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Bugs and Drugs Nawal AL Kaabi, MBBS, FAAP, FRCPC Pediatric Infectious disease consultant Deputy CMO Adjunct Faculty Cleveland clinic SKMC, Managed by Cleveland Clinic SEHA Objectives To learn an approach to antibiotic use using illustrative clinical scenarios: Skin and soft tissue infections Cellulitis Periorbital/Orbital cellulitis Necrotizing fasciitis Sepsis Meningitis Urinary Tract Infections/Pyelonephritis Pneumonia Approach to Antibiotic Use What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Approach to Antibiotic Use What is the infection? What are the most common organisms? What are their resistance patterns? Where is the infection? Where does the drug need to get to? Who is the host? Age status of immune system allergies underlying illness-eg, hepatic/renal dysfunction Approach-2 How do I diagnose the infection? Which Antibiotics should I use? Parenteral (intravenous) vs. oral side effects taste cost Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic 1. Natural Penicillin: Penicillin G, Penicillin V Most active against : 1. non-B-lactamase producing gram positive bacteria- Streptococcus pyogenes (Group A Streptococcus), susceptible Streptococcus pneumoniae. Streptococcus agalactiae (Group B Streptococcus) 2. Anaerobespeptostreptococcus, Corynebacterium diphtheriae, and Colstridium perfringens Natural Penicillin Most active against 3. Susceptible Neisseria meningitidis. 4. Treponema pallidum (Syphilis) Not active against Staphylococcus Most Gram negatives Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic 2. Penicillinase-resistant Penicillins Methicillin, Cloxacillin, Oxacillin. Drug of choice for S.aureus unless MRSA If S. aureus is resistant to cloxacillin it is resistant to all -lactams Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic 3. Aminopenicillins Ampicillin and Amoxicillin Possess the same spectrum as penicillin G plus they are more active against non-B lactamase producing gram negative cocci and some Enterobacteriaceae like Salmonella Listeria monocytogenes (ampicillin) First line for acute otitis media ( high dose Amoxil) Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic 4. Extended-spectrum ureidopenicillins and Carboxyand indanyl penicillins Piperacillin and Ticarcillin Increased gram negative coverage to include Pseudomonas Bacteroides, other anaerobes Most gram positive, including Enterococci Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic First Generation Cephalosporins : Parenteral: cefazolin Oral: cephalexin Active against gram positive cocci and have moderate activity against Moraxella catarrhalis, E.coli and some K. pneumoniae. Appropriate for S.aureus and non-enterococcal streptococcal infections Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic Second Generation Cephalosporins Parenteral: Cefuroxime Oral: Cefaclor, Cefuroxime axetil, Increased activity against H.influenzae, M.catarrhalis, Enterobacteriaceae: e.g Enterobacter, Klebsiella, Salmonella, Serratia, Shigella Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic Third Generation Cephalosporins Parenteral: Cefotaxime, Ceftriaxone and Ceftazidime Oral: Cefixime Active against facultative gram negative bacilli. They have potent antimicrobial activity against S.pneumoniae, S.pyogenes, and other streptococci, and with the exception of ceftazidime, have some activity against S.aureus Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic Third Generation Cephalosporins Also active against E.coli, Klebsiella Cefotaxime and ceftriaxone very effective therapy for meningitis caused by S.pneumoniae, H.influenzae, Neisseria meningitidis, Drug of choice for empiric therapy for meningitis Ceftazidime is the agent of choice for meningitis due to P.aeruginosa Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic Aminoglycosides Aerobic gram-negative organisms No antianaerobic activity Enterococci: only gram positive organism for which aminoglycosides are considered the drug of choice (with either penicillin/ampicillin or vancomycin) Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic Clindamycin gram positive cocci and anaerobes Active against many staphylococci (including penicillinase producers but not all MRSA) anaerobic lung abscess invasive GAS ( with penicillin) Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic Macrolides Clarithromycin and azithromycin extend erythromycin coverage to include more respiratory pathogens (esp. H. Influenzae) not recommended as first line therapy for otitis media or respiratory infections Vancomycin Essentially all gram positive and only gram positive organisms Approach to Antibiotic Use Antibacterial Spectrum of Antibiotic CARBAPENEMS CARBAPENEMS are a class of beta-lactum, broad spectrum antibiotics which act by inhibiting the cell wall synthesis and are known to be most effective against gram negative infections. Carbapenems, often in combination with other agents, remain a mainstay of therapy in patients with serious hospital-acquired infection. Carbapenems can be grouped as (2), Group 1 includes broad-spectrum Carbapenems, with limited activity against non-fermentative Gram-negative bacilli, particularly suitable for community acquired infections (e.g. ertapenem). Group 2 includes broad-spectrum Carbapenems, with activity against nonfermentative Gram-negative bacilli that are particularly suitable for nosocomial infections (e.g. imipenem and meropenem) Case #1 3 year old boy at family farm for the weekend Sustains many mosquito bites which he has been scratching Develops erythema around facial bites which is now spreading Has a low grade fever Otherwise a healthy boy with no known drug allergies Case #1 What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? What is the infection? Cellulitis What are the most common organisms? What are their resistance patterns? Cellulitis-What is the infection? Common organisms: Staphylococcus aureus Group A Streptococcus (GAS) Resistance patterns: Increasing antibiotic resistance of Staphylococcus aureus No known cases of penicillin resistance for GAS Case #1 What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Cellulitis-Where is the infection? Skin +/- blood Cellulitis What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Cellulitis- Who is the host? Age Status of immune system Allergies Underlying illness-eg, hepatic or renal dysfunction Cellulitis- Who is the host? Age Newborn– Include Group B Streptococcus in the differential diagnosis Status of the immune system In immunocompromised patients, consider Pseudomonas, Cryptococcus, in the differential diagnosis Cellulitis What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Cellulitis- How to diagnose? History can be very helpful- examples: Cellulitis following animal/human bites? recent dental work? Physical exam Lab Complete blood count/differential, blood c/s may be helpful Cellulitis What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Cellulitis-Which Abx? Parenteral vs. Oral? Cellulitis-Which Abx? Parenteral therapy generally used in the following situations: Newborn babies Severe +/- rapidly progressing cellulitis lymphangitis/adenitis First line parenteral agent: Cefazolin/Fluclox/clindamycin First line oral agents: cephalexin Clavulin (amoxicillin + clavulinic acid) Clindamycin IDSA Guidelines for CA-MRSA Endorsed by the AAP January 2011 Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Treatment for Skin / Skin Structure Infections (SSTI) Hospitalized children with complicated SSTI: Vancomycin Clindamycin is an option if the patient is stable, without ongoing bacteremia or intravascular infection, and if the clindamycin resistance rate is low (eg,10%); allows transition to oral therapy Linezolid is an alternative Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Treatment for Skin / Skin Structure Infections (SSTI) I&D for MRSA abscess is curative Oral antibiotics for Cellulitis: Clindamycin (if local strains susceptible) Staph + Strep [tastes bad] TMP-SMX (Septra/Bactrim) Staph + ?Strep Doxycycline [bacteriostatic, for children older than 7 years] Linezolid (Zyvox) Staph + Strep [expensive! Marrow toxicity for courses beyond 10 days] Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. Necrotizing Fasciitis Rapidly progressive infection of fascia which may extend into muscle Patients generally look toxic Infected area exquisitely tender which is often out of keeping with appearance A potential complication of any cutaneous cellulitis An association also exists between varicella, NSAID use and the development of necrotizing fasciitis Therefore, NSAIDs should not be used in patients with varicella Necrotizing Fasciitis Most often caused by GAS now can also be caused by Staphylococcus aureus consider gram negative organisms and anaerobes in differential diagnosis as well (especially if gas producing) Necrotizing Fasciitis Treatment: Empiric Therapy: cefazolin + clindamycin GAS known/highly likely: penicillin + clindamycin Surgical debridement (do not delay!) MRI may be helpful if diagnosis is in doubt Intravenous immunoglobulin Periorbital, Orbital Cellulitis Periorbital (preseptal) Cellulitis predisposing factors include trauma (including bites), impetigo, URI Usual causative organisms GAS Staphylococcus aureus Patients usually afebrile, non-toxic appearing Rx: cefazolin or cefuroxime +/- clindamycin Important to distinguish periorbital from orbital cellulitis! (Can be difficult to tell the difference) Orbital Cellulitis Infection of the orbit (post-septal) Pathogenesis different than in periorbital infection Systemic signs often present Local signs may include: proptosis impairment and pain with extraocular movements loss of visual acuity chemosis Possibility of extension into CSF! ethmoid orbit Lamina papyracea Orbital Cellulitis Usual etiologic organisms include: Staphylococcus aureus GAS “Sinus bugs” Streptococcus pneumoniae Haemophilus influenzae (non-typeable) Moraxella catarrhalis +/- Anaerobes Orbital Cellulitis Treatment If concerned re CNS involvement or if neonate then empiric therapy should include: Cefotaxime or Ceftriaxone Metronidazole Vancomycin Case #2 3 wk bb with fever, decreased feeding Otherwise, a healthy baby, normal pregnancy, labour and delivery Physical exam reveals a lethargic, mottled baby with a fever (39.5 rectal), and no focus of infection What tests would you order? Approach What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? What is the infection? Presumed sepsis +/- meningitis Common organisms- age dependant Resistance patterns-IMPORTANT Sepsis/meningitis-What is the infection? Common organisms: Newborn: Group B streptococcus Listeria Gram negative bacilli (eg, Escherichia coli) include Enterococcus, S. aureus for sepsis (not meningitis) >3 mos: Streptococcus pneumonia Neisseria meningitidis Haemophilus influenzae type B (rare since universal vaccination) 1-3 mos: overlap Sepsis/Meningitis-What is the Infection? Resistance patterns Streptococcus pneumoniae increasing resistance to B-lactam antibiotics rates vary geographically due to altered penicillin binding proteins on cell wall Sepsis/Meningitis What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Sepsis, Meningitis-Where is the Infection? Blood CSF Blood brain barrier more difficult to penetrate with age Some antibiotics penetrate CSF better than others May need higher doses Sepsis, Meningitis What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Sepsis, Meningitis-Who is the host? Age dependent: as mentioned Underlying conditions can influence etiology-examples: Sickle cell disease at higher risk for encapsulated bacteria (especially Salmonella sepsis) Central Venous catheters at risk for coagulase negative Staphylococcus and gram negative bacilli VP shunt at risk of coagulase negative Staphylococcus meningitis Sepsis, Meningitis What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Sepsis, Meningitis-How to diagnose? History variable presentation in neonates Physical exam Lab CBC diff, gm stain, blood C/S, other CSF cell count/diff, glucose, protein, gm stain, C/S Urinalysis, urine C/S Sepsis, Meningitis What is the infection? Where is the infection? Who is the host? How to diagnose? Which antibiotics? Sepsis, Meningitis-Which Antibiotics? For straightforward cases: <4 weeks: ampicillin/gentamicin alternative: amp/cefotaxime 4-6 weeks: amp/cefotaxime >6 weeks: vancomycin/cefotaxime Remember meningitic doses! Meningitis NEVER delay antibiotics if meningitis is suspected even if it means LP is done after Abx started! Case #3 5 year old girl with 2 days fever, dysuria, left sided flank pain, poor oral intake otherwise, past medical history unremarkable u/a: >50 WBCs, +nitrite, 2+ bacteria gram stain: Pyelonephritis/Urinary Tract Infection What is the infection? Where is the infection? Who is the host? How to diagnose? Which Abx? Pyelo/UTI Usual Organisms: Enterobacteriaceae (E. coli-70-90%, Klebsiella, Proteus spp) Less commonly: Enterococcus, Pseudomonas Newborns: include GBS Adolescent females: include Staphylococcus saprophyticus Resistance Patterns Increasing resistance of enterobacteriaceae ESBL Pyelo/UTI- Treatment Empiric parenteral therapy: ??ampicillin + gentamicin if uncomplicated Ampicillin should be included if enterococcal UTI is suspected. Third- or fourth-generation cephalosporins (eg, cefotaxime, ceftriaxone, cefepime) and aminoglycosides (eg, Amikacin or gentamicin) are appropriate first-line parenteral agents for empiric treatment of UTI in children First line oral therapy: Trimethoprim/sulfamethoxazole (septra) Follow-up important remember imaging, VCUG http://www.uptodate.com/contents/urinary-tract-infections-in-infants-and-children-older-than-one-month-acute-managementimaging-andprognosis?source=machineLearning&search=uti+children&selectedTitle=1%7E150§ionRank=1&anchor=H5#H5 Pyelo/UTI- Treatment Recent antibiotic exposure — treatment or prophylaxis Recurrent UTI — Review of the antimicrobial susceptibilities of the most recent urinary pathogens can be helpful in choosing empiric therapy for children with recurrent UTI. First line oral therapy: Trimethoprim/sulfamethoxazole (septra) Amoxicillin-clavulanate Third-generation cephalosporin (eg, cefixime, cefdinir, ceftibuten) Follow-up important remember imaging, VCUG http://www.uptodate.com/contents/urinary-tract-infections-in-infants-and-children-older-than-one-month-acute-managementimaging-andprognosis?source=machineLearning&search=uti+children&selectedTitle=1%7E150§ionRank=1&anchor=H5#H5 Pyelo/UTI- Treatment ESBL Parenteral therapy: Piperacillin-tazobactam is the 1st line if ESBL is sensitive Ertapenem. 2nd choice Meropenem or imipenem quinolones aminoglycosides Cefepime Case #4 5 year old girl with 6 days coryza, cough and escalating fever Poor oral intake and vomiting Looks unwell on exam, in mild resp distress, temp 39 po, HR 120, RR 25, decreased a/e RUL CXR: Approach What is the infection? Where is the infection? Who is the host? How to diagnose? Which Abx? Pneumonia-What is the infection? Common organisms Newborn GBS Listeria Gram negative bacilli Chlamydia trachomatis Past newborn period: most common is viral (always consider first in winter) Bacterial…… Pneumonia-What is the infection? Bacterial causes of pneumonia past the newborn period: Streptococcus pneumoniae GAS Staphylococcus aureus Hemophilus influenzae “atypicals” (eg, Mycoplasma pneumoniae) Anaerobes Pneumonia-What is the infection? Resistance patterns Increasing resistance of Streptococcus pneumoniae to B-lactam antibiotics Due to altered penicillin binding proteins on cell wall Resistance can be overcome by using high dose Blactam antibiotics (for infections outside of the CSF) Approach What is the infection? Where is the infection? Who is the host? How to diagnose? Which Abx? Pneumonia-Where is the infection? Lungs +/- blood blood culture positive in only 30% Approach What is the infection? Where is the infection? Who is the host? How to diagnose? Which Abx? Pneumonia-Who is the host? Age Underlying health status In immunocompromised patients (eg, those infected with HIV), consider unusual pathogens including Pneumocystis carinii, fungi, Cytomegalovirus Pneumonia-Who is the host? Underlying conditions (cont’d) In patients with underlying neurological disease, consider aspiration pneumonia In patients with nosocomial pneumonia, causative pathogens often different Approach What is the infection? Where is the infection? Who is the host? How to diagnose? Which Abx? Pneumonia-How to diagnose? History rapidity of onset, season can help Physical examination Labs CBCdiff sometimes unreliable Blood culture mycoplasma IgM may be helpful if index of suspicion is present +/- sputum gm stain, culture (children often do not expectorate though) Pneumonia-What is the infection? CXR--sometimes not helpful in distinguishing bacterial from viral etiology lobar: suggests typical bacteria pneumatocele: suggest Staphylococcus aureus effusion/abscesses: usually bacterial Streptococcus pneumoniae, GAS, Staphylococcus aureus diffuse: suggests viruses, atypical bacteria, PCP, MERS-CoV, NON-INFECTIOUS etc… Approach What is the infection? Where is the infection? Who is the host? How to diagnose? Which Abx? Pneumonia--Which Abx? Indications for parenteral therapy: Newborns with pneumonia Toxic appearing patients Those requiring oxygen Vomiting, can’t tolerate oral therapy Complications of pneumonia (abscess, empyema, effusion) Parenteral therapy: Viral: no Rx, unless bacterial superinfection suspected Pneumonia-Which Abx? CA-MRSA: Community-Acquired Pneumonia (CAP) For children hospitalized with severe CAP empiric therapy for MRSA is recommended (pending sputum and/or blood culture results): Those requiring an intensive care unit (ICU) admission, OR Necrotizing or cavitary infiltrates, OR Empyema Vancomycin recommended for children If the patient is stable without ongoing bacteremia or intravascular infection, clindamycin can be used as empirical therapy if the clindamycin resistance rate is low (eg, 10%) Linezolid is an alternative [watch for more data on this issue] Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. CA-MRSA: Vancomycin Dosing for Children Vancomycin 15 mg/kg/dose every 6 h (60 mg/kg/day) is recommended for serious or invasive disease (data are limited to guide vancomycin dosing in children). Trough concentrations of 15–20 mcg/mL should be considered in those with serious infections, such as bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia, and severe SSTI (eg, necrotizing fasciitis) Lui C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. Pneumonia-Which Abx? Parenteral Therapy Community acquired bacterial pneumonia: newborn: ampicillin + gentamicin Older child: Ampicillin Atypical bacteria: erythromycin, azithromycin Oral therapy: Amoxicillin Amox-Clav macrolide (especially if atypical pneumonia suspected) Practice Case 10 year old girl with mild cough x 8 days ,low grade fever, myalgias 6 year old sibling ill with similar symptoms Physical exam reveals that she is in mild respiratory distress with an oxygen saturation of 94% on room air, bullous myringitis, moderate a/e bilat, but no wheezes/crackles WBC is normal CXR: Practice Case What is the infection? Where is the infection? Who is the host? How to diagnose? Which Abx? Take Home Message How Can Resistance to Antimicrobials be minimized? 1. Limiting exposure to any antibiotic 2. Proper Antibiotics 3. Limiting the spectrum of activity of antimicrobials 4. Using the proper dosage of antimicrobials 5. Shortest effective duration 2000 B.C. – Here, eat this root 1000 A.D. – That root is heathen. Here, say this prayer. 1850 A.D. – That prayer is superstition. Here, drink this potion. 1920 A.D. – That potion is snake oil. Here, swallow this pill. 1945 A.D. – That pill is ineffective. Here, take this penicillin. 1955 A.D. – Oops....bugs mutated. Here, take this tetracycline. 1960-1999 – 39 more "oops"...Here, take this more powerful antibiotic. 2000 A.D. – The bugs have won! Here, eat this root. Thank you