditis (treatment and prevention)

Treatment of syphilis

Anti-Staphylococcal PCNs

Available Agents: Cloxacillin / Dicloxacillin: po Nafcillin / Oxacillin: iv

Limited to Staphylococci, Streptococci Activity decreased vs. Streptococci compared to PCN

Resistance in Staphylococci (Methicillin-resistant S. aureus,“MRSA”):

Increasing in both community and hospital settings (>50%)

Current Uses: Cellulitis/Skin & Soft Tissue infections (SSTIs) Osteomyelitis Endocarditis

Aminopenicillins

Available Agents: Ampicillin: po/iv Amoxicillin: po In combination with beta-lactamase inhibitors:

Ampicillin/Sulbactam (Unasyn®): iv Amoxacillin/Clavulanate (Augmentin®): po

Spectrum of Activity: Amoxicillin or Ampicillin alone:

good against most Gram-positive (e.g., streptococci, enterococci) and limited Gram-negatives (Haemophilus spp., E. coli)

Ampicillin/Sulbactam or Amoxacillin/Clavulanate: Improved Gram-positive activity (Staphylococci) & Gram-negative

activity (e.g., Klebsiella, Moraxella, Proteus) Improved anaerobic activity (e.g., Bacteroides spp.)

**Sensitivity is decreasing**

Aminopenicillins (cont.)

Current Uses:

Amoxicillin/Ampicillin: RTIs, otitis, sinusitis urinary tract infections (UTIs, 3rd or 4th line tx -

resist.) endocarditis (treatment and prophylaxis)

Amoxicillin/clavulanate (also resistance): As above, but also: intra-abdominal infections,

complicated SSTI (skin & soft tissue infection)

Cephalosporins: General Considerations

Classes of Cephalosporins: 1st Generation:

E.g., cephalexin (here, BBG), cefazolin 2nd Generation:

E.g., cefuroxime, cefotetan, cefoxitin 3rd Generation:

E.g., cefixime, ceftazidime, ceftriaxone (BBG) 4th Generation:

e.g., cefepime

Bactericidal against most targeted bacterial pathogens

Cephalosporins: Important Clinical Considerations

ALL cephalosporins have NO clinically reliable activity against enterococci

MOST cephalosporins have NO reliable activity against anaerobes (2 exceptions: cefotetan, cefoxitin)

Adverse effects (have less than PCNs): GI-related Approximately 5-10% of patients with

documented penicillin hypersensitivity will also be allergic to some or all cephalosporins

Need to be sure it is a true penicillin allergy, not side effect

1st Generation Cephalosporins

Cephalexin Spectrum of Activity:

Most Gram-positives (except enterococci, MRSA) Limited Gram-negatives (e.g., E. coli, Haemophilus)

Uses: SSTIs tonsillitis/pharyngitis, UTIs (2nd line, 7-day course needed)

2nd Generation Cephalosporins

Most Common Available Agents:

Cefuroxime (Ceftin®, Zinacef®): po/iv – MTC might have in donation cabinet

Cefprozil (Cefzil®): po – MTC sometimes donated

Cefaclor (Ceclor®,): po – MTC sometimes donated

poorly tolerated and more side effects (e.g., serum sickness) than other 2nd generation cephalosporins

2nd Generation Cephalosporins

Spectrum of Activity:

Good against most Gram-positives (except enterococci, MRSA), some beta-lactamase producing Gram-negatives

e.g., Haemophilus, Moraxella, E. coli

Current Uses:

RTIs, Sinusitis, tonsillitis/pharyngitis UTIs (2nd line, 7 days tx needed), intra-abdominal infections (cefoxitin,

cefotetan)

3rd Generation Cephalosporins

Commonly-Used Available Agents – we receive rare donations

Oral: Cefpodoxime (Vantin®) Cefdinir (Omnicef®) Cefditoren (Spectracef®) Ceftibuten (Cedax®) Cefixime (Suprax®)

Intravenous: Ceftazidime (Fortaz®) Ceftriaxone (Rocephin®) – only one used here at MTC Ceftizoxime (Cefizox®) Cefotaxime (Claforan®)

3rd Generation Cephalosporins

Spectrum of Activity:

Most gram-positives (except enterococci & MRSA) More stable to gram (-) beta-lactamases than 1st & 2nd generation

cephs Most gram-negatives (except Pseudomonas and certain strains of

Enterobacter, Klebsiella, Citrobacter spp.)

Current Uses:

Orally administered: RTIs, otitis, sinusitis SSTIs, UTIs (but no better than 1st, 2nd gen. cephs, PCNs)

IV administered: As above, but also: meningitis, serious/hospital-acquired RTIs, SSTIs,

bloodstream infections, UTIs

Macrolides

Erythromycin: po/iv/topical Azithromycin (Zithromax®): po/iv – Donation list at MTC Roxithromycin: po - Donation list at MTC

Bacteriostatic against most targeted organisms may be bactericidal at higher concentrations

Spectrum of activity: Gram positives: Streptococci, Staphylococci, Enterococci (+/-), Gram negatives: Primarily typical respiratory pathogens Anaerobes: primarily oral anaerobes Atypical bacteria – especially for atypical pneumonia Helicobacter pylori Mycobacteria

Macrolides (cont.)

Current Uses: RTIs, sinusitis (esp. azithromycin, clarithromycin) SSTIs (if PCN/Ceph allergic) Treatment of H. pylori infection (ulcers) Treatment/prevention of Mycobacterial infections in HIV-

Infected patients (azithromycin, clarithromycin) STDs: Chlymydia, Syphilis treatment (in PCN-allergic

patient) Dental prophylaxis Campylobacter enteritis

GI upset, diarrhea common adverse effects

Tetracyclines

Tetracycline, Doxycycline, Minocycline (? Donation) Bacteriostatic Spectrum of activity

Gram positive: Streptococci, Staphylococci (including some MRSA), enterococci (+/-), Bacillus anthracis

Gram negative: common respiratory pathogens Oral anaerobes, Proprionobacteria (acne vulgaris), atypical

bacteria Helicobacter pylori Scrub typhus Amoebic dysentery Amoebiasis

Tetracyclines (cont.)

Current uses:

RTIs (community-acquired pneumonia) SSTIs (community-associated MRSA) Acne vulgaris STDs: Chlymydia trachomatis, Syphilis

treatment (in PCN-allergic patient) Malaria prophylaxis (doxycycline)

Tetracyclines (cont.)

Clinical Considerations:

Can cause photosensitivityphotosensitivity – increased burning from – increased burning from the sunthe sun

Do not take dairy products, antacids, or vitamin/mineral supplements within ~1-2 hours of the medication

Absorption reduced by aluminum & ferrous sulfate Can take with non-dairy food if GI upset

Doxycycline/Minocycline preferred due to daily or twice daily administration in most infections

Aminoglycosides

Gentamicin, streptomycin, amikacin

Rapidly Bactericidal - Concentration-dependent

Spectrum of Activity: Gram negatives: active against nearly all (including

Pseudomonas) Gram-positives: less active, but synergistic when combined

with beta-lactams against streptococci, staphylcocci, enterococci

Mycobacterium tuberculosis (streptomycin) NO anaerobic/atypical antibacterial activity

Aminoglycosides (cont.)

Current Uses: In combination with beta-lactams and other antibiotics against

streptococci, staphyolcocci, enterococci: E.g., Endocarditis, osteomyelitis

In combination with other gram-negative antibiotics for infections due to hospital-acquired pathogens (e.g., Acinetobacter, Pseudomonas, Enterobacter)

Combo w/ampicillin for severe pneumonia

Topical: ocular infections, otitis externa

Tuberculosis (streptomycin): 2nd/3rd line agent used in multi-drug resistant TB infections

Aminoglycosides (cont.)

Monotherapy with aminoglycosides results in rapid emergence of resistance, therefore, give in combination

Gentamicin 7mg/kg OD to everyone except patients with severe renal disease. No need to monitor peak/trough levels

Children < age 12: 4mg/kg OD

Side effects: ear and kidney toxicity Caution: old people, kidney failure (reduce dose) Interactions: avoid w/furosemide, give one in

morning & one in evening Absorption reduced by aluminum & ferrous sulfate

Nitrofurantoin: po

Spectrum of Activity (bacteriostatic): Gram-positives: Staphylococci, enterococci Gram-negatives: E. coli, Klebsiella, Proteus, Citrobacter

(UTI pathogens)

Current Use: Treatment/prevention of UTIs: **1st line therapy now in

updated Border Guidelines!! Dose: 50-100 mg QID, (child: 1/5mg/kg QID), 3-7 days

50-100mg hs for chronic recurrent Adverse effects: mild GI upset, orange-brown urine,

hemolysis if G6PD deficiency Not to be used after 38 weeks of pregnancy due to

hemolytic anemia risk

Fluoroquinolones (FQs) Ciprofloxacin: po/iv/topical Norfloxacin: po only Levofloxacin: po/iv – May have on MTC donation list

Rapidly Bactericidal Concentration-dependent

Spectrum of Activity:

Gram negatives: active against nearly all Cipro, Levo are most active FQs against Pseudomonas

Gram-positives: Streptococci, Staphylococci, Enterococci (+/-), Bacillus anthracis

Limited activity vs. MRSA Anaerobes Atypical bacteria Mycobacteria (including tuberculosis)

Fluoroquinolones (cont.)

Current Uses: RTIs, sinusitis SSTIs (but not if MRSA suspected/document) UTIs – not 1st line in Burma Border Guidelines, 2nd or 3rd

line only after Nitrofurantoin & Cephalexin! Pseudomonas infections

Use in combination if systemic infection!!! (resistance risks with monotherapy)

Bacterial gastroenteritis (Salmonella) Ocular infections / otitis externa (topical)

Fluoroquinolones (cont.)

Clinical Considerations: Need dose reductions in patients with moderate-severe

renal dysfunction Adverse effects:

May cause photosensitivity / rash Musculoskeletal: tendon rupture CNS: dizziness, headache Hypo- and/or hyperglycemia:

Especially if concurrent oral hypoglycemic agents ? in pregnancy / pediatrics – some doctors may use in both

populations Reduced absorption by aluminum & ferrous sulfate

Sulfonamides

Bactericidal/Bacteriostatic (depends on organism)

Sulfamethoxazole/Trimethoprim (Co-trimoxazole)

Spectrum of Activity: Gram-positives: Streptococci (+/-), Staphylococci

(including some MRSA), but NOT enterococci Gram-negatives: limited to respiratory pathogens

and select other organisms (e.g., E. coli, Enterobacter, Proteus)

Pneumocystis carinii (“PCP”) – in HIV/AIDS patients Poor against anaerobes and atypical bacteria

Sulfonamides (cont.)

Current uses:

RTIs, sinusitis, UTIs: Emergence of resistance currently limiting use Should not be used for pharyngitis (less effective than PCNs/Cephs)

Long-term outpatient tx of S. aureus infections (incl. MRSA, w/ confirmed susceptibility)

Pneumocystis carinii pneumonia treatment/prophylaxis in HIV-infected patients

Chloramphenicol

Spectrum of Activity (bacteriostatic): Most Gram-positives: Streptococci, Staphylococci

(including some MRSA), Enterococci (including some VRE) Gram-negatives: common respiratory pathogens Most anaerobes, most atypicals

Current Uses: Haemophilus infections (meningitis, endocarditis) in

patients intolerant of other therapies Antibiotic-resistant gram-positive infections

Clinical Considerations: Use limited by risks for severe toxicity (anemia)

Metronidazole: po/iv/topical

Bactericidal, amoebicidal, and trichomonicidal concentration-dependent

Spectrum of Activity Nearly all clinically significant

anaerobic bacteria (e.g., Bacteriodes, Clostridium)

Amoebic microorganisms Trichomonas vaginalis Helicobacter pylori

Metronidazole

Current Uses: All infections where anaerobic bacteria are present (intra-

abdominal infections, diabetic foot infections, abscesses, gynecologic infections)

STDs (Trichomonas vaginalis…oral or topical) Protozoal GI Infections (Giardia, Dysentery) H. pylori eradication (ulcers) Antibiotic-associated colitis

Adverse effects: Can cause metallic taste in mouth No alcohol within 2 weeks of use – severe reaction