Abx lecture 6.11

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:
 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 > 98.60
F (370
C)):
 circadian fluctuations
 influence of route of evaluation
 rectal/axillary temp. ~1.0 0
F (0.60
C) 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

 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

 Pain
 Inflammation
 Erythema
 Swelling
 Tenderness
 Purulent drainage

Antibiotics:
 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:
 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:
 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

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
1. Target the pathogen
 Correct drug/dose/timing/route saves lives
1. Use local data to know resistance
patterns of antibiotics

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


Aminopenicillins
 Available Agents:
 Ampicillin: po/iv
 Amoxicillin: po
 In combination with beta-lactamase inhibitors:

Ampicillin/Sulbactam (Unasyn®
): iv

Amoxacillin/Clavulanate (Augmentin®
): po
 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
 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
 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
 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
 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 the sun– increased burning from the 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
 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
 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.)
 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)
 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
 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

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

Abx lecture 6.11

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