Dept.

Pharmacology & Therapeutic

School of Medicine
Universitas Sumatera Utara
Haruskah diresepkan
antibiotika
untuk keadaan ini
 KENAPA ?
• Antibiotik obat yang lazim diresepkan
• Indonesia  tropis kejadian infeksi sangat
tinggi penggunaan antibiotik tinggi
• Kesalahan dalam penggunaan dan
pemberiannya.
• Pasien akan sering mengalami efek samping
yang tidak diinginkan.
Infeksi ≠ Penyakit infeksi
Mikroorganisme
infeksi

Tubuh manusia

Tidak Sakit Karier

sakit
Penyakit infeksi
 KEMOTERAPEUTIK
ANTI-INFEKSI

VIRUS BAKTERI

INFEKSI

PROTOZOA JAMUR
 Beta-lactam
tetracycline sulfonamide

amino-
macrolide INFECTION glikoside

etc. quinolone
fluoro-
quinolone

musculoskeletal pain, fever, BSR, leucocytosis

 PENGGUNAAN ANTIBIOTIK

Terapi Empiris Terapi Profilaksis

Terapi Definitif
PERTIMBANGAN PEMILIHAN
ANTIBIOTIK

Tempat infeksi
Tipe infeksi
Sumber infeksi
Keadaan klinis pasien
Faktor obat / antibiotik
Sensitivitas kuman terhadap antibiotik
 Bacteria by Site of Infection
Mouth Skin/Soft Tissue Bone and Joint
Peptococcus S. aureus S. aureus
Peptostreptococcus S. pyogenes S. epidermidis
Actinomyces S. epidermidis Streptococci
Pasteurella N. gonorrhoeae
Gram-negative rods

Abdomen Urinary Tract Upper Respiratory

E. coli, Proteus E. coli, Proteus S. pneumoniae
Klebsiella Klebsiella H. influenzae
Enterococcus Enterococcus M. catarrhalis
Bacteroides sp. Staph saprophyticus S. pyogenes

Lower Respiratory Lower Respiratory Meningitis

Community Hospital S. pneumoniae
S. pneumoniae K. pneumoniae N. meningitidis
H. influenzae P. aeruginosa H. influenza
K. pneumoniae Enterobacter sp. Group B Strep
Legionella pneumophila Serratia sp. E. coli
Mycoplasma, Chlamydia S. aureus Listeria
RATIONAL ANTIMICROBIAL THERAPY

SOP

SENSITIVITY
INFECTION CULTURE
TEST

EDUCATED
ANTIMICROBA GUESS
THERAPY

DOSAGE &
ADM.  resistance
 intolerable side effect
EVALUATION
 high cost
 Manifestation of Infection
Local Inflammation Systemic Inflammation
• initial and sometimes • fatigue,
final response • malaise,
• What is observed? • anorexia,
– wound margins • myalgia,
– exudates
• arthralgia, and
– sensations
– skin temperature
• fever
 Signs & Symptoms of Infection
• Fever
• Increased white blood cell count (WBC)
• Redness, warmth, swelling, tenderness
• Purulent drainage
menguji kepekaan bakteri patogen secara in vitro
terhadap antimikroba

UJI
KEPEKAAN

mengukur konsentrasi obat yang diperlukan untuk

menghambat perkembangan atau membunuh
organisme tersebut
 Antibiotic use
Susceptible
Antibiotic
Pathogen
Pathogen
resistant pathogen
Prevent Prevent
transmission infection

Antibiotic
resistance Infection
Optimize Effective
use diagnosis
and treatment
Antibiotic
use
 Selection of Antimicrobial Therapy:
Host Factors
 Allergies, age, pregnancy, hepatic and renal function,
concomitant drug therapy, immunocompentence,
and co-morbidities
 Site of infection
– Must cover common pathogens for specific infectious
diagnosis until culture results return
• Must consider temporal relationships
– Organisms differ with early vs late onset hospital-acquired
pneumonia
– Organisms may reflect selective pressure if antibiotics
previously administered (Antimicrobial history taking is
extremely important!)
 Selection of Antimicrobial Therapy:
Drug Factors
 Variable antibiotic tissue penetration
– Protected sites: pulmonary secretions, the central nervous system,
eye, prostate, abscess, bone
 Drug clearance: many are renally cleared
– Exceptions: the macrolides, amphotericin, caspofungin, voriconazole,
clindamycin, tetracyclines, moxifloxacin, linezolid, ceftriaxone, and
the antistaphylococcal penicillins
 Bioavailability
– Good absorption for most quinolones, linezolid, cotrimoxazole,
metronidazole, fluconazole, voriconazole, clindamycin, cephalexin,
doxycycline, minocycline
 Toxicity profile
 Cost truths:
– generic cheaper than brand name and oral/enteral cheaper than
parenteral, BUT: antimicrobial costs represent a small fraction of
infection treatment
 Drug Factors for
Selection of Antibiotic
 Pharmacokinetics
– tissue penetration
 Pharmacodynamics
 Toxicity
 Cost
Bacterial Targets for Antibiotics
 Classification of Antibiotics
• Bacteriostatic • Bactericidal
 PK/PD and Antibiotic Efficacy
 3 patterns of bacterial killing
– Concentration dependent with prolonged persistent effect
• Aminoglycosides, quinolones
• Correlated with AUC/MIC , Cmax/MIC
– Time dependent with no persistent effect
• Betalactams
• Correlated with Time above MIC (T>MIC)
– Time dependent with moderate to prolonged persistent
effect
• Macrolides, azalides, clindamycin, tetracyclines, glycopeptides,
oxazolidinones
• Correlated with AUC/MIC
 PAE

Craig, 4th ISAAR, Seoul 2003

PD parameters predictive of outcome

Parameter
correlating T>MIC AUC:MIC Cmax:MIC
with efficacy
RepresentativePenicillins Azithromycin Fluoroquinolones
Antimicrobial Cephalosporins Fluoroquinolones Aminoglycosides
Agents Carbapenems Ketolides Metronidazole
Macrolides
Organism kill Time-dependent Concentration- Concentration-
dependent dependent
Therapeutic Optimise Maximize Maximize
goal duration of concentration concentration
exposure exposure exposure
Drusano & Craig. J Chemother ;9:38–44,1997
Drusano et al. Clin Microbiol Infect 4(Suppl. 2):S27–41,1998
Vesga et al. 37th ICAAC 1997
 Pharmacodynamics of Bacterial Killing
Concentration-dependent (greater bacterial kill at higher concentrations) vs.
Concentration-independent
 6
Quinolone Serum Concentrations
and MICs for Difficult Organisms

5
Ciprofloxacin
Norfloxacin
Ofloxacin
Lomefloxacin

4
g/ml

2
S. pneumoniae MIC

P. aeruginosa MIC
1

0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hours)
 Major route of elimination
  Hepatobiliary Renal
Choloramphenicol Most beta lactams
Doxycycline Aminoglycoside
Moxifloxacin TMP-SMX
Macrolides Carbapenems
Nafcilin Polymyxin
INH Tetracycline
PRZ Vancomycin
Rifampin Most quinolones
Clindamycin Nitrofurantoin
Metronidazole
 Dosing Adjustments in Renal Disease?

• Yes • No
– Almost all cephalosporins and – Doxycycline
most other beta-lactams – Erythromycin, azithromycin
(penicillins, aztreonam, – Linezolid
carbapenems)
– Most quinolones – Clindamycin
– Vancomycin – Metronidazole
– Cotrimethoxazole – Oxacillin, nafcillin,
dicloxacillin
– Daptomycin – Ceftriaxone
– Fluconazole – Caspofungin
– Voriconazole PO
• Avoid use altogether – Amphotericin b
– Tetracycline
– Nitrofurantoin (CrCl <40)
– Voriconazole IV (CrCl<50)
– Aminoglycosides (if possible)
 Adverse Reactions to Antimicrobial
Agents
• There are three general types of adverse
reactions to antimicrobial agents:
• hypersensitivity reactions (which are not
dose related),
• direct drug toxicity (which usually is dose
related and manifests in a single organ or,
occasionally, in several organs), and
• microbial superinfection.
 direct drug toxicity
• to the kidney are aminoglycosides, polymyxins, and amphotericin B;
azotemia and renal tubular damage may be caused by any of these drugs.
• Penicillins, cephalosporins, tetracyclines, and rifampin can cause
hemolytic anemia, thrombocytopenia, and leukopenia that involve an
immune mechanism, but these reactions are uncommon. Neutropenia
can occur during therapy with penicillins, cephalosporins, or vancomycin.
• Macrolides and trimethoprim-sulfamethoxazole have been associated
with agranulocytosis.
• Trimethoprim can produce anemia, leukopenia, and thrombocytopenia
from folate deficiency; the effect is reversible with folinic acid.
• Amphotericin B commonly produces a reversible normocytic
normochromic anemia, probably secondary to injury to the red cell
membrane.
• Flucytosine causes bone marrow suppression (leukopenia or
pancytopenia) when its excretion is reduced by renal failure.
• Linezolid can also produce myelosuppression; although experience is
limited, bone marrow function usually recovers when the drug is
discontinued.
Duration of Antibiotic Therapy
Resolution of clinical parameters – 27 VAP pts
Mean log CFU/mL White blood cell count x 103/µL
7 17
6 16
5 15
4 14
3 13
2 12
1 11
0 10
-1 9
0 3 6 9 12 15 0 2 4 6 8 10 12 14 16
Antibiotic day Antibiotic day
Dennesen et al. Am J Crit Care Med 2001;163:1371–1375
Duration of Antibiotic Therapy
Resolution of clinical parameters – 27 VAP pts
Highest temperature (°C) PaO2:FiO2 ratio (KPa)
40 50

45

39 40

35

38 30

25

37 20
0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16
Antibiotic day Antibiotic day
Dennesen et al. Am J Crit Care Med 2001;163:1371–1375
Kapankah penggunaan ANTIBIOTIK
dikatakan berhasil?
setelah tiga hari terutama dilakukan
pemberian obat berdasarkan tampilan klinis

EVALUASI

parameter laboratoris : hitung menilai

leukosit, pemeriksaan kultur dan kegagalan
resistensi terapi
 Successful treatment outcomes
• Temperature returns to normal
• Symptoms improve
• Signs of infection resolve
• White blood cell counts normalize
• Cultures become negative
 Administration
• Schedule at regular intervals to maintain
steady blood levels
• Assess allergies prior to administration
• Monitor for adverse and therapeutic effects
• Drug interactions
• Importance of completing full course
• IV therapy changing to oral
• Patient education
Antibiotic Cyt.P-450 Related Interactions
Inhibits Cyt.P-450:
Anticoagulants oral -- hypoprothromb.>
• Erythromycins Carbamazepine toxicity -- >
Cisapride --Ventric. Arrhytmia
• Fluconazole Digoxin bl.levels -- >>

• Itraconazole Dilantin bl.levels -- <

Terfenadine -- Ventric. Arrhytmia
• Ketoconazole Theophylline bl.levels -- >
Valproate bl.levels -- >

Induces Cyt. P-450: Anticoagulants -- hypothrombinaeia <

• Rifampicin Chloramphenicol levels -- <

Contraceptives levels -- <
Corticoster. levels -- <
Cyclosporine levels -- <
 Failure of Antimicrobial Therapy

• Caused by drug selection

• Caused by host factors
• Caused by microorganisms
 Mengganti ANTIBIOTIK?
tidak adanya indikasi tidak ada indikasi untuk
lanjutan diberikannya konsentrasi antibiotik di
antibiotik intravena jaringan

Kriteria Klinis
ALIH TERAPI
tidak ada gangguan ANTIBIOTIK bebas demam
pada saluran cerna kurang lebih 2 hari

adanya perubahan leukosit, hitung

jenis dan protein fase akut ke arah
normal
 Permasalahan:
Profesi dan Pemerintah

• Dokter cari mudah

’hajar’ saja dengan antibiotika

cari ”aman”
penyakit seakan-akan sembuh,
dokter seakan-akan pintar/ahli.
cari untung
faktor pemasaran lebih penting
daripada ilmiah-rasional & pasien.

• Apotek menutup sebelah mata

• Pemerintah tidak peduli / tidak ahli / tidak tahu?
 Problems with Antibiotics
• Antibiotics needed are not available in the
market
• Inappropriate management
• Increasing resistance
• Side Effects: anaphylaxis, rashes and other
allergic phenomenon, C. difficile colitis, GI
upset and diarrhea
• Drug interactions
• Return visits for “something stronger”
 Pertimbangan Penggunaan
ANTIBIOTIK Kombinasi
 Terapi spektrum luas pada pasien-pasien
sakit parah
 Mengobati infeksi polimikroba
 Mengurangi munculnya strain resisten
 Mengurangi toksisitas terkait dosis
 Mendapatkan peningkatan penghambatan
atau pembunuhan bakteri
 KOMBINASI ANTIBIOTIKA
SINERGIS
• Penisilin (amoksisilin) + aminoglikosida (gentamisin)
• Amoksisilin + asam klavulanat
• Sulfametoksazol + trimethoprim
• Kloramfenikol + trisulfa
ANTAGONIS
• Penisilin (bakterisid) + tetrasiklin (bakteriostatik)
• Penisilin + aminoglikosida
[dalam satu wadah/spuit]
 drug interaction
Synergism
Penicillins Aminoglycosides
Cephalosporins Colistine
Synergism Synergism

Fosfomicin
Antagonism Synergism Additive

Macrolides
Tetracyclines
Chloramphenicols
 KOMBINASI ANTIBIOTIKA
Efek yang
Antimikroba Obat lain
tak diinginkan
Tetrasiklin Kalsium Absorpsi tetrasiklin
ber(-)
Gentamisin OAINS Efek samping
gentamisin ber(+)
Penisilin Probenesid Efek penisilin ber(+)

Sulfonamida NaHCO3 Kejadian kristaluria

ber(-)
 KESIMPULAN
ANTIMIKROBA bukan ANTIPIRETIKA
ANTI-TUSIVA
ANTI-DIARE
ANTI-ANXIETY
ANTIMIKROBA hanya diberikan bila terbukti atau disangka
kuat ada proses INFEKSI (kuman, jamur, virus, protozoa)

ANTIMIKROBA TUNGGAL lebih baik daripada

ANTIMIKROBA KOMBINASI
Waspada terhadap interaksi ANTIMIKROBA dengan
OBAT LAIN
 More info
for pharmacology of chemotherapy
and antibiotics
Principles of antimicrobial treatment
„when to give?” “how much to give?”
correct indication the satisfactory dose
„what to give?” is the multiple amount of MIC at
the most suitable the locus of infection!
1. the most effective one Dosage : age, liver and kidney
2. the less toxic one functions, BW, height,
pregnancy
3. (the cheapest)
„how long to give?”
Ad 1. effective as long as there is no danger of
 antimicrobial activity relapse
- spectrum = against which species is it acute infection: min. 5 days
effective?
- numerically expressed: MIC, MBC severe infection: 8-14 days
  the sensitivity of a bacterium can be sepsis/endocarditis: 3-4-6
detected in vitro weeks, tbc: 9-12 months
 pharmacokinetic features
 resistance
 Antimicrobial Drugs
Antibiotic: Substance produced by a microorganism
that in small amounts inhibits the growth of another
microbe.
Antibiotic producing microbes include:
 Gram-Positive Rods:
 Bacillus subtilis: Bacitracin
 Bacillus polymyxa: Polymyxin
 Fungi
 Penicillium notatum: Penicillin
 Cephalosporium spp.: Cephalothin
 Actinomycetes:
 Streptomyces venezuelae: Chloramphenicol
 Streptomyces griseus: Streptomycin
 Streptomyces nodosus: Amphotericin B
 Micromonospora purpurea: Gentamycin
 Antimicrobial Drugs
• Antibacterials: Relatively easy to develop and find with low toxicity
because prokaryotic cells are very different from host cells.
• Antihelminthic, antiprotozoan, and antifungal drugs: More difficult
to develop because eukaryotic cells resemble human cells.
• Antivirals: Most difficult to develop because virus reproduces using
host cell enzymes and machinery.
 Spectrum of Antimicrobial Activity
 Broad Spectrum: Effective against many different types of
bacteria (e.g.: both gram positive and negative). Examples:
Tetracycline
 Narrow Spectrum Antibiotics: Effective against a subset of
bacteria (either gram positive and negative).
 Examples: Penicillin, Isoniazid (Mycobacteria only}
Antimicrobial Mechanisms of Action
 Inhibition of Cell Wall Synthesis: Interfere with peptidoglycan synthesis.
 Result in cell lysis.
 Low toxicity.
 E.g.: Penicillin and vancomycin.
 Inhibition of Protein Synthesis: Interfere with prokaryotic (70S) ribosomes, also found in
mitochondria.
 Most have broad spectrum of activity
 Tetracycline, chloramphenicol, erythromycin, and streptomycin .
 Injury to the Plasma Membrane: Cause changes in membrane permeability.
 Result in loss of metabolites and/or cell lysis.
 Many polypeptide antibiotics.
 E.g.: Polymyxin B (antibacterial) or miconazole (antifungal).
 Inhibition of Nucleic Acid (DNA/RNA) Synthesis: Interfere with DNA
replication and transcription.
 May be toxic to human cells.
 E.g.: Rifampin and quinolones. .
 Inhibition of Synthesis of Essential Metabolites: Involve competitive inhibition
of key enzymes.
 Closely resemble substrate of enzyme.
 E.g.: Sulfa drugs inhibit the synthesis of folic acid .
Safety Concerns with the Use
of Antimicrobials
 Toxicity
 Kidney damage
 Liver damage
 Interactions with other medications
 May neutralize effectiveness of contraceptive pills
 Hypersensitivity reactions
 Anaphylactic reactions to penicillin
 Fetal damage/risk to pregnant women
 Tetracycline causes discoloration of teeth in children
and may cause liver damage in pregnant women
 Fluoroquinolones may cause cartilage damage.
 Antibiotic Resistance
 General Outline for Antibiotics
• Chemistry –MIP
• Effect on microbes - MIP
– Spectrum of coverage
– Mechanism(s) of action
– Mechanism(s) of resistance
• Pharmacology of antibiotic class – mostly new info
– Absorbance
– Fate after absorption
– Excretion
• Pharmacology of select agents – mostly new info
• Therapeutic uses – somewhat new info
• Toxicity/contraindications – mostly new info
– Common (> 10%)
– Uncommon (1-9%)
– Rare (< 1%)
 Sulfonamides
• Analogues of para-aminobenzoic acid
• Broad spectrum
• Competitive inhibitors of dihydropteroate
synthase – needed for folic acid synthesis
• Cidal in urine
• Mechanisms of resistance
– Altered affinity of enzyme for drug
– Decreased permeability or active efflux
– New pathway of folic acid synthesis
2.2 Mechanism of action
Sulfonamides are structural
analogs of para-aminobenzoic
acid (PABA) and act as
competitive inhibitors of
dihydropteroate synthase and
prevent the synthesis of bacterial
folic acid.
Trimethoprim (TPM) prevents the
reduction of dihydrofolate to
tetrahydrofolate by inhibiting
dihydrofolate reductase.
 Sulfonamides
• Mostly absorbed from GI tract
• Binds variably to serum albumin
• Wide tissue distribution, including
transplacentally
• Variably inactivated in liver by acetylation
and then excreted in urine
• Some agents can precipitate in acid urine
 Absorption of Sulfonamides
Rapidly
• Sulfisoxazole,
sulfamethoxazole,
sulfadiazine
• Bind extensively to plasma
proteins
• Highly concentrated in urine
(cidal)
• Sulfamethoxazole combined
with trimethoprim (Bactrim) is
widely used to treat a variety
of infections (esp. UTI)
Poorly
• Sulfasalazine
• Poorly absorbed in GI
tract
• Used to treat ulcerative
colitis and irritable bowel
syndrome
• Gut flora metabolize drug
into 2 compounds, 1
toxic, 1 therapeutic (5-
aminosalicylate)
 Sulfonamides for Topical Use
• Sulfacetamide
– Good penetration in eye
– Non-irritating
• Silver sulfadiazine
– Prevention and treatment of burn wound
infections
 Long Acting Sulfonamide
• Sulfadoxine
• Serum half-life is measured in days rather than
minutes or hours
• Combined with pyirethamine to treat malaria
 Toxicity/Contraindications
of Sulfonamides
• Crystallization in acid urine
– Common to uncommon depending on drug
– Alkalize urine or increase hydration
• Acute hemolytic anemia
– Rare to extremely rare
– Associated with glucose-6-phosphate dehydrogenase
activity in RBC
• Agranulocytosis (extremely rare)
• Aplastic anemia (extremely rare)
• Hypersensitivity reactions (common to uncommon)
– Skin and mucous membrane manifestations (rashes)
– Serum sickness
– Focal or diffuse necrosis of the liver (rare)
 The Quinolones
• Naladixic acid was a byproduct of chloroquine
synthesis
• Current drugs are fluoridated 4-quinolones
• Broad coverage (some broader than others)
• Targets DNA gyrase (G-) and topoisomerase IV
(G+)
• Resistance due to efflux and mutations in
targets
Pharmacological properties of different quinolones

Gram-negative bacteria that cause urinary tract

First generation infections, their intrinsic activity is limited.
nalidixic acid

Second generation Broad spectrum and more potent.

norfloxacin
ciprofloxacin
ofloxacin

Broader spectrum, especially gram-positive bacteria and

Third generation anaerobic microorganisms. More potent.
Other: Chlamydia, Mycoplasma, Legionella,
sparfloxacin
Mycobacterium.
 PK Quinolones
• Favorable pharmacological attributes
– Orally administered, quickly absorbed,
even with a full stomach
– Excellent bioavailability in a wide range of
tissues and body fluids (including inside
cells)
• Mostly cleared by the kidneys
– Exceptions are pefloxacin and
moxifloxacin which are metabolized by
liver
• Ciprofloxacin, ofloxacin, and “Got Cipro?”
pefloxacin are excreted in breast milk
 Flouroquinolones
• Spectrum: Broad coverage. Effective vs. gram +,
gram -, atypicals, and Pseudomonas.
– Respiratory quinolones (levofloxacin): active vs. GAS, S.
pneumo (including penicillin-resistant forms), S. aureus
(including MRSA), H. influ., and M. catarrhalis (including
penicillin-resistant strains).
– Antipseudomonas quinolones (ciprofloxacin): effective vs.
Pseudomonas and gram-negative bacteria.
– New floxins (Gati, Moxi, Gemi): similar to respiratory
quinolones but less activity vs. Pseudomonas and addition
of anerobic activity
 Therapeutic Uses of Quinolones
• ENT infections
• Urinary tract infections
• GI and abdominal infections
– Travelers diarrhea, Shigellosis
– Typhoid fever
• Respiratory tract
– All work well against atypicals
– New agents for strep. Pneumonia
• Bone, joint, soft tissue
• Ciprofloxacin for anthrax and tuleremia
• Combined with other drugs, useful for atypical
Mycobacterium sp. or for prophylaxis in neutropenic patients
 Toxicity/Contraindications
of Quinolones
• Nausea, vomiting, abdominal discomfort (common)
• Diarrhea and antibiotic-associated colitis (uncommon
to rare)
• CNS side effects
– Mild headache and dizziness (common to rare)
– Hallucinations, delirium, and seizures (rare)
• Arthropy in immature animals (common)
– Quinolones not given to children unless benefits outweigh
the risks
• Leukopenia, eosinophila, heart arythmias (rare)
– Sparfloxacin prolongs QT interval.
The Beta-Lactams
 Penicillins
• Penicillium notatum produces
the only naturally occuring
agent – penicillin G or
benzylpenicillin
• Dosage and potency based on
IU (1 IU = 0.6 micrograms pure
penicillin G)
• P. chrysogenum produces 6-
aminopenicillanic acid, raw
material for semi-synthetics
• Dosage and potency based on
weight
 Penicillins
• Spectrum of activity based on R groups added to 6-
aminopenicillanic acid core
• All are bactericidal and inhibit transpeptidases
• Mechanisms of resistance
– Alter affinity of transpeptidase
– Enzymatically cleave the beta-lactam ring
– Efflux pumps
– Poor penetration into cell
 Penicillins
• Administered orally, intramuscularly, or
intravenously depending on agent
• After oral dose, widely distributed in tissues and
secretions (except CNS, prostatic fluid, and the eye)
• Do not kill intracellular pathogens
• Food interferes with adsorption
• Rapid elimination through kidney, secreted in
breast milk
 Penicillins G and V
• Effective against aerobic G+ organisms except Staphylococcus, Pen G
active against Neisseria and anaerobes
• 2/3 of oral Pen G destroyed by stomach acid, Pen V is more resistant so
more is delivered to serum
• Rapid elimination through kidney so probenecid, procaine, of
benzathine added to slow excretion
• Most drug is bound to serum albumin but significant amounts show up
in liver, bile, kidney, semen, joint fluid, lymph, etc.
• Cautious use in neonates and infants because renal function is not fully
established
• Patients with renal failure clear the drugs through liver although at a
slow pace
 Isoxazolyl Penicillins
• Oxacillin, cloxacillin, dicloxacillin, nafcillin
• Designed to resist staphylococcal beta-lactamases
• Like Pen V, stable in stomach acid but usually given
parentally for serious staph infections
• MRSA not covered
• Absorption and fate of drugs after absorption, excretion
similar to Pen G and Pen V
 Aminopenicillins
• Ampicillin and amoxicillin
• Broad spectrum
– Not effective against beta-lactamase producers
– Beta-lactamase inhibitors extend spectrum
• Both are acid resistant but amoxicillin is better
aobsorbed, even with food
• Don’t bind plasma proteins as much as
predecessors
• Secreted through the kidney
 A Carboxypenicillin and
a Ureidopenicillin
• Ticarcillin and piperacillin
• Ticarcillin is anti-
Pseudomonas drug
• Piperacillin + tazobactam
has the broadest spectrum
• Give parentally
• Used for serious infections
 Toxicity/Contraindications
of Penicillins
• Hypersensitivity reactions (uncommon)
– Rash, fever, bronchospasm, vasculitis, serum sickness,
exfoliative dermatitis, SJS, anaphylaxis
– Drugs act as haptens when bound to serum proteins
– Rashes will disappear when drug is withdrawn or can
treat with antihistamines
– For patients with allergies, switch to a different class of
antibiotics or try to desensitize
 Toxicity/Contraindications
of Penicillins
• Pain and sterile inflammatory reaction at injection
site
• Large doses given to patients with renal failure can
cause lethargy, confusion twitching and seizures
• Sudden release of procaine can cause dizziness,
tinnitus, headache and hallucinations
• Pseudomembranous colitis
Cephalosporins
• Base molecule is 7-
aminocephalosporanic acid
produced by a Sardinian sewer
mold
• R groups determine spectrum
of activity and
pharmacological properties
• Mechanism of
action/resistance and class
pharmacology essentially the
same as penicillins
 First Generation
Cephalosporins
• Cefazolin, cephalexin, cephadroxil
• Excellent against susceptible staph and strep
• Modest activity against G-
• Cefazolin given parentally, others orally
• More than half of the drug is bound to plasma
proteins
• Excreted by kidneys unmetabolized
• Good for staph and strep skin and soft tissue
infections
 Second Generation
Cephalosporins
• Cefaclor, cefuroxime, cefprozil
• Modest activity against G+, increased activity
against G-, works against anaerobes
• Cefaclor and cefprozil given orally
• Absorption and excretion same as first gen.
• Good for treating respiratory tract infections, intra-
abdominal infections, pelvic inflammatory disease,
diabetic foot ulcers
 Third Generation
Cephalosporins
• Ceftaxime, ceftriaxzone, cefoperazone, cefpodoxime
• Broad spectrum killers
• Drugs of choice for serious infections
• No effect against Listeria and beta-lactamase producing
pneumococci
• Cefpodoxime given orally, others parentally
• Most excreted by kidney
• Therapeutic uses
– Bacterial meningitis (2 exceptions)
– Lyme disease
– Life-threatening G- sepsis
 Fourth Generation
Cephalosporin
– Cefepime
– Same antimicrobial spectrum as third
generation but resists more beta-
lactamases
– Given parentally, excellent penetration
into CSF
– Good for nosocomial infections
 Toxicity/Contraindications
of Cephalosporins
• Hypersensitivity reactions (uncommon)
essentially same as for penicillins
• Cross-reaction between 2 classes
 Carbapenems
• Beta-lactam ring is fused to a 5
member ring system
• Effect on microbes and
pharmacology of carbapenems
similar to penicillins
 Select Carbapenems
• Imipenem
– Broad spectrum including anaerobes and Pseudomonas
aeruginosa
– Parentally administered
– Must be combined with cilastatin to be absorbed
– Excreted by kidneys
• Meropenem, ertapenem, and doripenem are similar
to imipenem but don’t need co-administration with
cilastatin
 Aztrenam – a monobactam
• Works only on G-, including Pseudomonas
aeruginosa
• Useful for treating G- infections that require a
beta-lactam because it does not elicit
hypersensitivity reactions
 Toxicity/Contraindications
of Carbapenems
• Nausea and vomiting (common)
• Hypersensitivity reactions (uncommon)
– Essentially the same as for penicillins, exception is
the monobactam
– Cross-reactivity is possible, exception is the
monobactam
 Macrolides
• Produced by Streptomyces erythreus (erythromycin
is natural product)
• Mechanism: bind to 50s subunit of bacterial
ribosomes and block protein synthesis
• Resistance: target site alteration, antibiotic
alteration, altered transfer
• Distribution: good penetration into oropharyngeal
secretions.
 Macrolides
• Spectrum: effective against atypicals (Chlamydia,
Mycoplasma), Staph.(MRSA is resistant), Strep.,
Bordetella pertussis, H. influ, M. catarrhalis.
• ENT indications: Failed treatment of GAS in pharyngitis,
resistant S. pneumo, H. influ., and M. catarrhalis in
AOM (Bactrim/ Clarithromycin/ Azythromycin), Sinusitis
(Clarithromycin equal to Augmentin, Azythromycin
500mg qDx3d =Augmentin x10 days)
• Toxicity: generally considered safe—side effects are
rare. Ototoxicity (dose-dependant, peak)
• Eg. : Erythromycin, Azythromycin
 Clindamycin
• Derived from Streptomyces lincolnensis
• Mechanism: Inhibits protein synthesis by binding to
the 50s ribosome.
• Distribution: Poor CSF penetration, but excellent
bone, oropharyngeal secretion levels.
• Spectrum: gram +, anaerobes. No activity against
gram -.
• Resistance is mediated via decreased membrane
permeability and alteration of 50s binding site.
• Toxicity: nausea/vomiting, C. difficile colitis
 Vancomycin
• Glucopeptide produced by Streptomyces orientalis
• Mechanism: bacteriocidal via inhibition of cell wall
replication
• PO dosing has no systemic uptake
• Spectrum: gram +, MRSA. Vanc + Gent shows
synergy against mixed infections.
• Toxicity: red man syndrome, phlebitis
• ENT uses: MRSA, severe infections with resistant
gram + organisms
 Metronidazole

• Bacteriocidal via production of DNA toxic substances

within the cell
• Distribution: nearly all tissues, including CSF, saliva,
bone, abscesses.
• IV=PO
• Spectrum: active vs. anaerobes, parasites
• ENT uses: C. difficile, anaerobic infections
(abscesses)
• Toxicity: disulfram reaction, others are rare
 Aminoglycosides
• Produced by Streptomyces and Micromonospora
• Mechanism
– Bind to ribosomes and interfere with protein synthesis
– Bacteriocidal
• Clinical pharmacology
– PO poor absorption; IM or IV best
– Distribution: hydrophillic, poor CSF, cross placenta
• Metabolism
– Excreted unchanged, special dosing for renal failure
 Aminoglycosides
• Spectrum
– Gram-negative bacilli, P. aeruginosa (use with anti-
pseudomonas penicillins)
• Resistance
– Antibiotic modifying agents cause antibiotics to be unable
to bind to the ribosome
• Toxicity
– Nephrotoxic (trough)
– Ototoxic (concentrated in perilymph, corresponds with
prolonged therapy and peak levels)
– Neuromuscular blockade (think of this in Myasthenia
Gravis)
 Drug Resistance
• Resistance to antibiotics:
– inappropriate prescription
– microbial evolution pressures
– social pressures
– poor compliance
• A grim future
• Delta, Utah – a new hope?