Antibiotic Choices

Gary Skankey, MD, FACP

Outline
When to use and when not to use antibiotics Interpreting cultures Choosing appropriate empiric antibiotics Using antibiograms

Appropriate Use of Antibiotics

Employ empirically when there is a reasonable clinical suspicion of infection Choose antibiotics active against the most likely organism(s) Choose antibiotics known to penetrate involved tissue Use correct doses of antibiotics dont underdose Know when bacterostatic antibiotics are adaquate or bacterocidal drugs are required In serious, potentially life-threatening infections, start broad, then de-escalate after cultures back Stop antibiotics when infection resolved or when evidence accumulates against existence of infection

Inappropriate Uses of Antibiotics

Using wrong antibiotic for apparent infection Using wrong dose of right drug Using a 2nd or 3rd line drug when a first line drug could still be used Using antibiotics in situations when antibiotics are not indicated just in case Continuing antibiotics when infection is resolved or not likely Keeping coverage broad when cultures reveal a single organism Reacting to culture results by starting antibiotics without considering the significance of the culture

Results of Antibiotic Misuse

Incomplete, delayed, or failed resolution of infection Prolonged or unnecessary hospitalizations Increased incidence of antibiotic side effects Development of multi-drug resistant strains of bacteria Increased cost of health care

Knowing When and When Not to Use an Antibiotic

Infection is Diagnosed Clinically Based on Multiple Data Points

Pneumonia
Fever Leukocytosis Purulent sputum New infiltrate Cough, chest pain, dyspnea Hypoxia Sputum gram stain shows many WBCs, few epithelial cells

Infection is Diagnosed Clinically Based on Multiple Data Points

UTI
Dysuria Urinary frequency Fever Pelvic or flank pain Pyuria
Watch the number of epithelial cells in U/A

Infection is Diagnosed Clinically Based on Multiple Data Points

Wound infection
Wound is foul smelling Skin surrounding wound is red, indurated, tender Pus draining from wound Fever leukocytosis

Infection is Diagnosed Clinically Based on Multiple Data Points

Infections are not diagnosed by culture alone

Mistakes Doctors Make in Diagnosing Infection

Base their diagnosis on a single positive data point when other data points are negative React to a positive culture when there is no clinical evidence of infection Use serial cultures to determine when infection has resolved Obtain cultures randomly when clinical suspicion of infection is low

Interpreting cultures

First Step: Determine Whether Culture Represents Real Pathogen

Colonizer
And organism actually present in or on patient, but does not invade tissue or cause clinical disease

Contaminant
And organism growing in culture that is not actually present in or on the patient, but came from the environment directly to the culture medium

First Step: Determine Whether Culture Represents Real Pathogen

Every positive culture needs to be interpreted with respect to other data points Example:
A wound culture taken from a cleanappearing, granulating wound that is not painful, has no purulence in a patient with no fever and a normal WBC is a colonizer and should not be treated

First Step: Determine Whether Culture Represents Real Pathogen

Example:
A sputum culture taken from a patient without fever, leukocytosis, new infiltrate or pulmonary symptoms is a colonizer

Example:
A urine culture taken from a patient without dysuria, frequency, and with a small to moderate amount of WBC in the U/A has asymptomatic bacteriuria

Interpreting Individual Cultures

Blood Cultures
Pathogen if: Patient is febrile when culture drawn Fever persists without appropriate antibiotics Organism is a known pathogen Grows in 2 of 2 sets Grows in 24 to 48 hours Contaminant if: Patient is afebrile when culture drawn No fever despite lack of appropriate antibiotic Organism is a skin colonizer Grows in only one set Grows after 48 hours Note: Increased risk of contamination if drawn through line

Sputum Cultures
A pathogen if: Sputum is grossly purulent Patient is febrile Infiltrates on CXR > 5-10 WBC per hpf < 5-10 epithelial cells per hpf A colonizer if: Sputum is scant, clear or white Patient is afebrile No infiltrates on CXR < 5-10 WBC per hpf > 5-10 epithelial cells per hpf

Urine Cultures
A pathogen if: > 100,000 cfu If urinalysis reveals:
> 10 WBC Pos. leuk. esterase Pos. nitrite Few or no epis

A contaminant if: 10,000 cfu or less If urinalysis reveals:

< 10 WBC Neg. leuk. esterase Neg. nitrite Many epis

If patient symptomatic

If patient asymptomatic

Asymptomatic bacteriuria
> 100,000 cfu bacteria in urine culture in a patient with no symptoms Incidence increases in women by 1% per decade
70 80 year olds have 7 8% annual incidence

Prevalence in elderly
Men 10% Women 20% In nursing homes, prevalence is higher

Asymptomatic bacteriuria
NO increased morbidity or mortality if left untreated Spontaneously resolves If treated, patient subjected to potential side effects of antibiotics and selective pressure for MDR organisms unnecessarily Dont culture urine if no symptoms

Choosing the Right Empiric Antibiotic

Antibiotics for Head and Neck Infections

Organisms
Streptococcus viridans group, Lancefield group streptococci, staphylococcus, peptostrepococcus, Veillonella, fusobacterium, bacteroides spp, eikonella, etc.

Antibiotics
Beta lactam/beta lactamase inhibitor combos Clindamycin 2nd generation cephalosporins 4th generation Quinolones (moxifloxacin)

Antibiotics for Meningitis

Organisms
Most common - Streptococcus pneumoniae, Neisseria meningitidis Less common (in very young, elderly, or immunecompromised) Haemophilus influenzae, Klebsiella pneumoniae, Listeria monocytogenes

Antibiotics
High dose ceftriaxone, cefotaxime, and vancomycin (+ ampicillin)

Antibiotics for Community-Acquired Pneumonia (CAP)

Organisms:
S. pneumoniae, H. influenzae, M. catarhalis, K. pneumoniae, M. pneumoniae, C. pneumoniae, L. pneumophila

Antibiotics
2nd or 3rd generation cephalosporins Respiratory quinolones (Levofloxacin, Gatifloxacin) Advanced macrolides (clarithromycin, azithromycin)

IDSA Guidelines for Empiric Treatment of Outpatient CAP

Previously healthy, no use of abx in past 3 months Comorbidities, immune suppression, abx in last 3 months
A macrolide (Biaxin, Azithromycin) Doxycycline

If high incidence of macrolide-resistant pneumococcus, substitute FQ for macrolide

Respiratory FQ (Avelox, Tequin, Levaquin [750 mg]) Beta-lactam (cefuroxime, amox/clav) plus macrolide (clarithromycin, azithromycin)

IDSA Guidelines for empiric treatment of Inpatient CAP

Non-ICU
Respiratory FQ Beta-lactam (ceftriaxone, amp/sulb) or ertapenem plus macrolide

ICU
Beta-lactam or ertapenem plus macrolide or resp FQ (I add vancomycin to cover cephalosporin-resistant pneumococcus or CA-MRSA)

Timing and duration of therapy for CAP

First dose must be given in ER
Outcome dependent on early institution of appropriate antibiotics

Switch from IV to PO abx when pt hemodynamically stable and improving clinically, is able to ingest medications, and has a normally functioning gastrointestinal tract

Timing and duration of therapy for CAP

Rx for a minimum of 5 days, should be afebrile for 4872 h, and should have no more than 1 CAP-associated sign of clinical instability before discontinuation of therapy Criteria for clinical stability
1) Temperature 37.8C, 2) Heart rate 100 beats/min, 3) Respiratory rate 24 breaths/min, 4) Systolic blood pressure 90 mm Hg, 5) Arterial oxygen saturation 90% or pO2 60 mm Hg on room air, 6) Ability to maintain oral intake, 7) Normal mental status

Healthcare Associated Pneumonia (HCAP)

HCAP
Healthcare associated pneumonia (HCAP)
Any hospitalization in the past 90 days Any IV antibiotics in the past 30 days Resident of or transferred from a long term acute care facility or skilled nursing facility Pseudomonas, MDR acinetobacter, ESBL Klebsiella, MDR enterobacter, etc MRSA

Likely to be due to MDR hospital-acquired organisms

These patients are too frequently started on standard CAP empiric antibiotics

Empiric Therapy for HAP, VAP and HCAP in Patients With Late-onset Disease or Risk Factors for MDR Pathogens and all Disease Severity
Potential Pathogens MDR pathogens P aeruginosa K pneumoniae (ESBL+) Enterobacter Acinetobacter sp
Combination Therapy Antipseudomonal cephalosporin (cefepime, ceftazidime) or Antipseudomonal carbepenem (imipenem or meropenem) or Beta-lactam/beta-lactamase inhibitor (piperacillin-tazobactam) plus Antipseudomonal fluoroquinolone* (ciprofloxacin or levofloxacin) or Aminoglycoside (amikacin, gent, tobra) plus

MRSA

Linezolid suspected, a carbepenem *If an ESBL+ strain (eg, K pneumoniae or an Acinetobacter sp) is or vancomycin is a reliable choice. If L pneumophila is suspected, the combination regimen should include a macrolide (eg, azithromycin) or a fluoroquinolone (eg, ciprofloxacin or levofloxacin) rather than an aminoglycoside. If MRSA risk factors are present, or there is a high incidence locally.

ATS. Am J Respir Crit Care Med. 2005;171:388-416.

Antibiotics for Intra-abdominal Infections

Organisms
Enteric gram negatives, gram negative anaerobes, gram positive anaerobes, oral anaerobes, yeast

Antibiotics
Zosyn, Unasyn, Primaxin, Meropenem Ceftriaxone or Cefotaxime + Flagyl + Vancomycin + Fluconazole

Antibiotics for Urinary Tract Infections

Organisms
Gram negative enterics, enterococcus

Antibiotics
Ciprofloxacin, Levafloxacin, 2nd or 3rd generation cephalosporins, amoxacillin/ampicillin (if sensitive)

Antibiotics for Skin and Soft Tissue Infections

Organisms
Staphylococcus (75% MRSA), streptococcus

Antibiotics
PO TMP/SMX, Clindamycin, Linezolid IV Vancomycin, Daptomycin

Antibiogram HA-MRSA vs CA-MRSA

HA-MRSA
Sensitive to:
Vancomycin TMP/SMX Rifampin

CA-MRSA
Sensitive to:
Vancomycin TMP/SMX Rifampin Tetracyclines Erythromycin Clindamycin Quinolones

Resistant to:
Oxacillin Cephalosporins Quinolones Tetracyclines Erythromycin clindamycin

Resistant to:
Oxacillin Cephalosporins

Antibiotic Resistance

Things that promote drug resistance

Using antibiotics when no infection is present Treating cultures, not patients Using the incorrect empiric antibiotic Continuing antibiotics past the point that infection has resolved Failing to de-escalate antibiotic coverage after cultures are finalized Underdosing antibiotics Using an antibiotic that does not penetrate to the focus of infection Using a bacterostatic antibiotic when an infection calls for bacterocidal action
Example: using doxycycline for UTI Example: using Levaquin for cellulitis Colonizations or contaminants The just-in-case syndrome

Spread of MDR Organisms

Study at Johns Hopkins Medical Center
Only 40% of HCWs wash hands regularly and appropriately between every patient Of HCWs doctors were the worst washing hands only 18% of the time

MDRs are also transmitted on medical instruments

stethoscopes

Cultured-Based Antibiotic Choice

Know Your Local Antibiograms

Sensitivities of community-acquired and hospital-acquired organisms vary from region to region Knowledge of the general sensitivities will aid in choosing appropriate antibiotics and early institution of therapy

Inappropriate Antibiotic Therapy Increases Mortality

Appropriate therapy 100 90 80 70 60 50 40 30 20 10 0 Ibrahim Leibovici Luna Alvarez-Lerma Rello Bloodstream Infections Nosocomial Pneumonia/VAP Inappropriate therapy

Ibrahim, et al. Chest. 2000;118:146155. Leibovici, et al. J Intern Med. 1998;244:379386. Luna, et al. Chest. 1997;111:676685. Alvarez-Lerma, et al. Intensive Care Med.1996;22:387394. Rello, et al. AJRCCM.1997;156:196200.

Mortality (%)

Hospital Mortality Rate of Infected Patients

2000 consecutive patients admitted to an MICU or SICU Pneumonia in 411 cases
60 50 40 52.1%

30 305 with adequate therapy 106 with inadequate therapy 20 10 0

Mortality %

N = 312 P<.001

12.2%

Inadequate Adequate Antibiotic Treatment

Kollef, et al. Chest. 1999;115:462474.

Interpreting in vitro Sensitivity

MIC minimum inhibitory concentration In order to adequately kill bacteria, serum concentration must be at least 8x the MIC Sensitivity break-points vary among different antibiotics, because of differences in pharmacodynamics Best drugs to use are those with lowest MIC

Interpreting in vitro Sensitivity Panels

Not every antibiotic listed as sensitive in vitro will be effective in vivo Must consider tissue penetration
Ancef does not penetrate CSF Tetracycline is not excreted in urine

Must consider killing power

Clindamycin is too slowly bacterocidal to be useful in treating bacteremia Any bacterostatic antibiotic is contraindicated in treating serious infections like endocarditis and meningitis

Antibiograms

Sensitivity to Hospital-Acquired Gram Negatives City Wide

100 90 80 70 60 50 40 30 20 10 0 Pseudo E. cloacae Acinetob K. pneumo Meropenem Cefepime Pip/Tazo Levaquin

Sensitivity to Gram Positives City Wide

100 90 80 70 60 50 40 30 20 10 0 S.aureus S.pneumo E.faecium Ceftriaxone Vancomycin Penicillin Linezolid

Hospital-Specific Antibiogram
100 90 80 70 60 50 40 30 20 10 0 Pseudo-City Pseudo-UMC Meropenem Cefepime Pip/Tazo Cipro

Hospital-Specific Antibiogram
100 90 80 70 60 50 40 30 20 10 0 S.aureus-City S.aureus-UMC Oxacillin Vancomycin Clindamycin Levaquin

Summary
Use antibiotics judiciously to minimize treatment failure, higher morbidity and mortality and reduce development of resistance Know the antibiograms of you respective hospitals to guide choice of antibiotics Thoroughly evaluate every patient so that correct diagnosis is made