Principles of Infectious Diseases & Antimicrobial Regimen Selection 2024 (Sing) PDF
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2024
Brandon Sing
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This document presents lecture notes on principles of infectious disease and antimicrobial regimen selection, complete with detailed information on diagnosis, specific site symptoms, laboratory findings, and more. The material is suitable for a professional audience.
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Principles of Infectious Disease & Antimicrobial Regimen Selection BRANDON SING, PHARM.D., M.S., BCIDP [email protected] Objectives 2 By the end of the lecture students should be able to… Identify common diagnostic factors of inf...
Principles of Infectious Disease & Antimicrobial Regimen Selection BRANDON SING, PHARM.D., M.S., BCIDP [email protected] Objectives 2 By the end of the lecture students should be able to… Identify common diagnostic factors of infectious disease including labs, symptoms, and imaging studies Describe the process of pathogen identification and susceptibility testing and apply to case scenarios Differentiate between microbial infection vs. contamination vs. colonization Define empiric, definitive, and prophylactic antimicrobial prescribing and apply to cases Apply knowledge of antimicrobial prescribing principles to select case scenarios Identify important features of select microorganisms 3 Diagnosis of Infection General S&S of Infection 4 Vitals Hyperthermia (> 38 C) Hypothermia also possible (< 36 C) Tachycardia (> 100 bpm) Tachypnea (> 20 rpm) Hypotension (SBP < 100 mmHg) General Findings Headache, nausea/vomiting, fatigue, myalgia Site Specific S&S of 5 Infection Meningitis (CNS): change in mental status, confusion, dizziness, blurred vision, nuchal rigidity (stiff neck) Sinus infection: runny nose, congestion, headache, earache, dental pain Pneumonia: cough (productive or non-productive), shortness of breath, chest pain, hemoptysis GI/Intra-abdominal infection: abdominal pain, nausea, vomiting, diarrhea, bloody stools Urinary tract infection (UTI): dysuria, frequency, urgency, hematuria, flank pain Skin/Soft Tissue infection: erythema at infection site, swelling, pain, purulent discharge Imaging Studies 6 Usually site specific X-rays CT scans MRIs Ultrasounds Echocardiograms Etc. Laboratory Findings 7 Complete Blood Count with differential (CBC w/diff) WBC Leukocytosis Increased WBC (> 12,000 cells/mm^3) Leukopenia Decreased WBC (< 4,000 cells/mm^3) Differential Specifies percentage/count of WBC subtypes These findings can be non-specific Affected by things other than infection What else can affect WBC count? CBC Differential 8 Neutrophils- most common type of WBC in blood Leave the bloodstream and enter tissues in response to an infection Bandemia/Left shift (increase in bands - immature neutrophils) May exceed 10 – 20% of WBC in the presence of an infection Monocytosis (increase in monocytes) May occur in a variety of diseases including certain leukemias May indicate infections due to certain bacteria and protozoa Lymphocytosis (increase in lymphocytes) Often indicates presence of viral infection Eosinophilia (increase in eosinophils) May indicate parasitic infection or allergic reaction Other Lab Findings 9 Erythrocyte Sedimentation Rate (ESR) Normal (Westergren): 0 to 20 mm/h; females: 0 to 30 mm/h Non-specific (inflammatory marker) Used in osteomyelitis, endocarditis, IA anfections, SSTIs C-Reactive Protein Normal: 48 hours for culture results Culture Step 3: 17 Susceptibility Testing Used to determine in vitro susceptibilities of identified microorganism(s) to select antimicrobials Kirby-Bauer (disk diffusion) method Antibiotic wafer are placed on growing plate Clear ring, or “zone of inhibition” seen indicates susceptibility If organism is susceptible to an antibiotic is it okay to use? What’s in vitro? Minimum Inhibitory 18 Concentration (MIC) Testing Done with susceptibility testing to determine the MIC of each agent MIC The minimum concentration of antibiotic it takes to inhibit the growth of bacteria over a 24 hour period Agar/Broth dilution method What’s the MIC? MIC Breakpoints 19 CLSI & EUCAST publish breakpoints that are used to interpret MIC and zones of inhibition to classify each isolate-antibiotic pair as either susceptible, intermediate, or resistant. Susceptible (S): Bacteria susceptible to the antibiotic Intermediate (I): Bacteria partially susceptible to the antibiotic May be successful in urinary tract infection or if higher dosing is utilized (usually avoided) Resistant (R): Bacteria resistant to the antibiotic An alternative antibiotic should be utilized Can we compare breakpoints from one drug to another? MIC Breakpoint Example 20 Published E. coli breakpoints for ciprofloxacin Susceptible MIC < 0.25 Intermediate MIC 0.5 Resistant MIC > 1 How would you characterize this organism in relation to ciprofloxacin? Culture Timeline 21 Specimen Obtained Hour 0 Gram Stain/Preliminary Results Hour 24 Interim Results Hour 48 Final Results Hour 72 Susceptibility Testing Results Culture Report 22 Would cephalexin provide adequate coverage against this isolate? Additional Methods 23 MALDI-TOF Uses laser desorption/ionization time of flight mass spectrometry to identify pathogens Identification of pathogens can be done in several minutes instead of hours to days Antibody & Antigen Detection S. pneumonia urinary antigen, Legionella urine antigen Respiratory syncytial virus (RSV), herpes simplex virus, HIV surface antigen, C.diff antigen DNA/RNA Probes Often used for slow growing pathogens (Mycobacterium) Nucleic Acid Amplification Polymerase Chain Reaction (PCR) Useful for slow growing or fastidious organisms (Mycobacterium, Helicobacter pylori); C. diff MRSA nare swabs Is this an infection??? 24 Just because a culture grows doesn’t mean there’s an infection!!! Colonization Presence of organism at a site without the presence of an active infection Common with “UTIs” Contamination Organism isolated that came from a site other than the intended specimen site S. epidermidis is common blood contaminant Infection Invasive presence of organism at a site which usually results with host response Clinical Scenario 25 46 YOF presents to your hospital with 2 day complaint of “urinary burning” and frequent voiding (no other complaints). UA is indicative of infection and urine culture grows E. coli. Blood cultures are also collected which reveal coagulase negative staphylococcus in 1/4 bottles. The patient is hemodynamically stable, afebrile, and has a WBC count of 7,500 cells/mm^3. What should we treat??? 26 Antimicrobial Selection Types of Antimicrobial 27 Prescribing Prophylaxis Treatment to prevent an infection in an at-risk patient Empiric Therapy Treatment of a proven or suspected infection Organism responsible has NOT yet been identified Treat most likely causative pathogen(s) Definitive Therapy Treatment of a proven or suspected infection Culture and susceptibility results are known What type of prescribing? 28 1. Patient receives Ancef 30 mins prior to surgery to prevent a surgical site infection 2. Antibiotics are de-escalated from Zosyn to amoxicillin based on the susceptibility results of a urine culture 3. Patient receives vancomycin and ceftriaxone for suspected bacterial meningitis 4. Patient is given a prescription for azithromycin because of a cough 5. A female patient with AIDS and a CD-4 count of 12 receives azithromycin for prevention of Mycobacterium avium complex (MAC) Factors that influence 29 prescribing Allergies Age Patient History Pregnancy/Lactation Comorbid Conditions Drug Interactions Recent Antibiotic Use Local Resistance Patterns PK/PD Allergies 30 A careful assessment of allergy history should be performed and documented Drug & Type of Allergy (rash, hives, anaphylaxis, etc.) Differentiate between allergic reaction and adverse drug reaction Common antimicrobial allergies: Penicillin If the reaction is anaphylaxis, then all beta-lactams should be avoided Other beta-lactams may be okay, but avoid if can Aztreonam is safe to use in patients with penicillin allergy Cross Reactivity reported anywhere from < 1-10 % Sulfa Avoid sulfamethoxazole/trimethoprim (Bactrim) Sulfa ≠ Sulfur ≠ Sulfate ≠ Sulfite Antibiotic Cross Reactivity 31 ***Does not necessarily correlate to cross-reactivity*** Age 32 Age-dependent empiric selection Eg. Bacterial Meningitis Most likely pathogens differ for neonates, children, adults, and older adults Neonatal concerns Kernicterus – bilirubin displacement and accumulation Ceftriaxone Sulfamethoxazole/trimethoprim Age-related decline in renal function Renal adjustments to antibiotics may be necessary May be more susceptible to antibiotic toxicities Some antibiotics may not works at well (eg. nitrofurantoin for UTI) How do we renally adjust? Patient History 33 Recent Hospitalization Or other institutionalization Recent Antibiotic Usage IV, PO, when, what drug, treatment outcome Exposure to pathogens Travel, exotic pets/animals, work/living environment History of infection or colonization Past culture data Pregnancy/Lactation 34 Certain antibiotics are teratogenic Tetracyclines Drug accumulation in developing teeth and long bones Fluoroquinolones Toxic to developing cartilage Sulfamethoxazole/trimethoprim (1st trimester) Congenital malformations Beta-lactams are generally considered safe to use in pregnancy Drug clearance may increase for certain antibiotics during pregnancy, so increased dosages may be required Consider whether or not antibiotic is excreted in the breast milk Comorbid Conditions 35 Diabetes mellitus and peripheral vascular disease More likely to develop skin/soft tissue infections of the lower extremities (often polymicrobial infections) Seizure disorders Some antibiotics will lower the seizure threshold Examples: carbapenems and fluoroquinolones Important to consider patient’s level of immune function Immunocompromised patients may be predisposed to certain infections Chemotherapy → neutropenic fever AIDS → sulfamethoxazole/trimethoprim for PCP Drug Interactions 36 QTc prolongation Fluoroquinolones, macrolides, azole antifungals Review patient’s medication list for other QTc prolonging agents Methadone, antidepressants, antipsychotics, antiarrhythmics, etc. Multi-valent cations Calcium, magnesium, iron, multivitamins, antacids, etc. May decrease the absorption of tetracyclines and fluoroquinolones Make sure to separate administration General rules for separation: Give antibiotic 2 hours before or 4 hours after the interacting drug Birth control? Rifampin only proven risk Local Resistance Patterns 37 Antibiogram A collection of information obtained from culture and susceptibilities performed within an institution of a years time Others 38 Drug Cost Drug Toxicity/Adverse Effects Site of Infection Local vs systemic Severity of infection PK/PD PK/PD 39 Pharmacodynamics Bactericidal - Kills bacteria Beta-lactams, fluoroquinolones, vancomycin, metronidazole Bacteriostatic - Inhibits bacterial growth Macrolides, tetracyclines, oxazolidinones Post-antibiotic effect (PAE) Synergy & Antagonism Pharmacokinetics Distribution/penetration to site of infection Skins, Lungs, Bone, Brain, etc. Bioavailability – IV to PO Elimination – renal adjustments PK/PD Relationships Time-dependent, concentration-dependent, AUC:MIC Time-dependent 40 Goal: Maximize the duration of time that drug levels are above MIC Examples: Beta-lactams (penicillins, cephalosporins, carbapenems) Dosing strategies: Extended or continuous infusions Shorter dosing intervals (more frequent dosing) Concentration-dependent 41 Goal: Maximize peak concentration (Cmax) High peak; low trough Examples: Aminoglycosides, fluoroquinolones, daptomycin, etc. Dosing Strategy: Large doses given less frequently AUC:MIC-dependent 42 Goal: Maximize overall drug exposure over time Ratio of area under the curve (AUC) to the MIC Accounts for time and concentration Examples: Vancomycin (goal: AUC:MIC > 400) Macrolides Tetracyclines Post-Antibiotic Effect (PAE) 43 Persistent suppression of bacterial growth after exposure and removal of antibiotic Aminoglycosides, fluoroquinolones, macrolides, tetracyclines PAE Synergy & Antagonism 44 Synergy - antibiotics used in conjunction to achieve an effect greater than the sum of the individual effects May be important in treating organisms such as 1+1= 3 Pseudomonas or Enterococcus spp. Eg. Beta-lactam and Aminoglycoside for Enterococcal infections Antagonism - addition of second drug may counteract activity of first drug This may occur with drugs given concomitantly 1+1= 0 that have similar mechanisms Eg. azithromycin and clindamycin can compete for same binding site on ribosome Monotherapy vs. 45 Combination therapy Monotherapy Definitive therapy targeting one organism Empiric therapy where spectrum of agent is enough to cover all probable pathogens Combination Therapy Empiric therapy requiring spectrum larger than that of single agent Treating multiple infections/organisms at once Resistance may develop during therapy TB, HIV, Pseudomonas sp., Enterobacter sp., Serratia sp. Monotherapy shown not to eradicate organism Enterococcal bactermia or endocarditis Treatment Duration 46 May range from 1 dose to 6 months or longer Dependent on… The organism Type of infection Severity of infection Response to therapy Relapse or new infection Patient’s organ function Pharmacokinetics of the medications Refer to guidelines (IDSA) for site specific empiric therapy options and duration of therapy Treatment Outcomes 47 S/Sx Response Bacteriologic Response Clinical cure Yes Yes Microbiologic cure Maybe Yes Failure (relapse) Maybe (but then return) No Re-infection Yes (but then return) Maybe (but then return) 48 Microbiology Review Gram-Positive Organisms 49 https://upload.wikimedia.org/wikipedia/commons/thumb/0/03/Gram-Positive_Classification.png/660px-Gram-Positive_Classification.png Staphylococcus 50 Gram-positive cocci in clusters Coagulase positive S.aureus (MSSA vs. MRSA) Part of the normal flora of the body (nose, skin, resp. tract) Common cause of skin and soft tissue infections Capable of producing exotoxins (i.e. toxic shock syndrome) Coagulase negative S.epidermidis Part of the normal skin flora (can still be pathogenic) S.saprophyticus Part of the normal flora of the female genital tract Relatively common cause of UTI in young sexually active females MRSA 51 Methicillin-resistant Staphylococcus aureus Mechanism: altered penicillin-binding protein (PBP) Streptococcus 52 Gram-positive cocci in chains or pairs Alpha Hemolytic (partial) Streptococcus pneumoniae Common colonizer of the respiratory tract and sinuses Common cause of community acquired pneumonia and meningitis Viridans group Streptococci Common colonizers of the oral cavity Associated with infective endocarditis Beta Hemolytic (complete) GAS – Streptococcus pyogenes Common cause of pharyngitis (Strep throat) and skin infections GBS – Streptococcus agalactiae Common colonizer of vagina Vertical transmission to fetus is possible (importance of intrapartum antibiotics) Gamma Hemolytic (non-hemolytic) GDS - Enterococcus Enterococcus 53 Gram-positive cocci in pairs or short chains Common colonizers of the gastrointestinal (GI) tract Associated with many different types of infections UTIs, infective endocarditis, meningitis, wound infections, etc. Examples: Enterococcus faecalis More common and generally easier to treat Enterococcus faecium Less common and generally more difficult to treat Majority of vancomycin-resistant Enterococci (VRE) are E.faecium Enteric - of, relating to, or affecting the intestines Clostridium 54 Anaerobic gram-positive bacilli Spore forming and toxin producing Commonly found in soil Examples: Clostridium tetani Causes tetanus (Lockjaw) Clostridium perfringens Causes gas gangrene Clostridium botulinum Causes botulism (severe form of food poisoning) Clostridium difficile (now Clostridioides difficile) Produces pseudomembranous colitis Normal flora of intestine Gram-Negative Organisms 55 Enterobacteriaceae 56 Enteric gram-negative rods Often referred to as “coliforms” Common colonizers of the gastrointestinal (GI) tract Family includes E.coli, Klebsiella, Enterobacter, Serratia, Proteus, Morganella, Providencia, Citrobacter, Salmonella, Shigella, etc. Common causes of UTI, gastroenteritis, and peritonitis Increasingly associated with antimicrobial resistance Extended-spectrum beta-lactamase producers (ESBLs) Carbapenem-resistant Enterobacteriaceae (CRE) Enteric - of, relating to, or affecting the intestines Pseudomonas aeruginosa 57 Gram-negative, oxidase-positive rod Colonizes many different environments i.e. moist environments, humans, etc. A multi-drug resistant organism (MDRO) Multi-drug efflux pumps Beta-lactamase production Decreased permeability Associated with a wide variety of infections: Nosocomial infections Eg. ventilator-associated pneumonia Haemophilus influenzae 58 Gram-negative rod Common colonizer of the respiratory tract Often associated with beta-lactamase production Associated with mucosal infections such as pneumonia, sinusitis, otitis media, etc. One of the common community-acquired pneumonia (CAP) pathogens Bacteroides fragilis 59 Gram-negative anaerobic rod Somewhat tolerant to oxygen (2-8%) Common colonizer of the gastrointestinal tract Commonly associated with secondary peritonitis Example: bowel perforation, appendicitis, surgery, etc. Atypicals 60 Organisms with unique or atypical cell wall/cell membrane structures These organisms are also potential atypical causes of CAP Organisms include: Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophila Beta-lactams lack atypical coverage Aerobic vs. Anaerobic 61 Refers to way bacteria make energy Cellular respiration (Glucose → ATP) Aerobic Require oxygen to make energy Glycolysis → Krebs Cycle → Electron Transport Chain Anaerobic Oxygen not required Lactic Acid or Alcoholic Fermentation Facultative vs. obligate 62 Questions 63 References 64 Carroll KC, Hobden JA, Miller S, Morse SA, Mietzner TA, Detrick B, Mitchell TG, McKerrow JH, Sakanari JA. eds. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 27e New York, NY: McGraw-Hill. Lee GC, Burgess DS. Antimicrobial Regimen Selection. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 12e New York, NY: McGraw-Hill. Rybak MJ, Aeschlimann JR, LaPlante KL. Laboratory Tests to Direct Antimicrobial Pharmacotherapy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 12e New York, NY: McGraw-Hill.
