Antimicrobial Regimen Selection

By: Dagninet Derebe (B.pharm, MSc)

Address: dagninet37@yahoo.com
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 Introduction
 Antibiotics have 3 general uses:
 Empirical
 initiated before offending organism is identified and sometimes
prior to documentation of presence of infection
 Definitive
 Instituted when causative organism is known
 Prophylactic therapy
 In choosing the appropriate antimicrobial agent for therapy for a
given infection, a number of factors must be considered
1. Organism’s identity
2. Organism’s susceptibility to a particular agent
3. Host factors
4. Safety of the agent, and
5. Cost of therapy
 Selection of antimicrobial agents
• Far more complicated than matching a drug to a known
or suspected pathogen
• Systematic approach to select an antimicrobial regimen better
• Problems arise when this systematic approach is
replaced by prescribing broad-spectrum therapy to
cover as many organisms as possible
• Use of more expensive and potentially more toxic agents,
which can, in turn, lead to widespread resistance and difficult-
to-treat superinfections.
• Another abuse of antimicrobial agents is administration
when they are not needed such as
• when they are prescribed for self-limited clinical conditions
that are most likely viral in origin (i.e., the common cold).

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• Initial selection of antimicrobial therapy is nearly
always Empirical
• Infectious diseases generally are acute, and a delay in
antimicrobial therapy can result in serious morbidity or even
mortality
• Thus, Empirical antimicrobial therapy selection should
be based on information gathered from the
• Patient’s history
• physical examination
• Results of Gram stains
• Rapidly performed tests on specimens from the infected
site.
• This information, combined with knowledge
• The most likely offending organism(s) and
• An institution’s local susceptibility patterns, should result in
a rational selection of antibiotics to treat the patient.

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Systematic Approach for Selection of Antimicrobials
1. Confirm the presence of infection
• Careful history and physical
• Signs and symptoms
• Predisposing factors
2. Identification of the pathogen
• Collection of infected material
• Stains
• Serologies
• Culture and sensitivity
3. Selection of presumptive therapy considering infected site
• Host factors
• Drug factors
4. Monitor therapeutic response
• Clinical assessment
• Lab tests
• Assessment of therapeutic failure 5
 Confirming Presence Of Infection
• Determined by assessing presence
• Signs and symptoms
• Determining site of infection
• Establishing microbiological diagnosis when possible
 1. Signs and symptoms
• Fever
• Body temperature above normal range of 36.8° ± 0.4°C (98.2° ±
0.7°F) (measured orally), low in morning and peak in afternoon
• Rectal temperatures are 0.4°C (0.7°F) higher (Most reliable determination
of fever)
• Axillary temperatures are 0.6°C (1 0F) lower
• Hallmark of infectious disease
• Some medications can mask fever (aspirin, acetaminophen,
NSAIDs and corticosteroids)
• May be caused by drugs in absence of infection or other underlying
condition “false positives”
• Rheumatic diseases, Intracranial hemorrhage/ischemic stroke,
Thomboembolism, Aspiration pneumonitis, Acute pancreatitis, Thyroid
storm, Crystal-induced arthropathies, Drug-induced fever
 Does fever means infection at all times?
• “False-positives"
• Collagen-vascular (autoimmune) disorders; malignancies; fever of
unknown or undetermined origin
• Drugs - 5%
• Beta-lactam antibiotics, anticonvulsants, allopurinol, hydralazine,
nitrofurantoin, sulfonamides, phenothiazines, and methyldopa
• False-negative
• The absence of fever in a patient with signs and symptoms consistent
with an infectious disease.
• Masking fever: aspirin, acetaminophen, nonsteroidal
antiinflammatory agents, and corticosteroids
• Moreover, elevated body temperature, unless very high
(greater than 40.5°C [105°F]), is not harmful and may be
beneficial 8
 WBC count and Differential
Used to identify the presence of infection and/or inflammation

The typical normal range of the WBC is 4,000 to 10,000 cells/mm3

(4 × 109-10 × 109/L).
• This range will vary between laboratories and patients, as it is dependent
on patient age, gender, comorbidity status- elderly, cancer, severe sepsis,
pregnancy (WBC, especially neutrophils, increase during pregnancy)

WBCs usually are elevated in response to infection, but many

other noninfectious conditions can increase the WBC, including
• stress, inflammatory conditions such as rheumatoid arthritis, and leukemia
or in response to certain drugs (eg, corticosteroids)
• WBCs are divided into two groups:
• Granulocytes ▬► neutrophils, basophils, and eosinophils

• Agranulocytes ▬► monocytes and lymphocytes

• Neutrophils are the most common type of WBCs (70%)

 Bacterial infections associated with.
 Elevated granulocyte counts (neutrophils and basophils)

 Increased band neutrophils in peripheral smear (left-shift)

 Low neutrophil counts (neutropenia), indicating abnormal response;

associated with poor prognosis.

 Most common granulocyte defect is neutropenia, a decrease in the

absolute number of circulating neutrophiles
• Leukocytosis is a normal host response to infection
• Unfortunately, bacterial infection is a common complication of
neutropenia from cancer chemotherapy

• Patients who are neutropenic are incapable of increasing their

WBCs in response to infection
• In fact, susceptibility to infection in these patients is highly dependent on
their WBC status

• Patients with absolute neutrophil counts of less than 500

cells/mm3 (0.5 × 109/L) are at high risk for the development of
bacterial or fungal infections
• The absence of leukocytosis also frequently can occur in the
elderly and in severe cases of sepsis
• Lymphocytes the 2nd most common type of WBCs
• Lymphocytosis is frequently associated with acute viral
infections such as
• Epstein–Barr virus infection (mononucleosis) and
• Cytomegalovirus (CMV) infection and
• rarely with unusual bacterial infections (ie, Brucella species infections)
• Tuberculosis and viral or fungal infections
• Monocytes can be associated with tuberculosis or lymphoma
• Eosinophils can be associated with allergic reactions to
drugs or infections caused by metazoa
• Basophils associated with allergic reaction

Many types of infections can be accompanied by

a completely normal WBC count and differential
 Other Tests
• Erythrocyte sedimentation rate (ESR)
• During inflammation ↑ fibrinogen ▬► binds to RBCs and
fasten its sedimentation
• Fibrinogen has ½ life of 7 days
• NR= < 15 mm/hr in men and < 20 mm/hr in women
• Increased with age
• large elevations in ESR are associated with infections such as
endocarditis, osteomyelitis, and intraabdominal infections
• C-reactive protein (CRP)
• Elevated in the presence of an inflammatory process
• but do not confirm the presence of infection because they are
often elevated in noninfectious conditions, such as collagen-
vascular diseases and arthritis
• Hallmark of inflammation
• Procalcitonin (PCT)
• Another acute-phase reactant that is released in response to
various cytokines
• PCT appears to be a more specific marker for bacterial
infections than either CRP or ESR
• Very help for diagnosis of sepsis
• It can be a valuable tool for the clinician to help assess
mortality risks of patients with infections and also can help to
determine when to initiate antibacterial therapy in respiratory
tract infections
• Normal range
• Less than 0.15 ng/ml
• 0.10 – 0.49 ng/ml (minor or no significant inflamation)
• O,5- 1.99 ng/ml (moderate risk of pregration to severe systemic
infection)
• More than 2..0 ng/ml (high risk or sever sepsis)
• Inflammatory cytokines, such as interleukin (IL) IL-1, IL-
6, and IL-8 and tumor necrosis factor-α (TNF-α)
• Useful in staging and monitoring the response to therapy

• Spiked elevations in TNF are found in patients with serious

infections, such as sepsis

• Combination of elevations in endotoxin and cytokines

has correlated well with the mortality rate
• Especially IL-6 was by far the best individual cytokine that
predicted patient outcome
 Local Signs
• Pain and inflammation
• Swelling, erythema, tenderness, and
• Purulent drainage
• Meningitis, pneumonia, endocarditis, and UTI: examining
tissues or fluids
For example: Bacterial infection:
• CNS infection: Neutrophils in spinal fluid
• UTI: pyuria (precence of WBC in urine)
• Pyelonephritis: flank pain and dysuria
• Pulmonary infection: cough and sputum production
• Imaging studies
• To identify anatomic localization of the infection
• These studies usually are performed to establish or rule out the presence of
an infection
• X-rays to establish the diagnosis of pneumonia
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 IDENTIFICATION OF PATHOGEN
• Infected body materials must be sampled before
institution of any antimicrobial therapy
• First, a Gram stain of the material might reveal bacteria, or an
acid-fast stain might detect mycobacteria or actinomycetes
• Second, a delay in obtaining infected fluids or tissues until after
antimicrobial therapy is started might result in false-negative
culture results or alterations in the cellular and chemical
composition of infected fluids
• Blood cultures usually should be performed in the
acutely ill febrile patient (at sharp elevation of
temperature)
• Ideally, blood should be obtained from peripheral sites as two
sets (one set consists of an aerobic bottle and one set an
anaerobic bottle) from two different sites approximately 1
hour apart
 Interpreting Results
• Colonization Vs Infection Vs contamination
• After a positive Gram stain, culture results, or both are obtained,
• The clinician must be cautious in determining whether the organism
recovered is a true pathogen, a contaminant, or a part of the normal
flora
• Especially the sample obtained from skin, oropharynx, nose, ears,
eyes, throat, and perineum
• This could be minimized by using incombination with other test
• UTI = nitrate or leukocyte
• RTI = leukocytes instead of epithelial cells

• Caution in interpretation of positive culture results from

normally sterile sites (e.g., blood, CSF, or joint fluid)
 Examples of Normal Bacterial Flora
Gram-Positive Gram-Negative
Cocci Rods Cocci Rods Others
Skin Staphylococcus Corynebacteri Enteric bacilli
spp. (eg, S. um spp., (some sites),
epidermidis), Propionibacte Acinetobacter
Streptococcus rium spp. spp. (Coccobacilli)
spp.
Oropharyn Streptococci— Corynebacteri Neisseri Haemophilus spp. Spirochete
x viridans group um spp. a.meni s
st. pyrogrnes ngitdis
GI tract Enterococcus Lactobacillus, Bacteroides spp.,
spp., Clostridium Enteric bacilli (E.
Peptostreptococc coli, Klebsiella
us spp. spp.)
Genital Streptococcus Lactobacillus, Enterobacteriace Mycoplas
tract spp., Corynebacteri a, Prevotella spp., ma
Staphylococcus um spp Candidia spp.
spp.
 Common Bacteria by Site of infection
Mouth Lower Respiratory Coomunity Skin/soft tissues
• Peptococcus • S.pneumoniiae • S.aureus
• Peptostreptococcus • H.influenzae • S,pyrogenes
• Actinomyces • K.pneumonia • S.epidermids
• Legionellaa pneumophila • Pasteurella
• Mycoplasma
• Clamydia
Abdomen Lower Respiratory Hospital Bone and joint
• E. coli, proteus • Kpneumoniae • S. aureus
• Klebsiella • P.aeruginosa • S.epidermidis
• Entrococcus • Entrobacter Spp • Streptococci
• Bacteroides sp • Serratia Spp • N.gonorrhoeae
• S. aureus • Gram-negative rods
Upper Respiratory Meninigits Urinary tract
• S.pneumonia • S.pneumonia • E.coli
• H.influnzea • N.meningitides • Proteus
• M.catarahalis • H.influenzae • Klebsiella
• S.pyrogenous s • Group B strep • Entrococcus
• E.coli • Staph saprophyticus
• Listeria
 Direct Examination
• Direct examination of tissue samples or body fluids
believed to be infected can provide simple
• Gram stain is one of the first identification tests with
microscopic examination
• Gram-positive, Gram-negative, Gram-variable, bacillus, or cocci
• CSF, Ureteral smears in STDs, abscess or effusion specimens,
respiratory tract infections
• Extremely useful information for the selection of empirical
antibiotic therapy
• Other staining techniques
• Ziehl–Neelsen stain for acid-fast bacilli, which is used for the
identification of mycobacteria species and or actinomycetes
• India ink, potassium hydroxide (KOH), and Giemsa stains, which
are useful for detecting certain fungi
 • Four main groups of bacteria (according to sensitivity)
• Gram positive, Gram negative, Anaerobes
• Atypical bacteria (chlamydia, mycoplasma, legionella pneumophila)
Aerobic
Gram-positive Gram negative
Cocci Rods (bacilli) Cocci Rods (bacilli)
Streptococci: corynebacterium Moraxella  Enterobacteriaceae ● Salmonella
 S.pneumoniea diphtheriae Neisseria  Esherichia coli ● Shigella
 S. viridans Listeria  N. meningitides  Klebsiella ●Morganella
 Group A streptococci moncytogene  N. Gonorrhoeae  Entrobacter ●Providencia
Entroccoccus Erysipleothrix  Citrobacter’ ● Acinetobacter
Staphylococci  Proteus ●Acinetobacter
 Stap. aureus (MSSA, MRSA)  Pseudomonas ● Helicobacter
 Staph. Epidermidis  Serratia ●Haemophilus
 Staph. saprophyticus  Stenotrophomonos . Moganella
Anaerobic
Gram-positive Gram negative
Cocci Rods (bacilli) Cocci Rods (bacilli)
Peptococus Clostridia None Bacteroides
peptostreptococcus  C. perfringens  B. fragilis
 C.tetani  B. melaninogenicus
 C. difficile Fusobacterium
Propionibacterium Prevotella
acnes
Gardenerella
Nocardia
Actinomyces
 Cultures
• The most definitive method available for the diagnosis and
eventual treatment of infection
• Time taking and expensive
• Suspicion of a specific pathogen or group of pathogens is
helpful to the laboratory for the selection of a specific
cultivating medium
• Fastidious Microorganisms require special media
• Blood culture collection should coincide with sharp
elevations in temperature
• Ideally, blood should be obtained from peripheral sites as two sets
(one set consists of an aerobic bottle and one set an anaerobic
bottle) from two different sites approximately 1 hour apart
• Antimicrobial susceptibility testing that measures the ability
of a select organism to grow in the presence of an
antimicrobial agent
 Rapid Diagnostic Technologies (RDT)
• IMMUNOLOGIC ASSAYS
• Antibody and antigen detection to infection has become an
indispensable laboratory tool
• Antibody or antigen detection can be accomplished by a variety of
techniques, including
• Immunofluorescence, which has been used routinely for the detection of CMV,
respiratory syncytial virus, varicella-zoster virus, Treponema pallidum (syphilis),
Borrelia burgdorferi (Lyme disease), and Chlamydia trachomatis
• Latex agglutination is useful for detecting meningococcal capsular
antigens in CSF of patients suspected of having bacterial meningitis and
as an aid in the diagnosis of Legionella pneumophila
• Enzyme-linked immunosorbent assay (ELISA) is a commonly employed
method for detecting HIV, herpes simplex virus, respiratory syncytial
virus, pneumococcal serum antibody, Neisseria gonorrhoeae, and
Haemophilus pylori.
Molecular Techniques for the Detection of Microorganisms
• Nucleic Acid Hybridization Techniques
• Formation of hydrogen bonds between single stranded (ss)
DNA and/or RNA that are complementary to each other
• Components:
• Target/template – nucleic acid to be identified
• Probe –labeled nucleic acid that binds to a specific target sequence
• Detect a sequence specific to a certain microorganism or virus
• Detectable visually or using a machine
• The use of hybridization probes is particularly helpful for the
detection of pathogenic bacteria, and for slow-growing
organisms such as
• M. tuberculosis, N. gonorrhoeae, and certain species of fungi such
as Candida species
• Nucleic Acid Amplification Methods
• Now considered a standard laboratory tool
• Polymerase Chain Reaction (PCR)
• Stimulate the in vivo synthesis
• Steps
• Denaturation – Double stranded DNA is separated into 2 strands
• Annealing – primers attach to target DNA sequences
• Extension – DNA polymerases synthesize new DNA by extending the
primer
 EVALUATION OF ANTIMICROBIAL ACTIVITY
• Important component of the pharmacotherapeutic
management of infectious diseases
• Most antimicrobial susceptibility testing methods
that are used in the clinical laboratory are well
characterized and have been standardized by the
Clinical and Laboratory Standards Institute (CLSI)
• Most of the standardized and well-accepted test
methods evaluate the susceptibility of aerobic,
nonfastidious bacteria
• Broth dilution (MIC, MBC)
• Disk Diffusion Assay (Kirby–Bauer method)
• Epsilometer Test (E-test)
• AUTOMATED ANTIMICROBIAL SUSCEPTIBILITY TESTING
 3. SELECTION OF PRESUMPTIVE THERAPY
• Variety of factors must be considered
• Severity and acuity of the disease
• Host factors
• Factors related to the drugs used, and the necessity for using
multiple agents
• Local antimicrobial susceptibility data
• Each institution should publish an annual summary of
antibiotic susceptibilities (antibiogram) for organisms
cultured from patients
• Sometime unit-specific antibiograms in unique patient care
• The place where the infection was acquired should be
determined
• Home (community acquired), nursing home environment, or
hospital acquired (nosocomial).
 Host Factors
• Allergy
• Generally precludes its use (Penicillin, penicillin-related drugs)
• Age
• Different etiologic agent
• Bacterial meningitis, where the pathogens differ (neonatal,
infancy, childhood, adulthood)
• Pharmacokinetic difference
• In neonate Kernicterus when given sulfonamides
• In elder more nephrotoxicity of aminoglycosides
• Pregnancy
• Risk for drug teratogenicity (aminoglycosides, TTCS, FQS, Sulfonamide)
• Pharmacokinetic disposition of certain drugs can be altered
• Metabolic or Genetic Variation
• Slow acetylators of isoniazid are at greater risk for peripheral
neuropathy
• Patients with severe deficiency of G6D deficiency can develop
significant hemolysis (eastern Mediterranean origin)
• sulfonamides, nitrofurantoin, nalidixic acid, antimalarials, and dapsone
• Abacavir severe rash in LA-B*5701 (screening recommended)
• Organ Dysfunction
• Diminished renal or hepatic function
• Need dose adjustment in severe liver failure clindamycin, erythromycin,
metronidazole, and rifampin
• Liver and renal failure: cefotaxime, nafcillin, piperacillin, and
sulfamethoxazole.
• Concomitant Drugs
• Isoniazid, CAF inhibit of phenytoin metabolism
• Concomitant Disease States
• cystic fibrosis, diabetes mellitus, immunosuppressive diseases
• Drug Factors
• Pharmacodynamic Considerations
• Aminoglycosides and Fluoroquinolones exhibit concentration-
dependent bactericidal effects and long postantibiotic effect
• β-Lactams display time-dependent bactericidal effects
• Tissue Penetration
• Febrile neutropenia and deep-seated infections such as meningitis,
endocarditis, and osteomyelitis → Parenteral therapy is warranted
• Severe pneumonia often is treated initially with IV antibiotics and
switched to oral therapy as clinical improvement is evident
• Drug Toxicity
• Antimicrobial spectrum
• Cost
 Combination Antimicrobial Therapy
Combination therapy should be considered to:
 Broaden the spectrum of coverage for empiric therapy
• Intraabdominal and female pelvic infections
• Important when multiple aerobic and anaerobic bacteria are likely to be
present (eg, intraabdominal infections)
• aminoglycoside and metronidazole or clindamycin
• critically ill patients with presumed healthcare-associated infections
 Achieve synergistic activity against infecting organism.
• Advantageous for infections caused by gram-negative bacilli in
immunosuppressed patients.
• May produce better results in infections caused by Pseudomonas
aeruginosa and certain infections caused by Enterococcus spp.
 Prevent the emergence of resistance.
 clearly effective is in the treatment of tuberculosis, leprosy, HIV, H.
pylori, malaria.
 Disadvantages of Combination Therapy
• Increased cost
• Greater risk of drug toxicity
• nephrotoxicity with aminoglycosides, amphotericin, and
possibly vancomycin, and
• Superinfection with even more resistant bacteria
• Antagonistic effects
• Cefoxitin and imipenem inducing β-lactamases and may result
in more rapid inactivation of penicillins when used together
 Penicillin + tetracycline/chloramphenicol on pneumococci
 Penicillin + erythromycin for group A Streptococci and
 Nalidixic acid + nitrofurantoin for £. Coli
 Monitoring Therapeutic Response
• Culture and sensitivity reports
• Use of extended vs. narrowest spectrum
• anaerobic infection if suspected
• WBC count and temperature
• Physical complaints: decreased pain, shortness of breath,
cough, or sputum production
• Appetite
• Radiologic improvement (can lag behind clinical improvement)
• Antimicrobials serum concentration monitoring
• aminoglycosides, vancomycin, flucytosine, and chloramphenicol

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 Monitoring Therapeutic Response
• Switching the route of administration: Criteria
1. overall clinical improvement,
2. lack of fever for 8 to 24 hours,
3. decreased WBC count, and
4. a functioning gastrointestinal tract
• Oral vs. IV: (high oral BA)
• Ciprofloxacin, levofloxacin, moxifloxacin,
• Clindamycin, metronidazole
• Linezolid, doxycycline,
• Trimethoprim-sulfamethoxazole

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 Failure of Antimicrobial Therapy
• Lack of respond over 2 to 3 days (require reevaluation)
• Not infectious, nonbacterial in origin, undetected pathogen in
a polymicrobial infection
• Other factors:
• Drug selection, the host, or the pathogen.
• Drug interaction
• complexation of fluoroquinolones with multivalent cations
• Laboratory error in identification, susceptibility testing, or both
• Failure due to drug selection:
• Malabsorption (short-bowel syndrome)
• Rapid clearance (aminoglycosides in pregnancy & cystic fibrosis)
• Poor penetration into the site of infection: CNS, eye, and
prostate gland
• Chemically inactivated at the site of infection: Daptomycin
inactivated by surfactant 40
• Failure caused by host factors:
• Immunosuppressed (e.g., granulocytopenia from
chemotherapy or AIDS)
• Surgical drainage of abscesses or removal of foreign
bodies, necrotic tissue

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 Failures Caused by Microorganisms
• Intrinsic resistance
• Vancomycin Vs gram negative
• Acquired resistance
• Enterococci have been isolated with multiple resistance
patterns
• Beta-lactams
• by virtue of β-lactamase production, altered penicillin-binding
proteins [PBPs], or both
• Vancomycin
• via alterations in peptidoglycan synthesis
• High levels of aminoglycosides
• via enzymatic degradation
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 Failures Caused by Microorganisms
• Pneumococci resistant to penicillins, certain
cephalosporins, and macrolides
• Susceptible to vancomycin, the new fluoroquinolones, and
cefotaxime or ceftriaxone
• Linezolid =, daptomycin, telavancin, and tigecycline have been
targeted at resistant gram-positive bacteria.
• Enterobacter, Citrobacter, Serratia, or P. aeruginosa with
• Treatment with 3rd G cephalosporin or aztreonam may produce an initial
clinical response by eradicating all the susceptible bacteria in the population
• Within a few days, the highly resistant subpopulations have a selective
advantage and can overgrow the infection site to produce a relapse
• Host defenses are extremely important in this scenario
• Debilitated patients with pulmonary infections, abscesses, or
osteomyelitis are at high risk for drug failure
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 Antimicrobials: Overview

2/24/2021 44
 -Lactam antibiotics
 Bactericidal (except against Enterococcus sp.)
 Penicillins only get into CSF in the presence of inflamed
meninges
 parenteral 3rd and 4th generation cephs, meropenem, and
aztreonam penetrate the CSF
 Short elimination half-life (except for a few cephs like
ceftriaxone)
 Primarily renally eliminated (except nafcillin, oxacillin,
ceftriaxone, cefoperazone) → dosage adj required in the
presence of renal insufficiency
2/24/2021 45
 -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
 Cross- allergenicity - except aztreonam
2/24/2021 46
 -Lactams. . .Adverse Effects
 Neurologic – especially with penicillins and carbapenems
(imipenem and meropenem)
 Especially in patients receiving high doses in the presence of
renal insufficiency
 Irritability, confusion, seizures
 Hematologic
 Leukopenia, neutropenia, thrombocytopenia – prolonged therapy
(> 2 weeks)
• 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
2/24/2021 47
Natural Penicillins (Penicillin G, Penicillin VK)
Gram-positive Gram-negative
Pen- susc S. pneumoniae Neisseria sp.
Group A/B/C/G strep Anaerobes
viridans streptococci Clostridium sp.
Enterococcus
Other
Treponema pallidum (syphilis)
Penicillinase-Resistant Penicillins
(Nafcillin, Oxacillin, Methicillin)
Gram-positive
Methicillin - susceptible S. aureus
Penicillin-susceptible strains of Streptococci
2/24/2021 48
 Aminopenicillins(Ampicillin, Amoxicillin)
Increase activity against gram-negative aerobes
Gram-positive Gram-negative
Pen-susc. S. aureus Proteus mirabilis
Pen-susc. streptococci Salmonella,
viridans streptococci some E. coli
Enterococcus sp. L- H. influenzae
Listeria monocytogenes

2/24/2021 49
 Carboxypenicillins. . .
(Carbenicillin, Ticarcillin)
Developed to further increase activity against resistant
gram-negative aerobes
Gram-positive Gram-negative
Marginal Proteus mirabilis
Salmonella, Shigella
some E. coli
L- H. influenzae
Enterobacter sp.
Pseudomonas aeruginosa

2/24/2021 50
 Ureidopenicillins.(Piperacillin,
Azlocillin)

2/24/2021 51
 -Lactamase Inhibitor Combos
• Ampicillin- sulbactam, Amoxicillin- clavulanate, Ticarcillin-
clavulanate and Piperacillin-Tazobactam
• enhance activity against -lactamase producing organisms
(some better than others)
• Provides some or good activity against:
Gram-positive Gram-negative
S. aureus (MSSA) H. influenzae
E. coli
Anaerobes Proteus sp.
Bacteroides sp. Klebsiella sp.
Neisseria gonorrhea
Moraxella catarrhalis

2/24/2021 52
 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 A/B/C/G Streptococci P. mirabilis
viridans streptococci
But not
Listeria monocytogenes
Enterococci

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 Second Generation Cephalosporins
Gram-positive Gram-negative
meth-susc S. aureus E. coli
pen-susc S. pneumoniae K. pneumoniae
Group A/B/C/G strep P. mirabilis
viridans streptococci H. influenzae
M. catarrhalis
Neisseria sp.
The cephamycins (Cefmetazole, cefoxitin and cefotetan)
Anaerobes
Bacteroides fragilis

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 Third Generation Cephalosporins
Less on gram-positive
• Ceftriaxone and cefotaxime → pen-resistant S. pneumoniae
Gram-negative aerobes
• E. coli, K. pneumoniae, P. mirabilis
• H. influenzae, M. catarrhalis, N. gonorrhoeae (including beta-
lactamase producing); N. meningitides
• Citrobacter sp., Enterobacter sp., Acinetobacter sp.
• Morganella morganii, Serratia marcescens, Providencia
• Pseudomonas aeruginosa (Ceftazidime and Cefoperazone)

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 Fourth Generation Cephalosporins
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 cefpirome and cefepime is currently available

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 Fifth Generation Cephalosporins
• Ceftaroline and Ceftipiprole
• Exhibits broad-spectrum activity against Gram-positive bacteria,
including MRSA
• Efficacy against many respiratory pathogens including
Streptococcus pneumoniae, Haemophilus influenzae, and
Moraxella catarrhalis.

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 Carbapenems
• Imipenem/cilastatin , Meropenem, Doripenem and Ertapenem

• Most broad spectrum of activity of all antimicrobials

• Have activity against gram-positive and gram-negative aerobes

and anaerobes

• Bacteria not covered by carbapenems include MRSA, VRE,

coagulase-negative staph, C. difficile, Nocardia

• Additional Ertapenem exceptions:

• Pseudomonas and Enterococcus

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 Monobactams
• Aztreonam bind preferentially to PBP 3 of gram-
negative aerobes;
• has little to no activity against gram-positives or
anaerobes.

Gram-negative
E. coli, K. pneumoniae, P. mirabilis, S. marcescens
H. influenzae, M. catarrhalis
Enterobacter, Citrobacter, Providencia, Morganella
Salmonella, Shigella
Pseudomonas aeruginosa
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 Fluoroquinolones
• The most commonly used
Broad spectrum of activity
Improved PK properties
1. Excellent oral bioavailability (affected by Divalent cations)
2. Deep tissue penetration (intracellular )
3. Prolonged half-lives
Overall safety
1st G 2nd G 3rd G 4th G
Naldixic acid Norfloxacin Levofloxacin Moxifloxacin
Oxalinic acid Lomefloxacin Spatfloxacin Gamifloxacin
Ciprofloxacin Gatifloxacin Sitafloxacin
Ofloxacin Pefloxacin Prulifloxacin
Temafloxacin Trovafloxacin
Tosufloxacin Clinafloxacin
Prulifloxacin
Moderate Gram- lack S.pneumonia Improved Gram – Anaerobic also
negative
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 FQs Spectrum of Activity
• Gram-positive – newer FQs with enhanced potency
• MSSA, Streptococcus pneumoniae (including PRSP)
• Group A/B/C/G and viridans streptococci – limited activity
• Enterococcus sp. – limited 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
• Atypical Bacteria – all FQs have excellent activity against atypical
bacteria including:
 Legionella pneumophila, Chlamydia sp., Mycoplasma sp., Ureaplasma urealyticum
• Other Bacteria – Mycobacterium tuberculosis, Bacillus anthracis
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 Fluoroquinolones. . .Adverse Effects
• GIT – (most common)
Nausea, vomiting, diarrhea, dyspepsia
• CNS (due to GABA antagonistic action)
Headache, Dizziness, sleep disorders, mood changes, agitation,
rarely, hallucinations and seizures (elderly)
• Hepatotoxicity
LFT elevation (led to withdrawal of trovafloxacin)
• Photo toxicity (uncommon with current FQs)
Lomefloxacin>>sparfloxacin >pefloxacin)
• Cardiac
Variable prolongation in QTc interval
Led to withdrawal of grepafloxacin, sparfloxacin
Gatifloxacin, Moxifloxacin
 Bone, soft tissue, tendonitis (C/I children, pregnancy)
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 Macrolides
• Erythromycin
• problems with acid lability, narrow spectrum, poor GI
intolerance, short elimination half-life
• clarithromycin and azithromycin:
 Broader spectrum of activity
 Improved PK properties – better bioavailability, better
tissue penetration, prolonged half-lives
 Improved tolerability

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 Spectrum of Activity
• Gram-Positive Aerobes – erythromycin and
clarithromycin display the best activity
(Clarithro>Erythro>Azithro)
• MSSA, Streptococcus pneumoniae (only PSSP)
• Group A/B/C/G and viridans streptococci
• Bacillus sp., Corynebacterium sp.
• Gram-Negative Aerobes – newer macrolides with
enhanced activity
(Azithro>Clarithro>Erythro)
• H. influenzae (not erythro), M. catarrhalis, Neisseria sp.,
Campylobacter jejuni, Bordetella pertussis
• The greater activity of azithromycin against the
Enterobacteriaceae is of questionable clinical significance

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 Spectrum of Activity. . .
Anaerobes – activity against upper airway anaerobes
Atypical Bacteria – all macrolides have excellent activity
against atypical bacteria including:
• Legionella pneumophila
• Chlamydia sp.
• Mycoplasma sp.
• Ureaplasma urealyticum
Other Bacteria – Mycobacterium avium complex (MAC –
only A and C), Treponema pallidum, Campylobacter,
Borrelia, Bordetella, Brucella. Pasteurella

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 Pks ---
• Erythromycin – variable absorption (15-45%); 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, 55% bioavailable
regardless of presence of food
• Azithromycin –acid stable; 38% bioavailable; food decreases
absorption of capsules
• Extensive tissue and cellular distribution – clarithromycin and
azithromycin with extensive penetration
• Minimal CSF penetration
• 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
2/24/2021 66
 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

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 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

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 AMINOGLYCOSIDES
Spectrum of Activity
Gram-Positive Aerobes
Most S. aureus and coagulase-negative staph viridans
streptococci (in combination with a cell-wall agent)
Enterococcus sp. (only in combination with a cell-wall agent)
Gram-Negative Aerobes (not streptomycin)
E. coli, K. pneumoniae, Proteus sp.
Acinetobacter, Citrobacter, Enterobacter sp.
Morganella, Providencia, Serratia, Salmonella, Shigella
Pseudomonas aeruginosa (tobra>amik>gent)
Mycobacteria
 tuberculosis - streptomycin
 atypical - streptomycin or amikacin
2/24/2021 69
 PKs-----
• Absorption - poorly absorbed from GI tract
• Distribution
• primarily in extracellular fluid volume; are widely
distributed into body fluids but NOT the CSF
• distribute poorly into adipose tissue, use LBW for dosing
• Elimination
• eliminated unchanged by the kidney via glomerular
filtration; 85-95% of dose
• elimination half-life dependent on renal fxn
 normal renal function - 2.5 to 4 hours
 impaired renal function - prolonged

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 Aminoglycosides. . .Adverse Effects
Nephrotoxicity
• nonoliguric azotemia due to proximal tubule damage;
increase in BUN and serum Cr; reversible if caught early
• risk factors: prolonged high troughs, long duration of
therapy (> 2 weeks), underlying renal dysfunction, elderly,
other nephrotoxins
Ototoxicity
• 8th cranial nerve damage - vestibular and auditory
toxicity; irreversible and saturable
• vestibular: dizziness, vertigo, ataxia
• auditory: tinnitus, decreased hearing (irreversible)
• risk factors: same as for nephrotoxicity
Neuromuscular blocking
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 Vancomycin

Spectrum of Activity
Gram-positive bacteria
• Methicillin-Susceptible AND Methicillin-Resistant S.
aureus and coagulase-negative staphylococci
• Streptococcus pneumoniae (including PRSP), viridans
streptococcus, Group A/B/C/G streptococcus
• Enterococcus sp.
• Corynebacterium, Bacillus. Listeria, Actinomyces
• Clostridium sp. (including C. difficile), Peptococcus,
Peptostreptococcus
• Bactericidal (except for Enterococcus)
No activity against gram-negative aerobes or
anaerobes
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 Vancomycin. PKs--
• Poor Oral, BA (PO only for GI infection)
• IV (slowly), never IM
• Widely distributed into body tissues and fluids, including adipose
tissue; use TBW for dosing
• Inconsistent penetration into CSF, even with inflamed meninges
• primarily eliminated unchanged by the kidney via glomerular
filtration

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 Oxazolidinones
• Linezolid
• available PO (100% bioavailable) and IV
• readily distributes into well- perfused tissue; CSF
penetration  70%
• Activity against resistant gram-positives (MRSA,
GISA, VRE)
• Bacillus. Listeria, Clostridium sp. (except C. difficile),
Peptostreptococcus, P. acnes
Gram-Negative Aerobes – relatively inactive
Atypical Bacteria
• Mycoplasma, Chlamydia, Legionella

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 Linezolid . . .Adverse Effects
• Gastrointestinal – nausea, vomiting, diarrhea (6 to 8 %)
• Headache – 6.5%
• Thrombocytopenia – 2 to 4%
• Most often with treatment durations of > 2 weeks
• Therapy should be discontinued – platelet counts will
return to normal
Drug–Drug/Food interactions
• Linezolid is a reversible, nonselective inhibitor of
monoamine oxidase.
• Tyramine rich foods, adrenergic drugs and
serotonergic drugs should be avoided due to the
potential drug-food and drug-drug interactions
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 Clindamycin

Mechanism of Action
 Inhibits protein synthesis by binding exclusively to the
50S ribosomal subunit
 Binds in close proximity to macrolides – competitive
inhibition
 Clindamycin typically displays bacteriostatic activity, but
may be bactericidal when present at high concentrations
against very susceptible organisms

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 Clindamycin
Spectrum of Activity
Gram-Positive Aerobes
• Methicillin-susceptible Staphylococcus aureus (MSSA)
• Methicillin-resistant Staphylococcus aureus (MRSA) – some
isolates
• Streptococcus pneumoniae (only PSSP) – resistance is developing
• Group and viridans streptococci
Anaerobes – activity against Above the Diaphragm
Anaerobes (ADA)
• Peptostreptococcus some Bacteroides sp
• Actinomyces Prevotella sp.
• Propionibacterium Fusobacterium
• Clostridium sp. (not C. difficile)
Other Bacteria – Toxoplasmosis gondii, Malaria
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 Clindamycin. . .PKs---
• Available IV and PO (Rapidly and completely absorbed (90%))
• Good tissue penetration including bone; minimal CSF
penetration
• Clindamycin primarily metabolized by the liver
Clindamycin. . .Adverse Effects
• Gastrointestinal – 3 to 4 %
 Nausea, vomiting, diarrhea, dyspepsia
• C. difficile colitis – one of worst offenders
 Mild to severe diarrhea
 Requires treatment with metronidazole
• Hepatotoxicity - rare
 Elevated transaminases
• Allergy - rare
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 CHLORAMPHENICOL
• Currently a backup drug for infections due to Salmonella
typhi, B. fragilis, Rickettsia, and possibly in bacterial
meningitis
• Orally effective, with good tissue distribution, including
CSF
• Metabolized by hepatic glucuronidation, and dose
reductions are needed in liver dysfunction and in
neonates
• Inhibition of cytochrome P450
Side effects:
• Dose-dependent bone marrow suppression common;
aplastic anemia rare (1 in 35,000)
• “Gray baby” syndrome in neonates (↓ glucuronosyl
transferase)
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 Sulfamethoxazole- trimethoprim
(cotrimoxazole):
• DOC in Nocardia
• Listeria (backup)
• Gram-negative infections (E. coli, Salmonella, Shigella,
H.influenzae)
• Gram-positive infections (Staph., including
communityacquired MRSA, Strep.)
• Fungus: Pneumocystis jiroveci (back-up drugs are
pentamidine and atovaquone)
• Protozoa: Toxoplasma gondii (sulfadiazine +
pyrimethamine)