Infectious disease pharmacotherapy

1. Infectious diseases Pharmacotherapy
Lesson 1
Antimicrobial Regimen Selection
By: Tsegaye Melaku
[B.Pharm, MSc, Clinical Pharmacist]
tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.etApril, 2017 +251913765609

2.  Upon completion of the chapter, you will be able to:
Describe factors that a clinician should follow to select an
appropriate antimicrobial regimen.
List the reasons for obtaining microbiology samples (i.e., blood
cultures, sputum, urine, etc.) before the institution of
antimicrobial therapy.
Elaborate the important host factors that must be considered
when choosing an antimicrobial regimen for a patient.
Discuss the advantages and disadvantages of combination
antimicrobial therapy.
Identify when a patient could be transitioned from intravenous
to oral therapy.
List reasons for a patient to fail a specific antimicrobial
regimen.

3. I AM
ANTIBACTERIA..
I AM BACTERIA
…PLZ SPARE
ME….

4. Choosing an antimicrobial agent to treat an infection is far more
complicated than matching a drug to a known or suspected
pathogen.
So, need systematic approach in selection.
Consequences of not using the systematic approach 
Use of more expensive agents.
Potentially more toxic agents.
Widespread resistance.
Difficult-to-treat super-infections.
Use for self-limited clinical conditions that are most
likely viral in origin (i.e., the common cold).

5. Initial selection of antimicrobial therapy is nearly always
empirical,
Which is prior to documentation and identification of
the offending organism.
Infectious diseases generally are acute.
A delay in antimicrobial therapy can result in serious
morbidity or even mortality.

6.  Confirm the presence of infection
 Careful history and physical
 Signs and symptoms
 Predisposing factors
 Identification of the pathogen
 Collection of infected material
 Stains
 Serologies
 Culture and sensitivity
 Selection of presumptive therapy
considering every infected site
 Host factors
 Drug factors
 Monitor therapeutic response
 Clinical assessment
 Laboratory/diagnostic tests
 Assessment of therapeutic
failure

7. Fever
Temperature greater than the expected 37°C (98.6°F).
Hallmark of infectious diseases.
Is controlled elevation of body temperature above the
normal range.
Average normal body temperature range taken orally is
36.7 to 37°C (98.0–98.6°F).
Rule out other causes  drug induced, autoimmune
diseases and malignancies.
Rectally vs. axillary vs. oral temperatures
– Rectal= oral + 0.6 °C (1°F) ; Axillary= Oral- 0.6 °C (1°F)

8. ‘’False-positive’’
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, NSAIDS agents,
and corticosteroids
– Careful questioning of the patient or family is vital

9. WBC Count
Normal: 4,000 and 10,000 cells/mm3.
Bacterial infections:
– Granulocyte counts, often with immature forms (band
neutrophils)
WBC count and differential
Left shift: Presence of immature forms
– Indication of an increased bone marrow response to
the infection
Segmented neutrophils or polymorphonuclear (PMN) leukocytes
WBC higher than 30,000 to 40,000 cells/mm3 : rare

10. Neutropenia: poor prognosis
– Low leukocyte counts after the onset of infection
Tuberculosis and viral or fungal infections:
– Lymphocytosis, even with normal or slightly elevated total
WBC counts,
Tuberculosis or lymphoma:
– Monocytes
Allergic reactions to drugs or infections :
– Eosinophils can be associated with

11. Local Signs
Classic signs of pain and inflammation
–Swelling, erythema, tenderness, and purulent drainage.
–Only visible if the infection on superficial/bone or joint.
In deep seated (Meningitis, pneumonia, endocarditis, and
urinary tract infection): tissues or fluids.
 For example: Bacterial infection:
– CNS infection: Neutrophils in spinal fluid
– UTI: pyuria
– Pyelonephritis: flank pain and dysuria
– Pulmonary infection: cough and sputum production

12. Symptoms referable to an organ system must be sought out
carefully because 
– Help in establishing the presence of infection.
– Aid in narrowing the list of potential pathogens.
– E.g. a febrile patient with complaints of flank pain and
dysuria: pyelonephritis.
 Enteric gram-negative bacilli (E. coli) predominant
pathogens.
– A febrile individual with cough and sputum production
pulmonary infection.

13.  Infected body materials must be sampled, before institution of any
antimicrobial therapy
Gram stain
–might reveal bacteria, or an acid-fast stain might
detect mycobacteria or actinomycetes.
A delay in obtaining infected fluids or tissues until after
antimicrobial therapy is started might result in false-negative
culture.
Microbiology Issues
Specially in UTIs, meningitis, and septic arthritis.

14. Determining colonization versus Infection
Infection: presence of bacteria that are causing disease with
signs/symptoms of infection.
Colonization: presence of bacteria that are not causing
disease.
True pathogen, a contaminant, or a part of the normally expected
flora
Skin, oropharynx, nose, ears, eyes, throat, and perineum
Coagulase-negative staphylococci
blood, venous access catheters, or prosthetic devices).

15. Normal flora and concentrations of bacteria (organisms per milliliter)

16. Combination of tests:
Urine cultures and urinalysis
– WBCs, nitrite, and leukocyte esterase
Sputum:
Squamous epithelial cells and leukocytes; predominance of
epithelial cells with multiple organisms or leukocytes in large
numbers with one predominant type of organism

19. Variety of factors must be considered:
Severity and acuity of the disease.
Host factors.
Drugs related factors .
Necessity for using multiple agents.
Antibiogram(local)
Antibiotic susceptibilities a guide empirical antibiotic therapy
Determine DOC

20. Determine site(s) where infection was acquired:
Home vs. community acquired),
Nursing home environment, or
Hospital acquired (nosocomial)
–Exposed to potentially more resistant organisms
–often surrounded by ill patients who are receiving
antibiotics.
Infections above the diaphragm Cocci & Gram +ve organisms
Infections below the diaphragm  Bacilli & Gram -ve organisms

21. Other: ask for :
Are any other people sick at home?
Are any unusual pets kept in the home?
Where are you employed (i.e., are you exposed to
contaminated meat or infectious biohazards)?
Has there been any recent travel (i.e., to endemic areas of
fungal infections or developing countries)?

22. Drug allergies
Site of infection,
Age:
chloramphenicol (gray baby syndrome): newborn
Kernicterus: sulfonamides.
Renal toxicity: aminoglycosides
Pregnancy:
Penicillins, cephalosporins, and aminoglycosides (50%)
Check for safety and effectiveness

23. Genetic/metabolic variation:
– Peripheral neuropathy: Slow vs. Fast acetylators
(isoniazid)
Hemolysis:
– Glucose-6-phosphate dehydrogenase
– Sulfonamides, nitrofurantoin, nalidixic acid,
antimalarials, dapsone, and chloramphenicol
– Severity:
» African Americans vs. Eastern Mediterranean origin

24. Organ Function
Liver disease:
– Clindamycin, erythromycin, metronidazole, and
rifampin.
Renal dysfunction:
– Cefotaxime, nafcillin, piperacillin & sulfamethoxazole.
Any concomitant therapy:
– Isoniazid and phenytoin
– HAART and Anti TB

25. Concomitant Diseases
Diabetes mellitus
– Peripheral vascular disease; altered immunity
Chronic lung disease or cystic fibrosis
Immunosuppressive diseases
– Malignancies or acquired immunologic deficiencies
Chemotherapy
Trauma, burns, and surgery

26. Pharmacokinetic and pharmacodynamics considerations
Tissue Penetration
Drug Toxicity.
Cost

27. Pharmacokinetic and Pharmacodynamic Considerations
Aminoglycosides
concentration-dependent effect
high-dose, once-daily aminoglycosides
Post-antibiotic
Aminoglycosides, clindamycin, macrolides, ketolides, and
tetracyclines
Concentration-dependent killing
Fluoroquinolones

28. Pharmacokinetic and Pharmacodynamic Considerations
Beta-Lactams:
time-dependent bactericidal effects (T > MIC)
Effective dosing regimens require serum drug concentrations to
Exceed the MIC for at least 40% to 50% of the dosing
interval.
Beta-lactams:
Frequent small doses or a continuous infusion

29. Site with limited/no slit junctions to be considered
Hydrophilicity/hydrophobicity
CAF, Metronidazole, Ampicillin, Vancomycin, etc
Tissue penetration

30. CNS Toxicities
Penicillins, Cephalosporins, Quinolones, And Imipenem).
Hematologic Toxicities:
Nafcillin (Neutropenia)
Piperacillin (Platelet Dysfunction)
Cefotetan (Hypoprothrombinemia)
Chloramphenicol (Bone Marrow Suppression)
– Both Idiosyncratic And Dose-related Toxicity)
Trimethoprim (Megaloblastic Anemia)
Drug toxicity

31. Reversible nephrotoxicity:
Aminoglycosides and Vancomycin.
Reversible ototoxicity:
Aminoglycosides or erythromycin.
Photosensitivity:
Azithromycin, quinolones, tetracyclines, pyrazinamide,
sulfamethoxazole, and trimethoprim.
Clostridium difficile(AAD): Collateral damage
Drug toxicity

32. Storage, preparation, distribution, and administration, monitoring
Pharmacoeconomic
Cephalosporins, linezolid, and fluoroquinolones
Extended-spectrum killing activity vs. narrow-spectrum
Oral vs. intravenous
Convenient once-a-day expensive agents versus multiple-dose
inexpensive agents arises.
Costs

33. Polymicobial: Intraabdominal and female pelvic infections
Aminoglycoside and metronidazole or clindamycin
Synergism: in immunocmpromised
Aminoglycosides and -lactams (P. aeruginosa and Enterococcus)
Penicillin and streptomycin or gentamicin
 Enterococcal Endocarditis
Preventing Resistance:
The use of combinations to prevent the emergence of resistance
is applied widely but not often realized.

34. Disadvantages of Abx. Combination
Increased cost.
Greater risk of drug toxicity such as nephrotoxicity with
aminoglycosides, amphotericin, and vancomycin.
Superinfection with even more resistant bacteria.
Result in antagonistic effects.
Example:- when one drug induces ß-lactamase production and
another drug is ß-lactamase unstable.
 Cefoxitin and imipenem  drugs capable of inducing ß-
lactamases  result in more rapid inactivation of penicillins
when used together.

35.  Culture and sensitivity reports.
 The same parameters used to diagnose the infection.
 WBC count and temperature .
 Diminish in (i.e., decreased pain, SOB, cough/sputum production).
 Appetite, Radiologic improvement
 Antimicrobials serum concentration monitoring
 Aminoglycosides, flucytosine, and chloramphenicol
 Re-evaluated for route of administration should be
 Streamlining (switch) therapy: parenteral to oral.

36. You can also consider ‘’antibiotic descalation’’
Switching the route of administration: Criteria
Overall clinical improvement,
Lack of fever for 8 to 24 hours,
Decreased WBC count,
A functioning GIT.
Excellent oral BA when compared with IV formulations
Ciprofloxacin, levofloxacin, Moxifloxacin,
Clindamycin, doxycycline,
Metronidazole, linezolid, and trimethoprim-sulfamethoxazole.

37. Step-down therapy:
 Conversion of an IV antibiotic to another oral
Transitional therapy:
 Conversion from same IV antibiotic to oral but not of same dosage
or strength
Sequential therapy:
 Conversion from same IV antibiotic to oral of same dosage and
strength

38.  Lack of respond over 2 to 3 days
 Non-bacterial in origin, undetected pathogen
 Drug interaction
 Complexation of fluoroquinolones with multivalent cations
 Laboratory error
 Failure due to drug selection, dosage, or route of administration.
 Malabsorption (short-bowel syndrome)
 Other factors:
 The host, or the pathogen.

39.  Cystic fibrosis or during pregnancy
 Accelerated drug elimination
 Aminoglycosides
 Penetration problems
 CNS, eye, and prostate gland
 Failure caused by host factors:
 Immunosuppressed (e.g., granulocytopenia from chemotherapy or
AIDS)
 Surgical drainage of abscesses or removal of foreign bodies/indwelling
catheters, necrotic tissue : Poor source control

40.  Two types of resistance: intrinsic and acquired.
 Intrinsic resistance
 When the antimicrobial agent never had activity against the
bacterial species.
– E.g. gram(-)bacteria are naturally resistant to vancomycin.
 Acquired resistance
 When the antimicrobial agent was originally active against the
bacterial species but later develop resistance.
 Mxms
– Alteration in the target site,
– Change in membrane permeability,
– Efflux pump,
– Drug inactivation.

41.  Primary resistance (intrinsic)
 Enterococci, pneumococci, and Mycobacterium tuberculosis.
 Enterococci have been isolated with multiple resistance patterns.
 Beta-lactams (in case of enterococci)
 by virtue of B-lactamase production, altered penicillin-binding
proteins [PBPs], or both
 Vancomycin
 via alterations in peptidoglycan synthesis
 High levels of aminoglycosides
 via enzymatic degradation

42.  Pneumococci resistant to penicillins, certain cephalosporins, and
macrolides
 Causes:
 Overgrow; Overuse; immunosuppressed patients; long-term
suppressive antimicrobials
 P. aeruginosa:
 Resistance developed during antimicrobial therapy (20% to 30%)
 Beta-lactamase producing organisms:
 Enteric gram-negative bacilli (P. aeruginosa, Enterobacter aerogenes,
Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and
a few others)

45. Environmental
Factors
Drug Related
Factors
Patient Related
Factors
Prescriber
Related Factors
Antibiotic
Resistance

48. Spectrum of Activity of each antimicrobials
Antimicrobial resistance (Bacteria, Viral, protozoa, helminths, etc)
 Mechanisms
 Risk factors
 Burden
 How to tackle (your role as Pharmacist)

49. The End