Antibiotic Basics

Steven Bradley, MD Harborview Chief Medical Resident Inpatient Services

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Antimicrobial Considerations Likely organism and susceptibilities Site of infection - SSTI, bacteremia, pneumonia, meningitis, UTI Host factors - Immune deficiencies, age, allergies, renal and hepatic function Antimicrobial factors - Dosage, route, drug interactions, tissue penetration, toxicity, cost Public health considerations - Selection of resistance

Antimicrobial Case 1 20 yo woman presents with 3 days of fever, sore throat, and cervical adenopathy. Rapid strep test is positive. What is the preferred therapy?

A. Azithromycin for 5 days B. Penicillin V for 10 days C. Levofloxacin 500 mg for 10 days D. Vancomycin 1 gm BID for 7 days

Antimicrobials: Site of Action

Cell Wall - Beta-Lactams - Glycopeptides Cell Membrane - Daptomycin - Polymixin DNA Inhibitor - Fluoroquinolone - TMP-SMX - Metronidazole Protein Synthesis 50S Ribosome - Macrolides/Ketolides - Clindamycin - Chloramphenicol - Quinupristin-Dalfopristin 30S Ribosome - Aminoglycosides - Tetracyclines - Glycylcyclines 70S Initiation Complex - Linezolid

Adapted from David Spach, MD

Bacteria: Cell Wall Synthesis

Cell Wall Synthesis Penicillin Binding Protein Penicillin Binding Proteins Cell Membrane DNA Cell Wall

Adapted from David Spach,MD

Beta-lactam Antimicrobials 

Penicillins



Cephalosporins

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Carbapenems

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Monobactams

Site of β-lactamase Activity O S CH 3 R 1 C NH HC H C 2 C C CH 3 N C COOH O β-lactamase

Beta-Lactam: Mechanism of Action

Cell Wall Synthesis

Beta-Lactam

Cell Membrane Penicillin Binding Proteins DNA Cell Wall

Adapted from David Spach, MD

Penicillins    Penicillin G and penicillin V 

Streptococcus pyogenes

 Pharyngitis, syphilis Aminopenicillins    Ampicillin and amoxicillin H. influenzae, Enterococcus, Listeria Acute otitis media, acute bacterial sinusitis Penicillinase-resistant penicillins  Methicillin, nafcillin, oxacillin, dicloxacillin    Staphylococcus aureus (MSSA), Streptococcus No gram-negative activity SSTI, osteomyelitis, septic arthritis

Extended-spectrum Penicillins    Carboxypenicillins (Ticarcillin)  Gram-negative coverage including

Pseudomonas

Ureidopenicillins (Piperacillin)  Gram-negative coverage including

Pseudomonas

Penicillin β-lactamase inhibitor combinations   Amox-clav, amp-sulb, ticar-clav, pip-tazo Increase Staphylococcus and anaerobic coverage

Cephalosporins     First Generation  Cefazolin, cephalexin Second Generation   Cefuroxime Cefamycins: cefoxitin, cefotetan Third Generation  Ceftriaxone, ceftazidime Fourth Generation  Cefepime

Carbapenems    Imipenem/cilastin, meropenem  Broad spectrum of activity including

Pseudomonas

 Meropenem less likely to provoke seizures Ertapenem  Not active against Pseudomonas, Acinetobacter, and Enterococcus faecalis Most reliable activity against ESBL and ampC containing organisms

Monobactams    Aztreonam Activity restricted to aerobic gram negative bacteria including most

Pseudomonas

Does not display cross-reactive hypersensitivity reactions in patients with penicillin allergies

Beta-Lactam Allergy     10-20% of those reporting PCN allergy are truly allergic when assessed by skin testing  Positive predictive value of 14% Potential cross-reactivity with cephalosporins (8%) and carbapenems, but not monobactams Skin test for major (benzylpenicilloyl polylysine) and minor determinants   Positive skin test: 41-67% risk of significant allergy Negative skin test: 1-4% risk, none life threatening Desensitization when no other options

Antimicrobial Case 1 20 yo woman presents with 3 days of fever, sore throat, and cervical adenopathy. Rapid strep test is positive. What is the preferred therapy?

A. Azithromycin for 5 days B. Penicillin V for 10 days C. Levofloxacin 500 mg for 10 days D. Vancomycin 1 gm BID for 7 days

Antimicrobial Case 2 45 y o woman presents with 3 day history of acute onset of fever 39 C, chills, cough productive of green phlegm, SOB, and right-sided chest pain. CXR demonstrates RLL infiltrate.

Community-Acquired Pneumonia

   Most common pathogens S. pneumoniae, H. influenzae, Moraxella with concern for C. pneumonia, M. pneumoniae, and Legionella 2002-2003 US Survey revealed 34% non susceptible (16% intermediate, 18% resistant)  WA 2003: 16% intermediate, 7% resistant S. pneumoniae do not produce beta-lactamase   Alteration in penicillin binding protein with decreased affinity for beta-lactam Beta-lactamase inhibitors (clavulanate or sulbactam) will not improve efficacy

Streptococcus pneumoniae

Resistance Antimicrobial Resistant Percent Macrolide 29% TMP/SMX 32% Tetracyclines *21.9% of 16% isolates in 2002-2003 had fluoroquinolone Fluoroquinolones* 2.3%

Community-Acquired Pneumonia   Outpatient  Macrolide or doxycycline  Respiratory fluoroquinolone, if recent antimicrobial tx Inpatient medical ward     -lactam + macrolide vs. fluoroquinolone Retrospective analysis of 14,000 Medicare patients found lower mortality with cephalosporin + macrolide or fluoroquinolone compared to cephalosporin alone (Arch Intern Med 1999;159:2562-72) Lower in-hospital mortality among patients with bacteremic pneumococcal pneumonia treated with  lactam + macrolide compared to  -lactam alone (Clin Infect Dis 2003;36:389-95) Clin Infect Dis 2003;37:1405-33.

Fluoroquinolone: Mechanism of Action Fluoroquinolone

DNA Topoisomerase IV DNA Gyrase DNA Cell Membrane Cell Wall

Adapted from David Spach, MD

Fluoroquinolones

   Concentration-dependent killing (AUC:MIC) Moxifloxacin is hepatically eliminated, not for urinary infections Adverse events       GI CNS Photosensitivity Prolonged QTc Tendonitis/arthropathies Hyperglycemia or hypoglycemia, particularly elderly with DM

S. pneumoniae

and Fluoroquinolones

Drug MIC 90 AUC Free AUC:MIC Free Ciprofloxacin (750 bid) 1.0 28 28 Levofloxacin (500 qd) 1.0 34 34 Levofloxacin (750 qd) 1.0 70 70 Gatifloxacin (400 qd) Gemifloxacin (320 qd) 0.03 140 280 Moxifloxacin (400 qd) 0.25 26 106 0.12 24 200 Cutoff criterion of AUC:MIC >33.7 for gram-positives?

Clin Infect Dis 2005;41:S127-35

High-dose, Short-course Levofloxacin for

CAP

   Attempt to increase AUC:MIC ratio while decreasing overall drug exposure Multi-center, randomized, double-blind study comparing 750 mg qd x 5 days vs. 500 mg qd x 10 days in the treatment of CAP Found equivalent clinical and microbiological outcomes Clin Infect Dis 2003;37:752-60

Case Modified

  The patient decompensated and required intubation. He became afebrile after 48 hours.

They remained intubated at 96 hours and developed a new fever and infiltrate on CXR.

   What infection are you concerned for?

What pathogens need to be considered in this setting?

What antibiotic choices are appropriate?

Nosocomial Pneumonia/Ventilator Associated Pneumonia    Common pathogens include

coliforms, Staph and Pseudomonas aeruginosa

Coverage should now cover broadly for gram positives, gram negatives, and Pseudomonas  Anti-pseudomonal penicillin (pip/tazo) or fluoroquinolone  MRSA coverage (vanco) Eight day therapy equivalent to 14 day

Pseudomonas

and Fluoroquinolones

Drug Ciprofloxacin Levofloxacin Gatifloxacin Moxifloxacin Dose C max MIC AUC free :MIC 400 q12 4.1 0.125

144 400 q8 4.1 0.125 184 750 q24 12.1 0.5 152 400 q12 4.6 1.0 28 400 q24 4.2 2.0 10 New IDSA and ATS Guidelines for HAP/VAP recommend Ciprofloxacin 400mg IV q8hr or Levofloxacin 750 mg qd Am J Respir Crit Care Med 2005;171:388-416

Antimicrobial Case 6 20 y o woman presents with 2 day h/o dysuria, urgency, and frequency. UA with >50 WBC/hpf, +leukocyte esterase Cystitis treatment options: Amoxicillin, 40-50% resistance among

E. coli

Nitrofurantoin x 7 days cystitis only, does not achieve adequate blood levels TMP-SMX x 3 days, though increasing resistance culture selection bias reflecting hospital setting -85% predicted clinical cure rate with 30% resistance Fluoroquinolone, ? if >10-20% resistance to TMP-SMX Clin Infect Dis 1999;29:745-58

Antimicrobial Case #3

 What if this patient was 75 and had a chronic foley catheter?

Complicated UTI

    In the setting of obstruction (BPH), reflux, catheter Similar pathogen profile   Enterobacteriaceae (E.coli), enterococci Nosocomial bugs Treat for extended period (2 weeks) and remove obstruction if possible Beware of asymptomatic bacteruria  Treatment leads to resistance

Antimicrobial Case 5 35 y o man with a history of methamphetamine use presents to clinic with a right biceps abscess.

Previous “Standard of Care”    If abscess appreciated, I&D performed without culturing Depending on severity of SSTI, either admitted for IV beta-lactam (cefazolin or nafcillin), or discharged empirically on cephelexin without concern for resistant organisms This approach is no longer appropriate

Proportion of

S. aureus

Nosocomial Infections Resistant to Oxacillin (MRSA) Among Intensive Care Unit Patients, 1989-2003*

70 60 50 40 30 20 10 0 1989 1991 1993 1995 1997 1999 2001 2003 Year

*Source: NNIS System, data for 2003 are incomplete

Community-Associated MRSA

 

Clinical manifestations

   Predominantly skin and soft tissue (JAMA 2003;290:2976-2984) Necrotizing fasciitis (N Engl J Med 2005;352:1445 53) Necrotizing pneumonia (Clin Infect Dis 2005;40:100-7)

Different from HA-MRSA

 Panton-Valentine Leukocidin exotoxin associated with tissue necrosis and leukocyte destruction (JAMA 2003;290:2976-2984)

Nasal Carriage of

S. aureus

20-40% of people colonized with

S. aureus

–20% persistent, 60% intermittent, 20% never Increased Rates of MRSA          Healthcare contact    Surgery Dialysis Indwelling devices IDDM HIV Long-term care facilities IDU (Clin Infect Dis 2002;34:425-33) Correction facilities (Clin Infect Dis 2003;37:1384-8) MSM (Clin Infect Dis 2005;40:1529-34) Native Americans, Pacific Islanders Other close contact  Athletic (N Engl J Med 2005;352:468-75)

Antimicrobial Susceptibility Patterns

Clindamycin Erythromycin Fluoroquinolone Rifampin 94 Tetracycline TMP/SMX Vancomycin CA-MRSA 83 44 79 96 92 95 100 HC-MRSA 21 9 16 92 90 100 JAMA 2003;290:2976-2984

Treatment Options for MRSA Infections

Intravenous*      Vancomycin Linezolid Daptomycin Quinupristin/dalfopr istin Tigecycline Oral*      TMP-SMX Minocycline/Dox y Clindamycin Fluoroquinolone Linezolid *with or without rifampin, however NEVER use rifampin monotherapy due to rapid emergence of resistance

TMP/SMX Mechanism The Folic Acid Pathway Sulfonamides Trimethroprim PABA // Dihydrofolic Acid

Tetrahydropteroic acid synthetase

//

Dihydrofolate reductase

Tetrahydrofolic Acid Purines Adverse Events: -Hypersensitivity reaction -Marrow suppression -Hemolysis (G6PD deficiency) -Displace bilirubin from albumin DNA

Oxazolidinone: Mechanism of Action

50S Ribosome

Oxazolidinone

30S Ribosome

fMet-tRNA

50 S 30 S 70 S Initiation Complex DNA

Modified from David Spach, MD

Linezolid      Oxazolidinone Active against MSSA, MRSA, VRSA, coag-neg Staph, S. pyogenes, S. pneumoniae, E. faecalis, E. faecium including VRE, as well as some Nocardia and mycobacteria Oral bioavailability 100% Adverse events:      GI (nausea and vomiting) marrow suppression (thrombocytopenia, anemia, leukopenia) serotonin syndrome (weak monoamine oxidase inhibitor) lactic acidosis optic neuritis Linezolid-resistant VRE and MRSA reported due to mutation in 23S rRNA

Concerns with Vancomycin   Association between increasing MIC and clinical failure, particularly prolonged bacteremia Monitoring of serum levels  No clear relationship between level, efficacy and toxicity    Routine monitoring not necessary  Changing renal function or renal insufficiency Peak levels should not be measured as vancomycin is not “concentration-dependent” Trough of 15-20 mg/L in endocarditis, osteomyelitis, and VAP though clinical data is limited Clin Infect Dis 2006;42:S51-7 Am J Respir Crit Care Med 2005;171:388-416

MRSA Nosocomial Pneumonia      Retrospective analysis of a prospective, randomized, double-blind study  Vancomycin +/- aztreonam vs. linezolid +/ aztreonam Survival benefit with linezolid in the sub set of patients with MRSA pneumonia Vancomycin group with higher rates of bacteremia and co-morbidities (cardiac, diabetes, renal) Role of toxin inhibition with linezolid or clindamycin?

Awaiting prospective confirmation Chest 2003;124:1789-1797 Chest 2005;128:2732-2738

Antimicrobial Case X 60 yo male admitted to the hospital with one day history of fever, headache, photophobia, and neck stiffness. CSF reveals WBC 542 with neutrophil predominance, protein 90, and glucose 30. What empiric antibiotics should be started?

Bacterial Meningitis Condition < 1 month 2-50 years > 50 years Post-neuro Surgery Pathogen S. agalactiae, E. coli

L. moncytogenes

Antimicrobials Ampicillin + cefotaxime Ampicillin +aminoglycoside S. pneumoniae,

N. meningitidis

S. pneumoniae, N. meningitidis,

L. monocytogenes

Gram-neg (Pseudomonas), S. aureus, Coag-neg Staph Vanco + ceftriaxone Vanco + ceftriaxone+ amp Vanco + (cefepime, ceftazidime, or meropenem) Clin Infect Dis 2004;29:1267-84

Antimicrobial Case 4 70 y o woman with bronchitis treated with moxifloxacin who develops fever, abdominal pain, and profuse, watery, maloderous diarrhea. WBC 24K.

Clostridium difficile

     Colonization   3% healthy adults 20-40% of hospitalized patients Unintended consequence of antimicrobial therapy   Perturbation of competing flora Cephalosporins, clindamycin, and fluoroquinolones Recent reports of increasing frequency and severity Epidemic strain with 18-bp tcdC deletion and binary toxin Metronidazole or oral vancomycin  90% vs. 88% response rates (Lancet 1983;2:1043-6)  ?Increasing recurrence and failure with metronidazole Clin Infect Dis 2005;40:1586-90 Clin Infect Dis 2005;40:1591-7 N Engl J Med 2005;353:2433-41 N Engl J Med 2005;353:2442-9

Metronidazole      Reduced metabolites damage bacterial DNA Active against anaerobic gram-negative bacilli and most Clostridium Favored in management of C. difficile Absorbed well with good CSF penetration (used in CNS abscess as opposed to clindamycin which has poor CSF penetration) Adverse events:   Nausea, metallic taste Disulfiram-like reaction

Antimicrobial Case 7 42 y o sexually active man presents with 3 day h/o dysuria and purulent urethral discharge.

Increasing fluoroquinolone resistance IM ceftriaxone or PO cefpodoxime 15% co-infection with

Chlamydia

-azithromycin or doxycycline

Neisseria gonorrheae

Bad Bugs, No Drugs   Gram-positive bacteria  MRSA and VRE  Emergence of vancomycin-resistant S. aureus and linezolid-resistant Enterococcus Gram-negative bacteria  Pan-resistant Acinetobacter and Pseudomonas  Colistin/Polymixin E  nephrotoxicity 20-30%  neurotoxicity 7%  Extended-spectrum β-lactamase organisms Clin Infect Dis 2006;42:657-68

Antimicrobial Principles      Judicious use of antimicrobial therapy to optimize clinical outcomes while minimizing unintended consequences    Toxicity, drug-drug interactions Emergence of resistance

C. difficile

Understanding antimicrobial pharmocokinetics/dynamics and resistance mechanisms can help guide appropriate usage Knowledge of local susceptibility patterns is essential Development of antimicrobial resistance is directly related to antimicrobial usage Paucity of new drugs in the pipeline