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Wind and WaterCommonly Encountered Outpatient

Infectious Diseases Diagnoses

Christine Cho MDUniversity of IowaInfectious Diseases

Disclosure

• Will be focusing on adult populations• No financial disclosure

Objectives

• Pneumonia– Define pathogenesis and diagnostic criteria– Understand the empiric treatment for pneumonia

• Urinary tract infection (UTI)– Define pathogenesis and diagnostic criteria – Understand the empiric treatment for UTI

Objectives

• Pneumonia– Define pathogenesis and diagnostic criteria– Understand the empiric treatment for pneumonia

• Urinary tract infection (UTI)– Define pathogenesis and diagnostic criteria – Understand the empiric treatment for UTI

Pneumonia

• Pathogenesis/Etiology• Diagnosis• Treatment

Pneumonia-Pathogenesis

• Defect in host defense + exposure to virulent microorganism + inoculum size

• Host defense: – Upper airways: nasopharynx, oropharynx– Conducting airways: trachea, bronchi– Lower respiratory tract: terminal airways, alveoli

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Pneumonia-EtiologyBacteria Virus Fungi OtherStreptococcus pneumoniae

Influenzae A/B Histoplasma capsulatum

Coxiella burnetii

Haemophilusinfluenzae

Respiratorysyncytial virus

Coccidioides immitis Rickettsiarickettsiae

Staphylococcus aureus

Human metapneumonvirus

Cryptococcus neoformans

Mycoplasma pneumoniae

Legionella spp. Adenovirus Aspergillus spp. Chlamydia pneumoniae

Enterobacteriaceae Rhinovirus Mycobacterium tuberculosis

Mixed anaerobic bacteria (aspiration)

NTM

Pneumonia-Diagnosis

• Clinical history: sudden onset fever, cough,

sputum production, shortness of breath,

physical findings of consolidation

• Lab/radiograph: leukocytosis, lung infiltrate

• Microbiology

– Sputum Gram’s stain and culture: 80% positive

with pneumococcal pneumonia (within 6-12h abx)

– Blood culture: 20-25% positive with

pneumococcal pneumonia

Musher et al. NEJM. 2014;371:1619-28.

Pneumonia-Diagnosis

• Pneumococcal urine antigen: – Sensitivity: 74%– Specificity: 97.2%

• Legionella urine antigen: Serotype 1– Sensitivity: 74%– Specificity: 99.1%

Prina et al. Lancet. 2015;386:1097-108.

Pneumonia-Pro-calcitonin

Procalcitonin level (µg/L) Bacterial Etiology Recommendation<0.1 Very unlikely Antibiotics strongly

discouraged

0.1-0.25 Unlikely Antibiotics discouraged

>0.25-0.5 Likely Antibiotics recommended

>0.5 Very likely Antibiotics stronglyrecommended

Huang et al. NEJM. 2018;379(3):236-249.

Procalcitonin Antibiotic Consensus Trial (ProACT)

• Procalcitonin group vs usual-care group

• US academic centers

• Primary outcome: Total # antibiotic-days within 30 days

Procalcitonin Usual-careRandomized 830 834

Primary outcome 826 830

Completed 30-day follow up

675 670

Antibiotic-days by day 30

4.2±5.8 4.3±5.6

Huang et al. NEJM. 2018;379(3):236-249.

Pneumonia-Diagnosis

• Radiology– Radiograph

• 75% for alveolar consolidation• 47% for pleural effusion

– CT: most accurate technique • Other diagnoses (pulmonary embolism)• Fungal lung infection• Unclear chest X-ray• Detection of complication (lung abscesses)

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Vilar et al. European Journal of Radiology. 2004;51:102-113.

Pneumonia-Diagnosis

• Disease severity– CURB-65: confusion, blood urea nitrogen,

respiratory rate, blood pressure, age>65– Pneumonia Severity Index: demographic, co-

existing illness, physical exam finding, lab/radiographic finding

Pneumonia-Diagnosis

Prina et al. Lancet. 2015;386:1097-108.

Pneumonia-Treatment• Empiric treatment (IDSA/ATS guideline, 2007)

Preferred AlternativeOutpatient withoutcomorbidities; low severity

Macrolide Doxycycline

Outpatient with comorbidities or high rate of bacterial resistance

β-lactam + macrolide

Respiratory fluoroquinolone

Inpatient not in ICU; moderate severity

β-lactam + macrolide

Respiratory fluoroquinolone

Inpatient in ICU; high severity

β-lactam + macrolide

β-lactam + respiratoryfluoroquinolone

Mandell et al. Clin Infect Dis. 2007;44 (suppl 2): S27-72.

Antibiotics

• Macrolides– QT interval prolongation– Resistance development (especially S. pneumoniae)

• Fluoroquinolones– C.difficile infection– CNS effect: delirium, agitation, memory impairment– Peripheral neuropathy– Tendinopathy– QT interval prolongation

β-lactam monotherapy vs β-lactam+macrolide

• Randomized noninferiority trial• Moderately severe community-acquired pneumonia• Primary outcome:

– did not reach clinical stability by day-7

• Did not find non-inferiority of monotherapy (upper limit of the 1-sided 90% CI=13%; 8% boundary)

Randomized Completed follow up

Primary outcome

β-lactam monotherapy

300 291 120 (41.2%)

β-lactam +macrolide

302 289 97 (33.6%)

Garin et al. JAMA Intern Med. 2014;174(12):1894-1901.

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Community-Acquired Pneumonia-Study on the Initial Treatment with Antibiotics of Lower Respiratory Tract

Infections (CAP-START) Trial

• Randomized, cross over trial• Noninferiority: – β-lactam (BLM) monotherapy – β-lactam+macrolide– Fluoroquinolone (FQ) monotherapy

• Primary outcome: all-cause mortality within 90 days after admission

Postma et al. NEJM. 2015;372:1312-23.

CAP-START Trial

BLMmonotherapy BLM+Macrolide FQEnrolled 656 739 888

Adherence 93% 88% 92.7%

Crude 90-day Mortality

9% 11.1% 8.8%

• “BLM monotherapy was non-inferior to strategies with a BLM+macrolide combination or FQ monotherapy with regard to 90-day mortality”

Postma et al. NEJM. 2015;372:1312-23.

Pneumonia-Treatment Duration

• Duration of antibiotic treatment in Community-Acquired Pneumonia

• Multicenter randomized clinical trial• IDSA/ATS duration: 5 days (minimum),

achieving afebrile state for 48-72 hours and meeting no more than 1 CAP-associated instability criteria

Uranga et al. JAMA Int Med. 2016;176(9):1257-1265.

• Determined by physician (medial: 10-day) vs 5-day (Intervention)

• Outcome: resolution/improvement in sign/symptoms of pneumonia + CAP symptom questionnaire

Pneumonia-Treatment Duration

Control Intervention p-valueenrolled 150 16210-dayFollow up

71 (48.6%) 90 (56.3%) 0.18

30-dayFollow up

132 (88.6%) 147 (91.9%) 0.33

“withdrawing antibiotic treatment based on clinical stability criteria after a minimum of 5 days of appropriate treatment is not inferior to traditional treatment schedules in terms of clinical success”

Uranga et al. JAMA Int Med. 2016;176(9):1257-1265.

Niederman M.S. Annals of Internal Medicine. 2015;163(7):ITC1.DOI: 10.7326/AITC201510050

Objectives

• Pneumonia– Define pathogenesis and diagnostic criteria– Understand the empiric treatment for pneumonia

• Urinary tract infection (UTI)– Define pathogenesis and diagnostic criteria – Understand the empiric treatment for UTI

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UTI-Pathogenesis

Flores-Mireles et al. Nature Reviews-Microbiology. 2015;13:269-284.

Cystitis

Pyelonephritis

UTI-Epidemiology

Flores-Mireles et al. Nature Reviews-Microbiology. 2015;13:269-284.

UTI-Definition

• Uncomplicated: No structural abnormality• Complicated– Defect in host defense– Structural compromise

UTI-Diagnosis

• Symptoms: fever, flank/abdominal pain, dysuria, urinary urgency, hematuria

• Pyuria: Urine dipstick

– >10 WBC/mm3: sens=75-96%, spec=94-98%

– Pyuria ≠ UTI

• Positive urine culture:

– Cystitis > 103 colony-forming units (CFU)/mL of a uropathogen (sens=90%, spec=90%)

– Pyelonephritis > 104 CFU/ml (sens=90%, spec=90%)

UTI treatment in women

• Asymptomatic bacteriuria

– General population ~ 5%

– Women > 70: 15-17% (30-

50%)

• Chronic GU symptoms:

urinary frequency and

urgency

• Medications: diuretics

Mody et al. JAMA. 2014;311(8):844-854.

UTI in Older Women-Diagnosis

Mody et al. JAMA. 2014;311(8):844-854.Bent et al. JAMA. 2002;287(20):2701-2710.

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UTI-TreatmentAntimicrobial Mechanism of

ActionPharmacokinetics Pharmacodynamics

Nitrofurantoin Complex; inactivates/alters bacterial ribosomal proteins and other macromoleculesàDNAdamage

90% renal elimination (30-40% unchanged)

Bactericidal or static (concentration-dependent)

TMP/SMX Sequentially inhibits steps in bacterial folate synthesis

Renal elimination (mostly unchanged); renal dose adj CrCl<30

Bactericidal

Fosfomycin Binds/inhibits MurA(early stages of peptidoglycan synthesis)

38% renal elimination (unchanged); no dosage adj in renal impairment or elderly population

Bactericidal

Fluoroquinolones DNA gyrase and topoisomerase inhibitor (DNA synthesis)

Renal elimination; dose adj in renal impairment

Bactericidal

β-lactam Inhibit peptidoglycan synthesis

Renal elimination; dose adj in renal impairment

Bactericidal

Walker et al. Clinical Infectious Diseases. 2016;63:960-965.

Uncomplicated Cystitis-Treatment

• IDSA/ESMID 2010 update

• Rule out pyelonephritis (fever, flank pain)

• Nitrofurantoin 100mg BID x 5d, TMP/SMX DS BID x 3d, fosfomycin 3g single dose

• Fluoroquinolones x 3d

• β-lactam (amox/clauv, cefdinir, cefaclor, cefpodoxime-proxetil) x 3-7d– Ampicillin or amoxicillin have poor efficacy

Gupta et al. Clinical Infectious Diseases. 2011;52(5):e103-e120.

Acute Pyelonephritis-Treatment

• Urine culture with susceptibility• Ciprofloxacin 500mg BID x 7d– Not requiring hospitalization– Community resistance < 10%

• TMP/SMX DS BID x 14d– Not requiring hospitalization

Gupta et al. Clinical Infectious Diseases. 2011;52(5):e103-e120.

Antibiotics

• Nitrofurantoin– Not indicated for pyelonephritis– Nausea/vomiting, Pulmonary Reactions

• Fosfomycin– Not indicated for pyelonephritis– Diarrhea and headache

Mody et al. JAMA. 2014;311(8):844-854.

Fosfomycin vs Ibuprofen

• Uncomplicated cystitis in women• Fosfomycin 3g once vs Ibuprofen x 3 days• Primary outcome: – Total number of courses of antibiotics on days 0-

28– Burden of symptoms on days 0-7 (Daily symptoms

scores)

Gagyor et al. BMJ. 2015;351:h6544.

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Fosfomycin vs Ibuprofen

• “We have to reject the hypothesis of non-inferiority of initial symptomatic treatment, and we cannot generally recommend the ibuprofen first approach. This treatment option, however, can be discussed with women with mild to moderate symptoms in a shared decision making approach…”

Gagyor et al. BMJ. 2015;351:h6544.

Ibuprofen (n=241)

Fosfomycin(n=243)

% mean difference (95% CI)

P value

Received Abxduring f/u

75 (31%) 30 (12%) 18.8(11.6-25.9)

<0.001

Take Home Points-Pneumonia

• Pathogen: S. pneumoniae, H. influenzae, atypical (M. pneumoniae, C. pneumoniae, L. pneumophila), virus

• Diagnosis: Clinical history– Culture: useful if appropriately collected– Lab: procalcitonin is useful to rule out pneumonia

• Treatment: macrolide à β-lactam+macrolide

Take Home Points-UTI• E. coli is the most common pathogen• Diagnosis: – Clinical history: dysuria, back/flank pain– Pyuria ≠ UTI– Asymptomatic bacteruria ≠ UTI

• Treatment: – Cystitis: nitrofurantoin, TMP/SMX, fosfomycin,

fluoroquinolone, β-lactam (except ampicillin/amoxicillin)

– Pyelonephritis: ciprofloxacin, TMP/SMX

Questions?

christine-cho@uiowa.edu