Common Pediatric ID Curbsides Susannah Kussmaul, MD Pediatric - PDF document

Common Pediatric ID Curbsides Susannah Kussmaul, MD Pediatric Infectious Diseases Kaiser Permanente Medical Center UCSF Volunteer Faculty No disclosures Curbside Question Can I use ciprofloxacin and other fluoroquinolones in children?

Fluoroquinolones (FQs) in Children • Cartilage damage affecting weight-bearing joints in beagle puppies (late 1970s) o Avoidance of FQs when possible in children • Accumulation of clinical experience suggested as safe in children as adults o Compassionate use of ciprofloxacin: 2030 treatment courses in 1795 children: • 1.5% with mild to moderate arthralgia o 60% of those in patients with CF (long courses) • All resolved off of cipro • No reported cartilage damage Hampel, et al, Ped Inf Dis J 1997;16(1) Fluoroquinolones (FQs) in Children ≠ • 2006: AAP supports use of IV FQs as alternative therapy for resistant infections, or PO to avoid hospitalization Fluoroquinolones (FQs) in Children • Children with community acquired pneumonia or acute otitis were randomized to receive levofloxacin vs. comparator antibiotic • Slight increase in musculoskeletal problems (predefined as arthralgia, arthritis, tendinopathy, gait abnormality) o Most were arthralgia o All resolved without long-term issues (followed to 5 years) % with musculoskeletal FQ treated Control p ‐ value complaints 2 months 2.1% 0.9% <0.05 12 months 3.4% 1.8% <0.05 Noel et al, Ped Inf Dis J 2007; 26:879–891

Fluoroquinolones (FQs) in Children • Other studies have shown trends towards transient musculoskeletal effects – used with some caution • Concern for development of resistance: UCSF data % Strains Susceptible to Ciprofloxacin at UCSF (2012) Pathogen Adult inpatient Peds inpatient Acinetobacter baumanii 63 100 Citrobacter freundii 75 100 Enterobacter aerogenes 95 100 Enterobacter cloacae 89 95 E.coli 67 93 Klebsiella oxytoca 98 94 Klebsiella pneumonia 80 90 Proteus mirabilis 80 100 Pseudomonas aeruginosa 74 100 *does not include CF patients Serratia marcescens 96 100 http://clinicalpharmacy.ucsf.edu/idmp/antibiogram_home.htm Fluoroquinolones (FQs): Review • Musculoskeletal symptoms are feared, but are transient and relatively uncommon • Most common side effects: • GI symptoms (N/V/D/abdominal pain); risk for C.difficile • Rash, allergies, photosensitivity • Characteristics: • Bactericidal • Good bioavailability (70-95%; nearly 100% for levofloxacin) • Good penetration into cells, tissues, CSF Bradley et al, Pediatrics 2011;128;e1034; Choi et al, Kor J Ped 2013:56(5):196-201 Fluoroquinolones (FQs): Spectrum 1 st generation: nalidixic acid • Gram negative rods (Enterobacteriacae) / UTIs • FDA-approved in children > 3 months • Not currently available in the US 2 nd generation: ciprofloxacin/ofloxacin, levofloxacin • Greater Gram negative activity ( H.flu, Neisseria, Moraxella); Pseudomonas (cipro>levo); S.aureus (levo>cipro); S.pneumo (levo) • FDA-approved for children 1-17 years old (cipro) and for children >6 months (levo) for certain indications 3 rd generation: gemfloxacin • Increased S.pneumo and atypical coverage (e.g. Mycoplasma) • Not FDA-approved in children 4 th generation: moxifloxacin • Comparable Gram positive and Gram negative coverage as levofloxacin; increased anaerobic and mycobacterial coverage including MTB • Not FDA-approved in children, but used off-label (community acquired pneumonia, perioperative prophylaxis)

FQs in Children: Clinical Uses • FDA-approved indications o Nalidixic acid: UTIs o Ciprofloxacin: inhalational anthrax, complicated resistant E.coli UTI/pyelonephritis o Levofloxacin: inhalational anthrax AAP, Pediatrics 2006;118:1287 FQs in Children: Clinical Uses • 2006, American Academy of Pediatrics Guidelines o UTI with resistant organisms • E.coli, Pseudomonas, Enterobacter, Citrobacter, Serratia o Oral option for Pseudomonas infections • Cystic fibrosis, chronic suppurative otitis o Mycobacterial isolates (if susceptibility known) o GI infections • Resistant Shigella, Salmonella, Campylobacter, Vibrio cholera o Gram-negative bacterial infections in immunocompromised hosts • When oral therapy indicated or no other alternative o Sepsis or meningitis from resistant organism o Serious infections a patient with allergies AAP, Pediatrics 2006;118:1287 FQs in Children: Clinical Uses • More recent IDSA / PIDS guidelines o Pediatric community acquired pneumonia (2011) • Use of levofloxacin in children as young as 6 months depending on allergies and pathogen • First-line agent for highly resistant S.pneumo Bradley et al, Clin Inf Dis Aug 2011 o Pe diatric bacterial sinusitis (2013) • Use of levofloxacin in patients who are failing treatment with augmentin Wald et al, Pediatrics 2013;132;e262 o Pediatric otitis media (2013) • Use of levofloxacin as an “unconventional drug” (in consultation with specialist) for certain highly resistant strains of S.pneumo Lieberthal et al, Pediatrics 2013;131;e964

Increasing Resistance in Children • Epidemiologic study from 300 US surveillance labs Total isolates Enterobacteriaceae 1999 ‐ 2001 2010 ‐ 2011 during study isolates in children (start of (end of period study data) study data) 1 ‐ 18 years old N = 368,398 3 rd generation 1.97% cephalosporin 1.39% 3% (7255 isolates) resistance 0.47% ESBL ‐ producers 0.28% 0.92% (1734 isolates) o Stratified by source (e.g. urine, blood), inpatient/outpatient, age, sex, and year  results consistent across demographic and age groups, including outpatients • Highest proportion of resistant isolates in children 1-5 yrs old • Lower prevalence of resistant isolates in the upper Midwest Logan et al, J Ped ID Soc, March 2014 Curbside Question How should in interferon-gamma release assay (IGRA) test such as the quantiferon (QFT) be used in children? Why do we treat latent TB infection (LTBI)? • LTBI vs. TB disease o 9 months of INH decreases the risk of developing subsequent TB disease by 90% (if adherent) • Problem: o TST (tuberculin skin test / PPD) cross-reactivity with non- tuberculous mycobacteria, including BCG leads to overdiagnosis of LTBI • Approach: o Targeted rather than universal screening o Utilize new diagnostics (e.g. IGRA) to identify the patients most likely to benefit from LTBI therapy, and to inform decisions for BCG-vaccinated patients

Diagnosing LTBI in Children • Universal / routine screening is discouraged • Targeted TB screening should be based on presence of risk factors o Has a family member or contact had TB disease? o Has a family member had a positive tuberculin skin test result? o Was your child born in a high-risk country (countries other than the United States, Canada, Australia, New Zealand, or Western and North European countries)? o Has your child traveled (had contact with resident populations) to a high-risk country for more than 1 week? American Academy of Pediatrics, Red Book 2012 • Likely new addition: foreign-born parent o Compared with US-born children with US-born parents, TB rates are 32 times higher among foreign-born children, and 6 times higher among US-born children with foreign-born parents Pang, et al. Pediatrics 2014;133;e494 Diagnosing LTBI in Children Definition of positive PPD test also relates to risk: Induration 5 mm or greater •Children in close contact with known/suspected contagious people with TB disease •Children suspected to have tuberculosis disease: Findings on chest radiograph consistent with active or previous TB disease Clinical evidence of tuberculosis disease •Children receiving immunosuppressive therapy or with immunosuppressive conditions, including HIV Induration 10 mm or greater •Children at increased risk of disseminated tuberculosis disease: Children younger than 4 years of age Children with other medical conditions (cancer, diabetes, renal failure, malnutrition) •Children with likelihood of increased exposure to tuberculosis disease: Children born in high-prevalence regions of the world •Children who travel to high-prevalence regions of the world •Children frequently exposed to adults with risk factors (HIV, homelessness, illicit drugs, nursing home resident, incarceration, institutionalized) Induration 15 mm or greater •Children age 4 years or older without any risk factors American Academy of Pediatrics, Red Book 2012 What is an interferon-gamma release assay (IGRA)? • Blood test used to diagnose TB o Does not distinguish LTBI from active disease • Two FDA approved IGRAs available in the US o Quantiferon-Gold, T-Spot • What do they do? o Detect interferon gamma released by lymphocytes after stimulation with peptides simulating MTB o More specific than TST (no BCG or MAC cross-reactivity) • How do we use them? o For children ≥ 5, they are about as sensitive as a PPD in the US and other low-incidence settings o Helpful in identifying LTBI in BCG-vaccinated persons o Interpretation depends on age, prevalence of TB, risk of exposure, and other factors -- an evolving science, especially in pediatrics http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.htm