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Clinical use of antibiotic therapy Russell E. Lewis Associate Professor of Medicine, Infectious Diseases (MED/17) 26 February 2024 DMM Dipartimento di Medicina Molecolare Objectives Examine the clinical process of rationale and appropriate antibiotic therapy selection: BACTERIA-C concept Recognize p...

Clinical use of antibiotic therapy Russell E. Lewis Associate Professor of Medicine, Infectious Diseases (MED/17) 26 February 2024 DMM Dipartimento di Medicina Molecolare Objectives Examine the clinical process of rationale and appropriate antibiotic therapy selection: BACTERIA-C concept Recognize patient- and disease-specific factors that influence the choice of antibiotics Demonstrate how electronic medical resources can be used to select doses and screen for drug interactions to optimize antimicrobial dosing Antibiotics are miracle drugs… Source: Getty images Antibiotic resistance as cause of patient death: 1,270,000 patients Antibiotic resistance a contributor to patient death: 5,000,000 patients COVID 19 deaths in 2020: 1.8 million (some have estimated as high as 3 million excess deaths) Murray, C. J. L. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet (2022) World Health Organization (WHO) Critical Pathogens List The situation in Italy Methicillin-resistant Staphylococcus aureus Source: http://atlas.ecdc.europa.eu/public/index.aspx The situation in Italy Carbapenem-resistant Enterobacterales Source: http://atlas.ecdc.europa.eu/public/index.aspx The situation in Italy Multidrug-resistant Acinetobacter baumannii Source: http://atlas.ecdc.europa.eu/public/index.aspx Antibiotic resistance in Italy “The levels of carbapenem-resistant Enterobacteriaceae (CRE) and Acinetobacter baumannii have now reached hyper-endemic levels and, together with methicillin-resistant Staphylococcus aureus (MRSA), this situation causes Italy to be one of the Member States with the highest level of resistance in Europe.” Antibiotic discovery is faltering… 150 classes of antibiotics have been discovered and developed since 1935 COVID 19 deaths in 2020: 1.8 million (some have estimated as high as 3 million excess deaths) The Guardian Thu 11 Dec 2014 What would medicine look like without effective antibiotics? End of high-risk treatments? Intra-abdominal surgery Transplantation Cancer chemotherapy Increased mortality from common infections Pneumonia, urinary tract infections Increased maternal/child mortality A reversal of 100 years of medical progress… How can you effectively use antibiotics? BACTERIA-C: A framework for selecting antibacterials B A C T E R I A “C” Credit: Haya Njjar, M.D. UC San Diego with modifications by R. Lewis BACTERIA-C: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms A C T E R I A “C” Credit: Haya Njjar, M.D. UC San Diego with modifications by R. Lewis What is the most important test for establishing the diagnosis of an infectious diseases? 1. 2. 3. 4. Patient’s medical history Patient’s physical exam Radiographic imaging Laboratory (microbiological) studies Taking a medical history in infectious diseases History of presenting (chief) complaint -aka the worst symptoms ○ Ask questions about symptoms not mentioned by patient- primary organ system of concern ○ Other associated symptoms- Presence of other symptoms ○ 8 cardinal descriptors: Timing, Location, Character, Aggravating Factors, Alleviating Factors, Associated Symptoms, Severity, Setting Fever- How high, how long, what pattern? Travel history Animal exposures Social factors- Occupation, sexual history, alcohol or IV drug abuse, hobbies Dietary habits (e.g., raw or undercooked meat, unpasteurized cheese, seafood) History of healthcare exposure (e.g., hospitalizations, surgeries) History or exposure to infectious pathogens (have you been near someone who was sick) Host immune status Example case Chief complaint: 34 year-old farmer from Sicily presents with worsening back pain after sitting for more than couple of hours No other significant past medical history Spondylitis etiologies: ○ (> 50%) Staphylococcus aureus, Staphylococcus epidermidis ○ (>25%) Streptococcus spp., Enterococcus spp. Pseudomonas aeruginosa, Enterobacter spp., Proteus spp. E. coli, Serratia spp., Anaerobes, Mycobacterium tuberculosis (Pott’s disease) Initial lateral radiograph (left) shows a cortical disruption at the inferior epiphyseal plate of L4 vertebral body (arrows). The sagittal fat suppressed contrast enhanced T1-w MR image (right) shows septic discitis (open arrow) and bone marrow edema on both L4 and L5 vertebral bodies (arrows), suggesting spondylitis. Example case Sheep and cattle farmer in a small enterprise 54 minutes from Messina that produces milk and cheese ○ Pecorino salato and Ricotta Pistacchio Patient reported pain was first noticed at end of May after a bad case of flu “fever, achy joints, headache” Father (who also works on farm) also has worsening hip pain after sitting for long periods and will be evaluated by an orthopedic doctor for hip replacement? Other 3 brothers and cousin who work on farm report no illness. Brucellosis? Intracellular Gram negative coccobacilli Calculated occupational exposure risk of 25% Peak between April and June Temporal correlations suggest many infections are related to the production and consumption of fresh cheese Massis FD et al. Clinical Microbiology and Infection. 2005 Aug 1;11(8):632–6. Example case Sheep and cattle farmer in a small enterprise 54 minutes from Messina that produces milk and cheese ○ Pecorino salato and Ricotta Pistacchio Patient reported pain was first noticed at end of May after a bad case of flu “fever, achy joints, headache” Father (who also works on farm) also has worsening hip pain after sitting for long periods and will be evaluated by an orthopedic doctor for hip replacement? Other 3 brothers and cousin who work on farm report no illness. Diagnosis and treatment of Brucellosis spondylitis Blood cultures require special procedures (prolonged incubation), bone culture may be needed Brucella PCR from clinical specimen Combination serologic studies Treatment- Gentamicin + Doxycycline + Rifampin ○ Unconventional regimen, would not be covered by standard spondylitis regimens Common immunocompromising conditions 1. Chronic diseases (e.g., type 1 diabetes, chronic obstructive pulmonary disease) 2. Autoimmune diseases (e.g., lupus, rheumatoid arthritis) 3. Genetic diseases (primary immunodeficiencies) 4. Cancer and/or chemotherapy 5. Human immunodeficiency virus (HIV) 6. Solid organ or bone marrow transplant 7. Advanced age 8. Malnutrition 9. Chronic use of corticosteroids or other immunosuppressive medications 10. Chronic infections 11. Smoking Physical exam Vital signs Lymphatics (~600: generalized vs. localized lymphadenopathy) Skin (rashes, skin lesions, distal extremities) Foreign bodies Inspection, palpitation, percussion, auscultation Radiology Timing and appearance of lesions CXR CT Consolidation with air bronchogram Favors acute bacterial process? Perivascular (interstitial) Viral pneumonia or atypical bacteria Nodular infiltrates Tuberculosis or fungi? Clinical presentation may favor specific pathogen example: cellulitis Staphylococcus aureus with pus β-hemolytic streptococci (erysipelas) Classic clinical presentations example: Meningococcal infection rash Individuals at greater risk of meningococcal infection include Early stage Early stage Later stages infants and children up to 5 years old late adolescence and early adulthood (15-19 years old) laboratory workers who handle meningococci university students and new military recruits living in residential colleges (particularly in their first year) others groups of people who occupy small areas of living space An important early sign suggestive of meningococcal meningitis! Most likely infectious etiology Where did the infection develop? Lower respiratory tract infection Community-acquired Viral (influenzae, Sars CoV-2) Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Atypical bacteria ○ (e.g., Mycobacteria, Chlamydia, Legionella) Hospital-acquired Gram negatives, including possibility of MDR isolates (K. pneumoniae, E. coli) Non-fermenting Gram-negatives, including MDR (P. aeruginosa, Acinetobacter baumannii) Methicillin-resistant Staphylococcus aureus (MRSA) Sanford Guide Summary of very useful information for antibiotics Laboratory tests Red blood cell (anaemia) White blood count (w/differential) Lymphocytosis Eosinophilia Thrombocytopenia Erythrocyte sedimentation rate, C-reactive protein Empiric vs. pathogen-specific therapy Patient population https://www.mdcalc.com/calc/324/curb-65-score-pneumonia-severity Common microbiological cultures Taken before starting antibiotic therapy images: www.medmastery.com BACTERIA-C: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection C T E R I A “C” Credit: Haya Njjar, M.D. UC San Diego with modifications by R. Lewis Pharmacology of antimicrobials Dosing regimen Concentration versus time in serum Absorption Distribution Metabolism Elimination Pharmacokinetics “PK” What the body does to drug Craig WA. Clin Infect Dis 1998;26:1-12. Concentration versus time in tissue and other body fluids Pharmacologic or toxicologic effect Concentration versus time at site of infection Antimicrobial effect versus time Pharmacodynamics “PD” What the drug does to the body (and bacteria) Antibiotics pharmacokinetics are described by concentration-time curves in serum Concentration versus time in serum Absorption Distribution Metabolism Elimination Cmax or “peak” Distribution phase Conc (mg/L) Antibiotic dose Absorption Phase (oral) 0 Me ta bo (e lism lim ina /exc tio ret n) ion Area under the curve (AUC) Time (hours) Craig WA. Clin Infect Dis 1998;26:1-12. Cmin or “trough” Volume of distribution (Vd) The volume which appears to hold the drug if it was present in the body at the same concentration found in plasma – – – It is estimated, not directly measured Reported in liters (L) or liters per kilogram (L/kg) Average plasma volume in adults is approximately 3 L Plasma volume= 3L+ Extracellular water 16 L (~20L) >46 L Vd= sequestered in depot (e.g., fat) Before dose Low Vd High Vd Another way to think of volume of distribution Low Vd Fixed antibiotic dose (i.e. 100 mg in 50 mL) High Vd Same amount of drug “poured in” body, but different drugs and different patients have different beaker sizes Apparent plasma concentrations Volume of distribution (Vd) Volume of distribution is affected by the physicochemical properties of the drug Factors that favor low Vd: high water solubility, high protein binding, decreased tissue binding → converse is also true Example: >500 L Drug concentrated in tissues (lipophilic antibiotics like rifampin, macrolides) Low Vd Hydrophilic High Vd Lipophilic Volume of distribution (Vd) Provides information on how much antibiotic is distributed in tissues vs. plasma → some clinical relevance Example: 12-20 L Example: >500 L Drug concentrated in intravascular space (bloodstream) and extracellular water Drug concentrated in tissues, fat (hydrophilic drugs like beta-lactams, aminoglycosides) Low Vd Bloodstream > tissue sites High Vd (lipophilic antibiotics like rifampicin, macrolides, tetracyclines, sulfonamides, fluoroquinolones) Tissue > bloodstream e.g., doxycycline, tigecycline do not achieve peak concentrations in bloodstream that surpass the MIC of many pathogens Examples of factors that affect volume of distribution (Vd) Sepsis alters the volume of distribution of antibiotics Release of inflammatory mediators causes damage to the vascular endothelium, resulting in expansion of extravascular space (increased volume of distribution) Where is the drug concentrated or excreted? Concentrations often much higher than bloodstream Biliary tree (cholecystitis) Urinary tract Excreted in bile: Ampicillin Ceftriaxone Piperacillin-Tazobactam Doxycycline Excreted in urine: Most β-lactams Gentamicin Ciprofloxacin (but not moxifloxacin) Antibiotic penetration into urine Which antibiotics are excreted in urine? Gilbert, D. N. Urinary tract infections in patients with chronic renal insufficiency. Clin. J. Am. Soc. Nephrol. 1, 327–331 (2006) Antibiotic penetration at the site of infection Inflammation, abscess, necrosis Anatomically-privileged sites capillary small junctions 20 Å endothelial cells Blood-brain barrier Antibiotic penetration influenced by: Blood-retinal barrier ▪ ▪ ▪ ▪ ▪ Serum drug concentrations Physicochemical properties of drugs Alterations in anatomic permeability (e.g., inflammation) Physiological barriers (e.g., blood-eye, blood brain barrier) Drug inactivation due to local pH, anaerobic conditions or enzyme activity Other anatomically- and immune- privileged sites Testicles Placenta Joint spaces Antibiotic penetration in ventilator-associated pneumonia Lodise, T. P. et al. Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia. Antimicrob. Agents Chemother. 55, 1606–1610 (2011). Clinical pharmacology information Some drugs are inactivated at specific body sites Daptomycin is inhibited by pulmonary surfactant Silverman JA et al. J Infect Dis 2005; 191:2149–2152 Antibiotic activity is reduced in abscess Aminoglycosides Bind and are inactivated by purulent material Decrease aminoglycoside uptake into facultative aerobic bacteria at low pH Penicillins and tetracyclines Bound by hemoglobin, less effective with hematoma formation Highlights importance of source control (abscess drainage, removal of prosthetic material) for improving antibiotic activity at the site of infection BACTERIA-C: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection Coverage of antibiotic T E R I A “C” Credit: Haya Njjar, M.D. UC San Diego with modifications by R. Lewis Timeline of antibiotic selection 0h 1h 24h 36-48h 72h New technologies for more rapid identification How broad of coverage do we need? What resistance patterns are we suspecting? Requires general knowledge of which antimicrobials cover which pathogens Consideration of patient’s risk for resistant pathogens ○ e.g., recent infection with resistant organism, previous antibiotic therapy, immunocompromised condition Narrowest spectrum therapy should be used when possible If broad-spectrum therapy is started, attempts should be made to de-escalate to a narrower spectrum when culture and sensitivity results are available Case A patient s/p liver transplantation two months ago Patient had a prior history of extended-spectrum beta-lactamase producing E. coli bacteremia associated with spontaneous bacterial peritonitis Patient is now admitted with septic shock due to abdominal source Sanford antibiotic spectrum tables ++ Drug of choice + Effective ± May have activity (confirm by susceptibility testing) 0 Avoid Cumulative institutional or unit antibiograms Susceptibility patterns for individual hospitals or even units Usually reported using bloodstream breakpoints Detailed guidance in reference A recent case from a hospital in Veneto… Why not always give the broadest spectrum therapy? BACTERIA-C: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection Coverage of antibiotic Total duration of therapy E R I A “C” Credit: Haya Njjar, M.D. UC San Diego with modifications by R. Lewis How long to treat?... Historically, antibiotic treatment duration in infectious diseases is dogma-driven and based on clinical experience, not clinical trials (i.e. 7 days, 14 days, 6 weeks etc.) “Antimicrobials [when first introduced in the 1940s] were far more effective at reducing death from disease than virtually any other therapy. They were so effective that by the time randomized controlled trials became the means of establishing care standards, therapeutic paradigms for typical bacterial infections were already locked in place, and many were never challenged.” Davar, K. et al. Can the future of ID escape the inertial dogma of its past? The exemplars of shorter is better and oral is the new IV. Open Forum Infect. Dis. 10, ofac706 (2023). Antibiotic duration: Shorter is better Generally important to use the shortest appropriate duration based on available data for specific syndromes as well as the patient’s clinical response to treatment Shorter regimens have less risk of adverse effects ○ ○ ○ 20% of patients develop adverse effects, each 10 additional days of therapy adds 3% risk. Shorter regimens have less risk of antibiotic superinfection Shorter regimens have less risk of selecting resistance Davar, K. et al. Can the future of ID escape the inertial dogma of its past? The exemplars of shorter is better and oral is the new IV. Open Forum Infect. Dis. 10, ofac706 (2023). Tamma, P. D., Avdic, E., Li, D. X., Dzintars, K. & Cosgrove, S. E. Association of adverse events with antibiotic use in hospitalized patients. JAMA Intern. Med. 177, 1308–1315 (2017). Shorter is better for most infections Davar, K. et al. Can the future of ID escape the inertial dogma of its past? The exemplars of shorter is better and oral is the new IV. Open Forum Infect. Dis. 10, ofac706 (2023). Example: Some serious toxicities emerge after longer-term treatment Thrombocytopenia On the contrary, the use of linezolid for >28 days resulted in more severe adverse events, such as peripheral neuropathy, myelosuppression, or optic neuritis. According to a meta-analysis, 64% of patients with MDR-TB discontinued linezolid permanently due to peripheral neuropathy. Therefore, the development of peripheral neuropathy has limited the total duration and therapeutic dosage of linezolid, resulting in treatment failure Gerson, S. L. et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob. Agents Chemother. 46, 2723–2726 (2002). When should shorter regimens be given? 1. The patient is clinically and hemodynamically stable; 2. Procedural source control has been achieved when appropriate ideally with clearance of bacteremia 3. The patient’s gut is functioning and likely to absorb oral medications 4. A published regimen is available for the target pathogen(s) 5. There are no patient-level, psychosocial, or economic factors that would cause IV therapy to be favored Davar, K. et al. Can the future of ID escape the inertial dogma of its past? The exemplars of shorter is better and oral is the new IV. Open Forum Infect. Dis. 10, ofac706 (2023). When are longer durations are often required? Patient has slow clinical response (e.g., time to fever resolution, clearance of bacteremia, resolution of symptoms) Endovascular infections (i.e. infective endocarditis) Osteomyelitis Lack of source control (undrained, abscess, infected prosthetic materials) Immunocompromised patients BACTERIA-C: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection Coverage of antibiotic Total duration of therapy Effective dose of antibiotics R I A “C” Credit: Haya Njjar, M.D. UC San Diego with modifications by R. Lewis Serum drug concentrations and the minimum inhibitory concentration (MIC) How to predict which doses are effective? Absorption Phase (oral) Cmax or “peak” Conc (mg/L) Distribution phase Me tab o (el lism im ina /excr tio eti n) on Cmin or “trough” Area under the curve (AUC) 0 Time (hours) Dosing regimen Concentration versus time in serum Concentration versus time in tissue and other body fluids Pharmacologic or toxicologic effect Concentration versus time at site of infection Antimicrobial effect versus time Pharmacokinetics/Pharmacodynamics (PK/PD) Predicted or measured serum concentrations Cmax/MIC Concentration AUC/MIC Cmin/MIC MI C Time > MIC Time AUC = Area under the concentration–time curve; MIC = Minimum Inhibitory Concentration; Cmax = Maximum or peak plasma concentration; Cmin = Minimum or trough plasma concentration Time-dependent killing antibiotics β-lactams against S. pneumonia Activity best correlates Cefotaxime vs. S. pneumoniae in mouse infection model with %T>MIC CFU/Thigh at 24 hours 10 R2 =0.94 9 8 7 6 5 1 10 100 1000 Cmax/MIC Craig WA. Diagn Microbiol Infect Dis 1995: 22:89-96 1 10 100 1000 24-Hr AUC/MIC 0 25 50 75 %T>MIC 100 Concentration-dependent killing antibiotics Fluoroquinolones against P. aeruginosa Ciprofloxacin Treatment in Experimental P. aeruginosa pneumonia 125 Patient cured with ventilator-associated pneumonia 80 60 125 40 % Cured % Mortality rate 100 20 0 3 10 30 100 300 1,000 AUC/MIC at 24 hours Craig WA. Infect Dis Clin N Amer 2003;17:479 Forrest A et al. Antimicrob Agents Chemother 1993;37:1073-81. PK/PD parameters predictive of antimicrobial efficacy in humans Cmax/MIC AUC/MIC T>MIC Examples Aminoglycosides Fluoroquinolones Polymyxins Azithromycin Fluoroquinolones Ketolides Linezolid Daptomycin Vancomycin Tigecycline Penicillin Cephalosporins Carbapenems Monobactams Macrolides Organism kill Concentration dependent Concentration and time dependent Time-dependent Dosing goal Maximize exposure (multiples of MIC) Maximize exposure over time (multiples of MIC over time) Optimize duration of exposure (time above MIC) Cmax/MIC ratio of peak antibiotic concentrations to MIC; AUC/MIC relationship of area of the the curve to MIC; T> MIC, time antibiotic concentrations surpass the MIC Roberts, J. A. et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect. Dis. 14, 498–509 (2014). 35 y/o male in ICU with SeCr 0.9 (eGFR 113 mL/min) meropenem 1 gram intravenously over 30 min every 8 hours Dosing target reported in literature : 75% T>MIC for clinical cure 87.6 % T> MIC MIC 0.5 mg/L 26 % T> MIC MIC 8 mg/L Just double the dose of meropenem? Dosing target reported in literature : 75% T>MIC for clinical cure 1000 mg IV 30 min infusion q8h 26 % T> MIC 1000 mg IV 30 min infusion q8h 26 % T> MIC 👍 2000 mg IV 30 min infusion q8h 41.3 % T> MIC Start 1500 mg IV 7.5 hour infusion q8h immediately after 1000 mg dose: 95.0 % T> MIC T> MIC is maximized when β-lactam is administered as a continuous infusion BACTERIA-C: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection Coverage of antibiotic Total duration of therapy Effective dose of antibiotics Renal and hepatic function I A “C” Credit: Haya Njjar, M.D. UC San Diego with modifications by R. Lewis Antibiotic clearance Absorption Phase (oral) Drug elimination from the body Described by volume of blood removed of drug unit per time Cmax or “peak” Unit of measure mL/min or L/hr Conc (mg/L) Distribution phase 0 Me ta bo (e lism lim ina /exc tio ret n) ion Area under the curve (AUC) Time (hours) Clearance is affected by patient’s disease, organ function genetics, interactions with other drugs…etc. Total body clearance: Cmin or “trough” – CL renal + CL hepatic + CL other Formulas for calculating antibiotic clearance can be found in the medical literature or some drug references How to volume of distribution (Vd) and clearance (CL) interact? Vd and CL are both physiologically-based ▪ A change in patient fluid status or distribution can affect volume of distribution (Vd) ▪ A change in patient kidney or liver function affects drug clearance (CL) ▪ However, these parameters do not directly interact with each other ▪ A change in volume of distribution does not change clearance and vice versa Why is this distinction important? Volume of distribution - Useful for calculating an initial dose of antibiotic regimens (loading dose) Clearance - Useful for calculating maintenance doses of antibiotic regimens - CL is NOT USED to determine how much of an initial dose (or loading dose) of an antibiotic to give to a patient Let's return to our patient… Hypotension, requires norepinephrine SeCr. 0.9 mg/dL (eGFR 113 mL/min) SeCr. 1.0 mg/dL (eGFR 109 mL/min) SeCr. 3.9 mg/dL (eGFR 26.18 mL/min) SeCr- Serum creatinine eGFR- estimated glomerular filtration rate SeCr. 4.2 mg/dL (eGFR 22.69 mL/min) SeCr. 4.4 mg/dL Many antibiotics eliminated by the kidneys must be adjusted for a patient’s renal function Assessing the glomerular filtration rate Inulin: ○ A nonendogenous polysaccharide (must be given IV) ○ An ideal indicator for GFR because it is: Freely filtered Not reabsorbed Not secreted ○ Used for research purposes, but not commonly used in clinical practice Creatinine: ○ A by-product of muscle metabolism ○ Good indicator for GFR: Freely filtered Not reabsorbed Small amount secreted: slight tendency to overestimate GFR (because some is cleared by secretion rather than filtration) ○ Clinical standard for GFR estimation and overall kidney function: Endogenous product of muscle metabolism Easily measured on routine blood tests (e.g., basic metabolic panel) Can easily adjust for slight inaccuracy from secretion effect Para-amino hippurate (PAH): ○ Ideal indicator for RPF (freely filtered, not reabsorbed, fully secreted) ○ Not endogenous (must be given IV) ○ Not commonly used in practice Estimating glomerular filtration (eGFR) Serum creatinine can have true changes in several common circumstances other than AKI or CKD: ○ Pregnancy: Decreases slightly during 1st and 2nd trimesters Returns to prepregnancy value in 3rd trimester ○ Aging: Rises very slowly with age GFR can decrease by 0.5–1 mL/min/year in healthy adults. ○ Diabetes: Serum creatinine decreases early in the disease course owing to hyperfiltration. Over time, hyperfiltration causes damage and results in elevated serum creatinine. ○ Very low muscle mass: cirrhosis, malnutrition, amputation: Often have serum creatinine < 0.5 at baseline GFR equations will overestimate true kidney function. Small changes (e.g., serum creatinine 0.5 → 1) represent severe AKI in these patients (commonly missed by clinicians). Estimating renal function Renal function impairment ▪ Cockcroft-Gault formula (other formulas MDRD…etc.) Formula developed primarily in Caucasian males with chronic renal disease Does not take into account effects on older age, comorbidities and drug interactions with renal tubular secretion Antibiotic dosing in dialysis (drug-specific dosing guidance) What happens if we follow the Sanford’s guide dose adjustment? 1000 mg every 8 hours (eGFR 113 mL/min) 500 mg every 12 hours (eGFR 26.18 mL/min) Be careful about adjusting doses in patients with acute renal failure associated with infection! Antibiotic renal dose adjustments in drug labels are based on patients with chronic kidney disease Renal impairment is acute, not chronic, in up to 50% of patients with infection and frequently resolves within the first 48 hours Creatinine-based equations for estimates of CrCl are based on steady-state conditions, and not as accurate in acute kidney injury ○ Decreases in SeCr are delayed with respect to injury resolution Renal dose reduction in the first 48 hours of therapy may unnecessarily result in underdosing of antibiotics, especially for safe antibiotics Crass RL et al. Clin Infect Dis 2019; 68:1596–1602. Improvement in renal function requires increase in the maintenance dose SeCr 2.2 mg/dL SeCr 1.5 mg/dL SeCr 0.9 mg/dL Liver function and drug interactions Cytochrome P450 and other enzyme drug interactions Acute liver dysfunction Chronic liver cirrhosis (Child Pugh Score) Uptodate drug interaction checker I have posted a PDF on how to register for access via University of Padova libraries Example of CYP-P450 inducing drug interaction Example of CYP-P450 inhibitor drug interaction Caution: QT-prolonging medications/drug interactions BACTERIA: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection Coverage of antibiotic Total duration of therapy Effective dose of antibiotics Renal and hepatic function Intravenous, oral or rectal administration? A C Contraindications? Credit: Haya Njjar, M.D. UC San Diego How do we choose a route of administration? Site of infection Severity of infection Patient’s ability to take oral medications Patient’s ability or absorb oral medications Bioavailability of oral medication Do some infections always require IV antibiotics? Classic teaching ○ Endocarditis (endovascular infections) ○ Osteomyelitis ○ Febrile neutropenia Patient cannot tolerate oral therapy, questionable absorption, compliance issues ID dogma that not supported by evidence from clinical trials… or based on observational data showed that cure rates were lower with oral sulfonamides, erythromycin, or tetracycline vs. IV penicillin for bloodstream infections Volume of distribution (Vd) Provides information on how much antibiotic is distributed in tissues vs. plasma → some clinical relevance Example: >500 L Example: 12-20 L Drug concentrated in tissues, fat Drug concentrated in intravascular space (bloodstream) and extracellular water (hydrophilic drugs like beta-lactams, aminoglycosides) Low Vd Bloodstream > tissue sites High Vd (lipophilic antibiotics like rifampicin, macrolides, tetracyclines, sulfonamides, fluoroquinolones) Tissue > bloodstream e.g., doxycycline, tigecycline sulfonamides, fluoroquinolones may not achieve concentrations in bloodstream that surpass the MIC of many pathogens Why oral therapy is prefered when feasible Oral therapy is safer vs. intravascular catheter Patient satisfaction Markedly decreases length of hospital stay and cost BACTERIA: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection Coverage of antibiotic Total duration of therapy Effective dose of antibiotics Renal and hepatic function Intravenous, oral or rectal administration? Adequate source control Credit: Haya Njjar, M.D. UC San Diego Abscess Aminoglycosides Bind and are inactivated by purulent material Decrease aminoglycoside uptake into facultative aerobic bacteria at low pH Penicillins and tetracyclines Bound by hemoglobin, less effective with hematoma formation Emphasizes importance of source control (abscess drainage, removal of prosthetic material) BACTERIA: A framework for selecting antibacterials Bugs associated with the presenting signs/symptoms Activity at the site of infection Coverage of antibiotic Total duration of therapy Effective dose of antibiotics Renal and hepatic function Intravenous, oral or rectal administration? Adequate source control Contraindications? Credit: Haya Njjar, M.D. UC San Diego Common antibiotic contraindications 1. 2. 3. 4. 5. 6. Allergy or hypersensitivities Drug interactions Pregnancy or breastfeeding Toxicity Superinfections Age-related (historically fluoroquinolones/tetracyclines in pediatrics-although still sometimes used) How can you effectively use antibiotics? B A C T E R I A C Bugs associated with the presenting syndrome Activity at the site of infection Coverage of antibiotic Total duration of treatment Efficacious dose Renal/hepatic function Intravenous, oral, rectal or intramuscular Adequate source control Contraindications?