Antibiotics

Training Manual
Microbiology, Infections, and Antibiotic Therapy

Microbiology
 Shapes of Bacteria

 Coccus
 Chain = Streptoccus
 Cluster = Staphylococcus
 Bacillus
 Chain = Streptobacillus
 Coccobacillus
 Vibrio = curved
 Spirochete
 Bacterial Structures

 Flagella
 Capsule
 Plasma Membrane
 Cytoplasm
 Cell Wall
 Lipopolysaccharides
 Teichoic Acids
 Inclusions
 Spores
 Cytoplasm

 80% Water {20% Salts-Proteins)

 DNA is circular,
 More efficient; grows quicker
 Mutations allow adaptation to environment quicker
 Plasmids; extra circular DNA
 Antibiotic Resistance
 No organelles (Mitochondria, Golgi, etc.)
 Cell Wall

 Peptido-glycan Polymer (amino acids + sugars)

 Unique to bacteria
 Sugars;
 N- acetylglucosamine
 N- acetylmuramic acid
MEMBRANE STRUCTURE

Gm+ve

Gm-ve
 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 Bacilli

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
 Bacterial Growth
 Binary Fission = Exponential Growth
 Four Phases of Growth
Microbiology, Infections, and Antibiotic Therapy

Infections
Respiratory Tract Infections
(R.T.I.s)
Tonsillopharyngitis
 Definitions
 tonsillitis: inflammation of pharyngeal tonsils
 tonsillopharyngitis: inflammation extending from
tonsils to the adenoids and lingual tonsils
 recurrent tonsillitis: 7 episodes in 1 year, 5 infections
in 2 consecutive years, or 3 infections each year for 3
years consecutively chronic tonsillitis: chronic sore
throat, halitosis, tonsillitis, and persistent tender
cervical nodes for greater than 4 weeks
 quinsy: Greek term used for inflammation of throat
and tonsils, historically used for peritonsillar abscess
 Epidemiology
 most cases occur in school-age children
 uncommon in the first 2 years of life
 5-7 URIs per child per year
 GAS (Group A-Betahymolytic Streptococci) is found in
35% of children with pharyngitis
 Causes of Tonsillopharyngitis
• Beta hemolytic streptococcal infection — 22 %
• Mycoplasma pneumoniae — 9.4 %
• Chlamydia species strain — 8.4 %
• Viruses — 25.5 %
Huovinen, et al 1995
 Why antibiotics
 Treatment of GABHS pharyngitis is important
 To prevent complications of infection,

 particularly
rheumatic fever
 suppurative complications
 To speed recovery
 To prevent spread of the infection
 Recommendations on the Management of
Acute and Chronic Tonsillitis

 Adequate supportive care

 Use of analgesics, oral anesthetics, and antiseptics
 Antibiotics
1-in the AHA (American Heart Association) guidelines,
prevention of rheumatic fever as a poststreptococcal
complication depends on eradication of GABHS bacteria
from the pharynx
2-prevention of rheumatic fever and other nonsuppurative
complications of GABHS pharyngitis still occurs when
antibacterial therapy is postponed by as many as 9 days
after the onset of pharyngitis symptoms
 Factors influencing antibiotic choice

 ability to eradicate GABHS bacteria from the pharynx

 Ability to resolve signs and symptoms of the infection
(bacteriologic and clinical efficacy)
 adherence (frequency of daily administration,
duration of therapy, and palatability),
 Antibacterial spectrum (narrow versus broad activity),
 potential treatment-related side effects
 cost.
Acute Bacterial Sinusitis
(ABS)
Anatomy of Paranasal Sinuses
 Where are the sinuses?

 Four pairs of paranasal sinuses

 Frontal-above eyes in forehead bone
 Maxillary-in cheekbones, under eyes
 Ethmoid-between eyes and nose
 Sphenoid-in center of skull, behind nose and
eyes
 What are the sinuses?

 The sinuses are hollow air-filled sacs lined by mucous membrane. The
ethmoid and maxillary sinuses are present at birth. The frontal sinus
develops during the 2nd year and the sphenoid sinus develops during
the 3rd year.
 Sinuses have small orifices (ostia) which open into recesses (meati) of
the nasal cavities.
 Meati are covered by turbinates (conchae).
 Turbinates consist of bony shelves surrounded by erectile soft tissue.
 There are 3 turbinates and 3 meati in each nasal cavity (superior,
middle, and inferior).
 The funtion of sinuses is to reduce the weight of the skull and adjust
temperature of the air
 Sinusitis
 Inflammation of paranasal sinuses
 Predisposing Factors

 Allergies, nasal deformities, cystic fibrosis, nasal

polyps, and HIV infection.
 Cold weather
 High pollen counts
 Day care attendance
 Smoking in the home
 Reinfection from siblings
 Acute or Chronic Sinusitis?

 Acute Sinusitis – respiratory symptoms last longer than 10

days but less than 30 days.
 Subacute sinusitis – respiratory symptoms persist longer
than 30 days without improvement.
 Chronic sinusitis – respiratory symptoms last longer than
120 days.
 Etiology of Sinusitis

70% of bacterial sinusitis is caused by:

 Streptococcus pneumoniae 30%
 Haemophilus influenzae 20%
 Moraxella catarrhalis 20%
Other causative organisms are:
 Staphylococcus aureus
 Streptococcus pyogenes,
 Gram-negative bacilli
 Respiratory viruses
 Subjective Symptoms of Sinusitis

 History of URI or allergic rhinitis

 History of pressure change
 Pressure, pain, or tenderness over sinuses
 Increased pain in the morning, subsiding in the afternoon
 Malaise
 Low-grade temperature
 Persistent nasal discharge, often purulent
 Postnasal drip
 Cough, worsens at night
 Mouthing breathing, snoring
 History of previous episodes of sinusitis
 Sore throat, bad breath
 Headache
 Pharmacological Plan of Care

 Codeine – for severe pain

 Corticosteroid or Nasal decongestant spray – 2 sprays
in each nostril every 12 hours for children over 6 years
of age.
 Antimicrobials-treat for 10-14 days, depending upon
severity
 OTC Medications

 Acetaminophen or ibuprofen to relieve pain

 Decongestants
 Antihistamines
 Nasal saline
 Non-pharmacological treatment

 Humidifier to relieve the drying of mucous membrances

associated with mouth breathing
 Increase oral fluid intake
 Saline irrigation of the nostrils
 Moist heat over affected sinus
 Prolonged shower to help promote drainage
 Patient Education

 Patient should not dive.

 Patient should not travel by airplane.
 Urge parent to eliminate triggers in the
home (dust, smoking)
 Have all members of the family treated, if
indicated.
Otitis Media
Ear Anatomy
 OTITIS MEDIA
 Definition: Presence of a middle ear infection
 Acute Otitis Media: occurrence of bacterial infection within
the middle ear cavity.
 Otitis Media with Effusion: presence of nonpurulent fluid
within the middle ear cavity
 OM is the second most common clinical problem in
childhood after upper respiratory infection.
 EPIDEMIOLOGY
 Peak incidence in the first two years of life (esp. 6-12
months)
 Boys are more affected than girls
 50% of children 1 yr of age will have at least 1 episode.
 1/3 of children will have 3 or more infections by age 3
 90% of children will have at least one infection by age 6.
 Occurs more frequently in the winter months
 MICROBES AT FAULT!!!
 Streptococcus pneumoniae
 Haemophilus influenzae(non-typeable)
 Moraxella catarrhalis
 Group A Streptococcus
 Staph aureus
 Pseudomonas aeruginosa
 Classification of Otitis Media

 Acute Otitis Media: presents with fever, otalgia, and

hearing loss
 Otitis Media with Effusion: evidence of middle ear
effusion on pneumatic otoscopy
 Recurrent Otitis Media: inability to clear middle ear
effusions
 Chronic Serous Otitis Media: presents as ‘fullness in the
ear’, tinnitus, or another acute disease.
 SIGNS & SYMPTOMS

 Neonates/Infants: change in behavior, irritability, tugging

at ears, decreased appetite, vomiting.
 Children(2-4): otalgia, fever, noises in ears, cannot hear
properly, changes in personality
 Children (>4): complain of ear pain, changes in
personality
 TREATMENT

 Antibiotic
 Symptomatic treatment
Bronchitis
 Acute exacerbations of chronic
bronchitis (A.E.C.B)

 Chronic bronchitis: cough and sputum production most

days for >3 months in two consecutive years.
 AECB - Some combination of worsening dyspnea,
increased sputum volume, and/or increase in sputum
purulence
 Etiology: Nontypable H. influenzae 50-60%, M. catarrhalis
15-20%, S. pneumoniae 15-20%, Atypicals 5-10%.
 Most cases of CB are due to tobacco use (85-90%); also
environmental pollutants, genetic factors
 12 million cases of chronic bronchitis (CB) per year in the
U.S. - Most common category of chronic obstructive
pulmonary disease (COPtent to which specific bacterial
pathogens explain exacerbations is controversial.
Pneumonia
 Pneumonia
 6th leading cause of death in U.S.A.
 In USA,About 3 million cases per year; >
500,000 hospital admissions
 About 50% of cases and the majority of
deaths are due to bacteria
 Precise diagnosis is usually desirable but
difficult to obtain
Pneumonia

 Streptococcus pneumoniae the most

common cause of community-acquired
pneumonia requiring hospitalization
 Haemophilus influenzae and Moraxella
catarrhalis are increasing in frequency
 Legionella species and Chlamydia
pneumoniae have emerged
 Pneumocystis carinii (HIV disease)
 Pneumonia: pathophysiology

 Hypoxemia due to ventilation/perfusion mismatching

 Hyperdynamic circulation with increased cardiac output
 “Toxic cardiomyopathy”
 Increased oxygen demands
 Decreased lung compliance; increased work of breathing
 “Typical” versus “atypical” pneumonia

 “Typical” (virulent bacteria): abrupt onset; productive

cough with purulent sputum; pleuritic chest pain;
impressive physical findings; leukocytosis or
leukopenia
 “Atypical” (viral, Mycoplasma pneumoniae, others):
gradual onset, nonproductive cough; substernal chest
pain; unimpressive physical exam; white blood count
normal
Urinary Tract Infections
 Overview of UTI

 7 million office visits yearly

 1 million hospitalizations
 About 2/3rds of patients are women; 40% to 50% of
women have UTI at some point during their lives
 Important complications of pregnancy, diabetes mellitus,
polycystic disease, renal transplantation, conditions that
impede urine flow (structural and neurologic)
Overview of UTI by age and sex
 Terms
 “Upper UTI”: infection above the level of the bladder
 “Lower UTI”: infection at or below the level of the bladder
 “Urethral syndrome”: clinical manifestations of lower UTI
(dysuria, frequency, urgency) without significant
bacteriuria
 Pyuria: the presence of pus (WBC’s [leukocytes] in urine,
which may or may not be caused by UTI. The preferred
method for quantitation is enumeration in unspun urine
using a counting chamber. The leukocyte esterase nitrite
test has a sensitivity of between 70% and 90% for
symptomatic UTI
 Complicated vs Uncomplicated UTI

 UTI’s in elderly men are always considered

complicated
 UTI’s in women are complicated when:
 Recurrent UTI
 Secondary to structural abnormalities
 Catheters
 Stones
 Urinary retention
 Abscess formation or urosepsis
 Primary diagnostic and treatment focus in
research studies have been related to the elderly
female population
Swart, Soler & Holman, 2004
 Complicated vs Uncomplicated UTI

Recurrent UTI’s — culture-confirmed UTI’s

* >3 in 1 year or

* > 2 in 6 months

 Relapse UTI — occurs within 2 weeks of Rx

of an earlier UTI
same pathogen
 Re-infection UTI — occurs >4 weeks after earlier
UTI
different pathogen
Swart, Soler & Holman, 2004
 Routes of urinary tract infection

 Ascending infection is thought to be the common route

of nearly all forms of urinary tract infection (bacteria
initially colonize periurethral tissues)
 Descending (hematogenous) infection can be important
for a few organisms such as S. aureus and Candida
albicans, but in general the kidney resists “metastatic
infection.”
 Causative Pathogens

UTI in Women
 Escherichia coli—gram (-) etiologic agent in ~ 80% of all UTI’s
 Research indicates primary source of microbial invasion is retrograde colonization by intestinal
pathogens
 Other factors influencing colonization: vaginal pH, urethral length, capacity of bacteria to adhere to
urothelium
Polymicromial bacteriuria
 Contamination most frequent cause of multiple microorganisms
 25-33% in LTCF’s may be polymicrobic due to fistulas, urinary retention, infected stones, or
catheters
Age/Type Specific Pathogens
 Younger patients, rare in elderly—Staphylcoccus, saprophyticus (gram pos.) – 10-15%
 Elderly diabetics
 Klebsiella species (gram neg.) most common
 LTCF elderly
 E. coli ~ 30%
 Proteus species (part of host flori in GI tract) ~ 30%
 Staphylcoccus aureus, Klebsiella, Pseudomonas (gram neg.) and Enterococcus (gram pos.)
~ 40%

CTCF’s=long-term care facilities

 UTI Symptoms

1-Burning Sensation when you come to the end of

urination
2-Constant feeling to urinate
3-Cloudy and Foul smelling Odor
4-Fever,loss of appetite, nausea and vomiting
Pelvic Inflammatory
Disease
(PID)
 PID

 C. trachomatis
 produce mild form of salpingitis
 slow growth (48-72 hr)
 intracellular organism
 insidious onset
 remain in tubes for months/years after initial colonization of upper
genital tract
 more severe tubes involvement
 N. gonorrhoeae
 gram –ve diplococcus
 rapid growth (20-40 min)
 rapid & intense inflammatory response
 2 major sequelae (Result)
o infertility & ectopic pregnancy, strong asso. with prior Chalamydia
infection
 Risk factors
 Age of 1st intercourse
 Frequency of intercourse
 Number of sexual partners
 Marital status ; 33%  Nulliparous (is the medical term for a
woman who has never given birth to a viable, or live, infant)
 Increase risk
 IUD user (multifilament string)
 surgical procedure
 previous acute PID

 Reinfection  untreated male partners 80%

 Decrease risk
- barrier method
PID
 Sequelae
 Infertility
 ¼ of pt have acute salpingitis
 occur 20%
 infertility rate increase direct with number of episodes of acute pelvic infection
 Ectopic pregnancy
 increase 6-10 fold
 50% occur in fallopian tubes
(previous salpingitis)
 mechanism ; interfere ovum
transport entrapment of ovum
 Chronic pelvic pain
 4 times higher after acute salpingitis
 caused by hydrosalpinx, adhesion around ovaries
 should undergo laparoscope  R/o other disease
 Mortality
 acute PID 1%
 rupture TOA (Tubo-ovarian abscess)5-10%
Skin and Soft Tissue Infections (SSTI)
 Skin - Definitions

 Vesicles:
 small, fluid-filled lesions in the epidermis
(eg. chicken pox)
 Bullae:
 larger, fluid-filled lesions in the epidermis

 Macules:
 flat, reddish lesion from inflammatory
infiltrate

 Papules:
 raised lesion which, when it contains pus,
is called pustule
 Furunculosis(boils)

 A furuncle or boil is an
acute round, tender,
circumscribed,
perifollicular
staphylococcal
inflammation, which
generally tends to
suppurate.
 Folliculitis

 Folliculitis is bacterial
infection of skin
appendages that
originates within the hair
follicles.
 In infants and young
children, the scalp is the
commonest site involved
while in adults any hairy
area may be affected.
Cellulitis

Features:
Red
Swollen
Warm to
touch
No areas of
pus
Cellulitis Painful
Tender
Cellulitis
Abscess

Features:
Cellulitis
present
Swollen
Soft center,
feels like
fluid
underneath
Absces
s Painful
Cellulitis
Tender
 Treatment of Abscesses

 Abscesses should be drained

 This can be done at home with a sterilized single
edged razor blade, or an Exacto knife
 Sterilize by heating in a flame, allow to cool
 Clean the skin off with alcohol or iodine before
opening the abscess
 If the abscess has a lot of cellulitis around it, an
antibiotic is probably needed
Acne Vulgaris
 Acne vulgaris: overview
Introduction:

Definition:
Multi-factorial disease characterized by abnormalities in sebum
production, follicular desquamation, bacterial proliferation and
inflammation.

Prevalence:
 85% adolescents experience it
 Prevalence of comedones (lesions) in adolescents approaches 100%
 affects 8% of 25 - 34y yr olds, and 3% of 35-44yr olds
Initial pathogenesis (reason unknown):

follicular hyperkeratinization

proliferation +
decreased desquamation of keratinocytes

hyperkeratotic plug
(microcomedone)
Pathogenesis

Sebaceous glands enlarge

Sebum production increases

Growth medium for P. Acnes

plugs provide anaerobic

Lipid-rich environment
 Pathogenesis
Bacteria thrive

Inflammation results

Chemotactic factors attract neutrophils

Depending on conditions

Non-inflammatory Inflammatory papule/

open/closed comedones pustule/nodule
 Closed comedones (whiteheads)

 closed comedo
(a whitehead):

Accumulation of sebum
converts a
microcomedo into this.
 Open comedo (blackhead)

 open comedo
(a blackhead):
when follicular orifice is
opened + distended.

Melanin + packed
keratinocytes + oxidized
lipids  dark colour
 Cysts

 Cysts:

when follicles rupture into

surrounding tissues,
resulting in
papule/pustule/nodule.
Pustular
 External factors:

 Oils, greases, or dyes in hair products

 Cosmetics
 water-based products are less comedogenic
 Repetitive trauma may worsen inflammation
 Soaps decrease sebum but do not alter production
 Humidity
 perspiration
 Acne Treatment

 Topical Keratolytic

 Topical & systemic antibiotics

 Combination of both

 Combination rx more effective than mono in increased inflammatory

lesions.

 Hormonal treatment

 Lazer Therapy
Dental Infections
GINGIVITIS

Gingivitis usually precedes periodontitis.

Bacteria in plaque build up and cause the
gums to become inflamed (red and swollen)
and often easily bleed during tooth brushing.
The teeth are still firmly planted in their
sockets.
No irreversible bone or other tissue damage
has occurred at this stage.
 SYMPTOMS OF PERIODONTAL DISEASE

May progress painlessly, producing few obvious signs, even in the late
stages of the disease.

Symptoms include:
•Bleeding gums during and after tooth brushing
•Red, swollen, or tender gums
•Persistent bad breath or bad taste in the mouth
•Receding gums
•Formation of deep pockets between teeth and gums
•Loose or shifting teeth
•Changes in the way teeth fit together upon biting down, or in the fit
of partial dentures.

In some people, gum disease may affect only certain teeth, such as the
molars.
Microbiology, Infections, and Antibiotic Therapy

Antibiotic Therapy
 History of Antibiotics

Time line of events

1932, 1952, 1956, Linezolid
Sulfonamides Erythromycin Vancomycin becomes
discovered discovered introduced available
1900 2000

1980’s, Fluorinated
1928, 1962, Quinolones available
Penicillin 1940’s: Penicillin Quinolones
discovered becomes commercially discovered More potent
available and
Cephalosporins are Less toxic
synthesized
Changes to increase
activity
 Antibiotic Therapy

Choice of Antibiotic:
 Identify infecting organism
 Evaluate drug sensitivity
 Target site of infection
 Drug safety/side effect profile
 Patient factors
 Cost
 Classification of Antibiotics

 Bacteriostatic  Bactericidal
 Classification of Antibiotics

 Chemical Structure
 Spectrum of Activity
 Mechanism of Action
Mechanism of Action
Inhibitors of Cell Wall Synthesis
 Beta Lactam Antibiotics

 Penicillins
 Cephalosporins
 Carbapenems
 Monobactams
Beta-Lactam Structure
 Penicllins

 Derived from the fungus Penicillium

 Therapeutic concentration in most tissues
 Poor CSF (Cerebrospinal Fluid) penetration
 Renal excretion
 Side effects: hypersensitivity, nephritis, neruotoxicity,
platelet dysfunction
 ALL -lactams

• Mechanism of Action
 interfere with cell wall synthesis by
binding to penicillin-binding proteins
(PBPs) which are located in bacterial
cell walls
 inhibition of PBPs leads to inhibition of
peptidoglycan synthesis
 are bactericidal
 ALL -lactams

• Mechanisms of Resistance
 production of beta-lactamase enzymes
 most important and most common

 hydrolyzes beta-lactam ring causing

inactivation
 alteration in PBPs leading to decreased binding
affinity
 alteration of outer membrane leading to decreased
penetration
 Antistaphylococcal Penicillins
 Methicillin

 Nafcillin

 Oxacillin

 Dicloxacillin
 Aminopenicillins

 Amoxicillin +/- clavulanate

 Ampicillin +/- sulbactam

 Antipseudomonal Penicillins

 Carbenicillin
 Ticarcillin +/- clavulanate
 Piperacillin +/- tazobactam
 Cephalosporins

 Structurally similar to
penicillins
 Therapeutic
concentration in many
tissues, 3rd and 4th
generation into CSF
 Renal Excretion
 Side Effects
• allergy
• disulfiram-like effect
• anti-Vitamin K
 Classification and Spectrum of Activity of
Cephalosporins

• Divided into 4 major groups called “Generations”

• Are divided into Generations based on
 antimicrobial activity
 resistance to beta-lactamase
 First Generation Cephalosporins

Best activity against gram-positive aerobes, with limited

activity against a few gram-negative aerobes
Gram-positive Gram-negative
meth-susc S. aureus E. coli
pen-susc S. pneumoniae K. pneumoniae
Group streptococci P. mirabilis
viridans streptococci
 Second Generation Cephalosporins
Spectrum of Activity
Gram-positive Gram-negative
meth-susc S. aureus E. coli
pen-susc S. pneumoniae K. pneumoniae
Group streptococci P. mirabilis
viridans streptococci H. influenzae
M. catarrhalis
Neisseria sp.
Third Generation Cephalosporins
Spectrum of Activity
Gram-negative aerobes
E. coli, K. pneumoniae, P. mirabilis
H. influenzae, M. catarrhalis, N. gonorrhoeae
(including beta-lactamase producing); N. meningitidis

Citrobacter sp., Enterobacter sp., Acinetobacter sp.

Morganella morganii, Serratia marcescens,
Providencia

Pseudomonas aeruginosa (ceftazidime and

cefoperazone)
 Fourth Generation Cephalosporins !!!

• 4th generation cephalosporins for 2 reasons

 Extended spectrum of activity
 gram-positives: similar to ceftriaxone

 gram-negatives: similar to ceftazidime, including

Pseudomonas aeruginosa; also covers beta-
lactamase producing Enterobacter sp.
 Stability against -lactamases; poor inducer of extended-
spectrum  -lactamases
• Only cefepime is currently available
 Cephalosporens
1st Generation 2nd Generation 3rd Generation
Cefazolin – Ancef Cefuroxine – Ceftriaxone – Rocephin
Zinacef
Cephalexin – Keflex Cefamandole – Cefotaxime – Claforan
Mandol
Cefadroxil – Duricef Cefoxitin – Ceftozoxime - Cefizox
Mefoxin
Cephalothin – Keflin Cefotetan – Cefoperozone – Cefobid
Cefotan
Cephradine – Velosef Cefonicid – Ceftibutin – Cedax
Monocid
Cephapirin – Cefadyl Cefprozil – Cefpodoxime – Vantin
Cefzil
Cefaclor – Cefixime – Suprax
Ceclor
Lorcaebef – Cefditoren - Meiact
Lorabid
Ceftazidime - Fortum
4th Generation
Cefepime - Maxipime
 Monobactams

 Aztreonam
 single beta lactam ring
 narrow spectrum: gram-
negative aerobes
• Enterobacteriacea
• Pseudomonas
 given IV/IM
 renal excretion
 little cross-reactivity with
other beta lactams
 side effects: phlebitis,
rash, elevated LFT’s
 Carbapenems

 Meropenem/Imipenem
 broad spectrum
 active against MRSA
 given IV
 penetrates CSF
 renal metabolism and
excretion
 addition of cilastin
 side effects: GI upset,
eosinophilia, neutropenia,
lowering of seizure threshold
 -Lactams Adverse Effects

• Hypersensitivity – 3 to 10 %
 Higher incidence with parenteral administration or
procaine formulation
 Mild to severe allergic reactions – rash to anaphylaxis
and death
 Antibodies produced against metabolic by-products or
penicillin itself
 Cross-reactivity exists among all penicillins and even
other -lactams
 Desensitization is possible
 -Lactams Adverse Effects

• Neurologic – especially with penicillins and carbapenems

(imipenem)
 Especially in patients receiving high doses in the
presence of renal insufficiency
 Irritability, confusion, seizures
• Hematologic
 Leukopenia, neutropenia, thrombocytopenia –
prolonged therapy (> 2 weeks)
 -Lactams Adverse Effects

• Gastrointestinal
 Increased LFTs, nausea, vomiting, diarrhea,
pseudomembranous colitis (C. difficile diarrhea)
• Interstitial Nephritis
 Cellular infiltration in renal tubules (Type IV
hypersensitivity reaction – characterized by abrupt
increase in serum creatinine; can lead to renal failure
 Especially with methicillin or nafcillin
 Vancomycin

 Tricyclic glycopeptide
 Inhibits synthesis of phospholipids and cross-linking of
peptidoglycans
 Activity against gram-positive organisms
 Useful for beta lactam resistant infections
 Widely distributed, penetrates CSF
 Renal elimination, follows creatinine cl.
 Side effects: phlebitis, red man syndrome, ototoxicity,
nephrotoxicity
 Protein Synthesis Inhibitors

 Human Ribosome
 80S
• 40S
• 60S

 Bacterial Ribosome
 70S
• 30S
• 50S
 Protein Synthesis Inhibitors

 Mostly bacteriostatic
 Selectivity due to
differences in prokaryotic
and eukaryotic ribosomes
 Some toxicity –
eukaryotic 70S ribosomes
 Review of Elongation of Protein Synthesis

P A Tetracycline P A

Tu GTP Tu GDP + Pi

GTP Ts
Ts Tu
Ts GDP
Chloramphenicol

GDP
+
Fusidic Acid G

G GDP + Pi
G GTP
P A P A

Erythromycin
 Tetracyclines

 Isolated from Streptomyces aureofaciens

 Reversibly bind 30S ribosomal subunit
 Penetrate sinus mucosa, saliva and tears
 Metabolized in liver-->excreted in bile--> reabsorbed--
>eliminated in urine
 Side effects: GI upset, hepatotoxicity, photosensitivity,
bony deposition
 Contraindicated in pregnant or breast feeding women,
children under 8 y/o
 Macrolides

 Macrocyclic lactone structure

 Irreversible binding to 50S subunit
 Therapeutic concentrations in oropharyngeal and
respiratory secretions
 No CSF penetration
 Metabolized in liver, excreted in feces and urine
 Side effects: GI upset, ototoxicity, hepatotoxicity
 Alternate Macrolides

 Clarithromycin  Azithromycin
 Macrolides

Mechanisms of Resistance
 Active efflux (accounts for 80%) – mef gene encodes
for an efflux pump which pumps the macrolide out of
the cell away from the ribosome; confers low level
resistance to macrolides
 Altered target sites encoded by the erm gene which
alters the macrolide binding site on the ribosome;
confers high level resistance to all macrolides,
clindamycin and Synercid
 Cross-resistance occurs between all macrolides
 Macrolides Pharmacokinetics

Absorption
 Erythromycin – variable absorption food may decrease the
absorption
• Base: destroyed by gastric acid; enteric coated
• Esters and ester salts: more acid stable
 Clarithromycin – acid stable and well-absorbed regardless of
presence of food
 Azithromycin –acid stable; food decreases absorption of capsules
 Macrolides Pharmacokinetics

Distribution
 Extensive tissue and cellular distribution – clarithromycin
and azithromycin with extensive penetration
 Minimal CSF penetration
Elimination
 Clarithromycin is the only macrolide partially eliminated
by the kidney (18% of parent and all metabolites);
requires dose adjustment when CrCl < 30 ml/min
 Hepatically eliminated: ALL
 NONE of the macrolides are removed during
hemodialysis!
 Variable elimination half-lives (1.4 hours for erythro; 3 to
7 hours for clarithro; 68 hours for azithro)
 Macrolides Adverse Effects

• Gastrointestinal – up to 33 %
 Nausea, vomiting, diarrhea, dyspepsia
 Most common with erythro; less with new agents

• Cholestatic hepatitis - rare

 > 1 to 2 weeks of erythromycin estolate
• Thrombophlebitis – IV Erythro and Azithro
 Dilution of dose; slow administration
• Other: ototoxicity (high dose erythro in patients
with RI); QTc prolongation; allergy
 Macrolides Drug Interactions

Erythromycin and Clarithromycin ONLY– are

inhibitors of cytochrome p450 system in the
liver; may increase concentrations of:

Theophylline Digoxin, Disopyramide

Carbamazepine Valproic acid
Cyclosporine Terfenadine, Astemizole
Phenytoin Cisapride
Warfarin Ergot alkaloids
 Fluoroquinolones

• Novel group of synthetic antibiotics developed

in response to growing resistance
• Agents available today are all structural
derivatives of nalidixic acid
• The fluorinated quinolones (FQs) represent a
major therapeutic advance:
 Broad spectrum of activity
 Improved PK properties – excellent bioavailability,
tissue penetration, prolonged half-lives
 Overall safety
• Disadvantages: resistance, expensive
 Gyrase

 Fluoroquinolones antibiotics target gyrase:

 Quinolones

 Inhibit topoisomerases/DNA synthesis

 Trap enzyme-DNA complex after strand breakage
 DNA gyrase (topo III) (gyrA/gyrB)
o Primary target in Gram-negatives

 Topoisomerase IV [parC/parE (grlA/grlB in S.aur)]

o Primary target in Gram-positives
 Fluoroquinolones

O O
Basic Structure O O
5 F
R6 4 OH
3 OH
1 2 N N
R7 X N Ciprofloxacin
8 HN
R1

O O Gemifloxacin
O O
F
OH F
OH

N N Levofloxacin H
N N
HN Moxifloxacin
N O CH3
H3 OCH3
C H
H
Fluoroquinolone Classification System (2-12)0

General
Brand Generic Manufacturer Generation Microbiology
Indications

NegGram Nalidixic acid Sanofi-synthelabo 1st Gram Negative but not Uncomplicated
pseudomonas UTIs

Noroxin Norfloxacin Merck 2nd As above but including UTIs,

pseudomonas. Some gram + Pyelonephritis,
Maxaquin Lomefloxacin Searle / Pfizer 2nd including s.aureus. Not strep STD,
pneumoniae. Atypical including Prostatitis,
Tarivid Ofloxacin Sanofi Aventis 2nd
chlamydia, mycoplasma and Skin and soft
Ciprobay Ciprofloxacin Bayer 2nd legionella. tissue infections

Tavanic Levofloxacin Sanofi Aventis 3rd Same as above +expanded gram — Acute
including pen sensitive and exacerbations of
Zagam Sparfloxacin Sanofi Aventis 3rd resistant s. pneumoniae. More so chronic
with Tequin and Avelox bronchitis and
Tequin Gatifloxacin Bristol-Myers Squibb 3rd
community
acquired
pneumoniae
Avelox Moxifloxacin Bayer 3rd

Factive Gemifloxacin LG Life sciences 3rd As other 3rd generation plus Acute
activity against gram –ve as 2nd exacerbations of
generations+Activity against chronic
MDRSP (Multi-Drug Resistant bronchitis ,
Streptococcus Pneumoniae) community
acquired
pneumoniae and
ABS
+UTI,Prostatitis

Trovan Trovafloxacin Pfizer 4th Same as above plus broad As above except
anaerobic coverage UTIs and
pyelonephritis.
Plus intra-
abdominal
infections, PID
and nosocomial
pneumonia
 Fluoroquinolones

• Mechanism of Action
 Unique mechanism of action
 Inhibit bacterial topoisomerases which are
necessary for DNA synthesis
 DNA gyrase – removes excess positive supercoiling in
the DNA helix
 Primary target in gram-negative bacteria
 Topoisomerase IV – essential for separation of
interlinked daughter DNA molecules
 Primary target for many gram-positive bacteria

 FQs display concentration-dependent bactericidal

activity
 Fluoroquinolones

• Mechanisms of Resistance
target sites – chromosomal
 Altered
mutations in genes that code for DNA
gyrase or topoisomerase IV
 most important and most common
 Alteredcell wall permeability –
decreased porin expression
 Expression of active efflux – transfers
FQs out of cell
 Cross-resistance occurs between FQs
 The Available FQs

Older FQs
 Norfloxacin (Noroxin®) - PO
 Ciprofloxacin (Ciprobay®) – PO, IV
Newer FQs
 Levofloxacin (Tavanic®) – PO, IV
 Gatifloxacin (Tequin®) – PO, IV
 Moxifloxacin (Avelox®) – PO, IV
 Gemifloxacin (Factive®) – PO
 FQs Spectrum of Activity

Gram-positive – older agents with poor

activity; newer FQs with enhanced
potency
o Methicillin-susceptible Staphylococcus
aureus
o Streptococcus pneumoniae (including PRSP)
o Group and viridans streptococci – limited
activity
o Enterococcus sp. – limited activity
 FQs Spectrum of Activity

Gram-Negative – all FQs have excellent activity

(cipro=levo>gati>moxi)
• Enterobacteriaceae – including E. coli, Klebsiella sp,
Enterobacter sp, Proteus sp, Salmonella, Shigella,
Serratia marcescens, etc.
• H. influenzae, M. catarrhalis, Neisseria sp.
• Pseudomonas aeruginosa – significant resistance
has emerged; ciprofloxacin and levofloxacin with
best activity
 FQs Spectrum of Activity

Anaerobes – only trovafloxacin has adequate activity

against Bacteroides sp.
Atypical Bacteria – all FQs have excellent activity against
atypical bacteria including:
o Legionella pneumophila
o Chlamydia sp.
o Mycoplasma sp.
o Ureaplasma urealyticum
Other Bacteria – Mycobacterium tuberculosis, Bacillus
anthracis
 Fluoroquinolones Pharmacology

• Concentration-dependent bacterial killing –

AUC/MIC (AUIC) correlates with efficacy
• Absorption
 Most FQs have good bioavailability after oral
administration
 Cmax within 1 to 2 hours; coadministration with food
delays the peak concentration
• Distribution
 Extensive tissue distribution – prostate; liver; lung;
skin/soft tissue and bone; urinary tract
 Minimal CSF penetration
• Elimination – renal and hepatic; not removed by HD
 Fluoroquinolones Adverse Effects

• Gastrointestinal – 5 %
 Nausea, vomiting, diarrhea, dyspepsia
• Central Nervous System
 Headache, agitation, insomnia, dizziness, rarely,
hallucinations and seizures (elderly)
• Hepatotoxicity
 LFT elevation (led to withdrawal of trovafloxacin)
• Phototoxicity (uncommon with current FQs)
 More common with older FQs (halogen at position 8)
• Cardiac
 Variable prolongation in QTc interval
 Led to withdrawal of grepafloxacin, sparfloxacin
 FluoroquinolonesAdverse Effects

• Articular Damage
 Arthopathy including articular cartilage damage,
arthralgias, and joint swelling
 Observed in toxicology studies in immature dogs
 Led to contraindication in pediatric patients and
pregnant or breastfeeding women
 Risk versus benefit
• Other adverse reactions: tendon rupture, dysglycemias,
hypersensitivity
 Prophylactic Antibiotics

 Cover bacterial flora involved in the surgical field

 Administer within 2 hours before or 3 hours after surgery
has begun
 Maintain therapeutic blood level during lengthy
procedures
 Continue prophylaxis for the 24 hour period surrounding
surgery