Shocking revelations about toxic shock syndrome therapy Iona Berger - PowerPoint PPT Presentation

Shocking revelations about toxic shock syndrome therapy Iona Berger December 21, 2016 1

Objectives 1) Describe the pathophysiology of Staphylococcus aureus toxic shock syndrome 2) Explain the mechanism of action of linezolid and clindamycin 3) Summarize the evidence of using linezolid and clindamycin in toxic shock syndrome 2

Meet our Patient ID CL - 14 y/o ♂ 66.7 kg CC S. aureus toxic shock syndrome HPI 4 day history of feeling unwell, initially: myalgia then fever followed by rash, emesis (4x NBNB), diarrhea and sore throat. Went to GP,++ dizzy & poor perfusion, BP: 50/30 mmHg Taken to Langley Memorial Hospital and subsequently transferred to BCCH PICU Allergies NKDA Immunization UTD 3

Meet our Patient PMHx Previously healthy MPTA None Social From Langley history Lives with mom & dad Family • Brother: autism spectrum disorder history • Mom: type 1 diabetes ID history • No sick contacts • No recent travel history • No recent antibiotic use 4

Review of Systems Vitals T: 40.6, HR: 150, BP: 95/50, RR: 25 CNS Sedated HEENT Unremarkable CVS Cap refill > 6 secs, peripherally warm, centrally mottled. Poor radial & pedal pulses. Strong femoral pulse. RESP Intubated (Dec 6) CXR (Dec 7): LLL atelectasis, pulmonary edema GI/Liver NG tube inserted INR: 2.4, AST: 155, ALT: 88, ALP: 35, Total Bili: 50, Alb: 28 5

Review of Systems GU/renal Receiving CRRT, AKI stage 3, Cr: 417, BUN: 19 Lytes/Fluids Na: 135, K: 3.8, ++ fluid overloaded, ++ edematous Endo LDH: 1254, CPK: 3789 Heme WBC: 13.8, Neuts: 3.45, L bands: 8.7 Plt: 30, Hgb: 108, CRP: 202 MSK Right arm pain + myalgia, right knee scab noted Derm Diffuse erythematous macular blanched rash 6

Review of Systems Site Culture Susceptibilities Dec 6 Peripheral blood S. aureus (@ 18hrs) Pending – likely MSSA 12:05 culture (@ LMH) (2/2 bottles) Dec 6 Peripheral blood S. aureus (@ 18hrs) Pending – likely MSSA 12:10 culture (@LMH) (2/2 bottles) Dec 7 Arterial line No growth Dec 7 Central line No growth 7

Medical Problem List (Dec 7) Medical Problems Medications Methicillin-sensitive Vancomycin 1g IV Q12H (=30 mg/kg/day) Staphylococcus aureus Cefotaxime 2 g IV Q6H (=120 mg/kg/24h) toxic shock syndrome Clindamycin 600mg IV Q8H (=27 mg/kg/24h) Cloxacillin 2 g IV Q4H (=180 mg/kg/24h) Linezolid 600 mg Q12H (=18 mg/kg/24h) Severe hypotension Norepinephrine infusion Epinephrine infusion Kidney failure Replavite Sodium Chloride (Dialysate) Prismocal Sol Intubation/sedation Midazolam Rocuronium Ketamine Hydromorphone 8

ID DTPs • CL is experiencing S. aureus toxic shock syndrome and requires reassessment of his antibiotic drug therapy 9

Staphylococcus aureus Peds in Review 2005; 26(12), 444 10

Pathogenesis of toxic shock TSST-1, PVL a-toxin, SEA 11

Goals of Therapy 1. Prevent mortality 2. Prevent morbidity (=deep seeded infections, amputation, multi- organ failure) 3. Eradicate the infection 4. Resolve signs and symptoms of shock (= cap refill <2 sec, normotensive (110-131/64-83mmHg) , ↓ edema, ++ radial/pedal pulses) Alleviate signs and symptoms of sepsis (= afebrile (34.7-37.3C (ax) ), 5. ↓ WBC, ↓ neuts, absence of band neutrophils, ↓ rash, -ive BCx) 6. Minimize adverse drug reactions 7. Optimize antimicrobial stewardship 12

Methicillin-sensitive S. aureus Treatment Alternatives Cell wall/membrane DNA synthesis Protein synthesis o Cloxacillin o TMP/SMX o Clindamycin o Pip/Tazo o Moxifloxacin o Linezolid o Cefazolin o Levofloxacin o Doxycycline o Cefuroxime, o Clarithromycin Cefprozil o Azithromycin o Cefotax, Ceftriax o Tigecycline o Cefepime o Meropenem o Vancomycin o Daptomycin 13

Methicillin-sensitive S. aureus Treatment Alternatives Cell wall/membrane DNA synthesis Protein synthesis o Cloxacillin o TMP/SMX o Clindamycin o Pip/Tazo o Moxifloxacin o Linezolid o Cefazolin o Levofloxacin o Doxycycline o Cefuroxime, o Clarithromycin Cefprozil o Azithromycin o Cefotax, Ceftriax o Tigecycline o Cefepime o Meropenem o Vancomycin o Daptomycin 14

Mechanism of Action of Clindamycin and Linezolid 15

Clindamycin’s role in TSS Clindamycin-Induced Suppression of Toxic- Shock Syndrome – Associated Exotoxin Production Schlievert PM, Kelly JA. 1984 16

Clindamycin’s role in TSS Concentration of TSS Log # of cells/mL exotoxin Clindamycin Typical Typical concentration Isolate MN 8 Isolate MN 8 isolates isolates ( µ g/mL) 0 9.8 9.6 12.8 2.9 0.001 9.3 9.7 3.2 (75%) 2.8 (3%) 0.01 9.5 9.6 0.10 (92%) 0.36 (88%) 0.1 8.7 <6.0 <0.10 (100%) <0.10 (100%) 1.0 9.3 <6.0 <0.10 (100%) <0.10 (100%) • Clindamycin is capable of stopping toxin production prior to inhibition of bacterial growth 17

Clinical Question Patient Staphylococcal toxic shock syndrome Intervention Linezolid Comparison Clindamycin or Placebo Outcome Efficacy: Mortality, morbidity (=deep seeded infection, amputation, organ failure), length of stay, time to first negative blood culture, toxin production Safety: Adverse drug events

Search Strategy Databases Medline/PubMed, Ovid/Embase, Google Scholar Search Terms 1. Toxic shock syndrome 2. Staphylococcal or staphylococcus aureus or methicillin- sensitive 3. TSST-1 or toxin or toxic shock 4. Clindamycin 5. Linezolid Limitations Excluded trials about: - Detection of PVL/TSST-1 studies - Characterization studies - Surveillance studies Limited to: English language Results 4 results: 1 case report & in-vitro study 1 in-vitro & in-vivo murine study 2 in-vitro study

Stevens, et al . 2006 Successful Treatment of Staphylococcal Toxic Shock Syndrome with Linezolid: A Case Report and In Vitro Evaluation of the Production of Toxic Shock Syndrome Toxin Type 1 in the Presence of Antibiotics D Case report P 56 y/o ♂ with staphylococcal toxic shock syndrome (with high likelihood of MRSA) secondary to an abdominal surgical site infection I Linezolid O Efficacy: blood pressure and pulses were normal at 48 hours, urine output and azotemia resolved. Safety: none reported Follow Culture results at 48 hours revealed S. aureus susceptible to oxacillin, up clindamycin, erythromycin, and linezolid Was switched to IV clinda and discharged 24 hrs later with PO clinda 20

Stevens, et al . 2006 Successful Treatment of Staphylococcal Toxic Shock Syndrome with Linezolid: A Case Report and In Vitro Evaluation of the Production of Toxic Shock Syndrome Toxin Type 1 in the Presence of Antibiotics D In-vitro study 56 y/o ♂ w/ toxic shock syndrome; S. aureus isolate (1 x 10 8 CFU/mL) P I Linezolid 20 µ g/mL C Vancomycin 5 µ g/mL, Nafcillin 4 µ g/mL, Clindamycin 0.5 µ g/mL O Antibiotic effects on the growth of S. aureus and the production of toxic shock syndrome toxin (TSST-1) 21

Results • Maximal TSST-1 production btwn 8-24 hrs in untreated, naficillin- treated, & vanco-treated • Clinda & linezolid completely suppressed toxin synthesis • Linezolid at ¼ of the MIC (=1 µ g/mL) significantly suppressed TSST-1 production 22

Conclusion • The ability of linezolid and clindamycin to suppress TSST-1 production contributed to a positive outcome in this case of S. aureus toxic shock syndrome 23

Limitations Evidence • Case report and in-vitro study Quality Generalizability • Only 1 pt’s isolate used in-vitro (? virulence) • Patient’s rapid resolution of symptoms not in keeping with CL’s course • Patient = 56 y/o male, infection secondary to abdominal SSTI 24

Turner C, Sriskandan S. 2015 Panton–Valentine leucocidin expression by Staphylococcus aureus exposed to common antibiotics D In-vitro & in-vivo murine model study Female balb/c mice infected subcutaneously with ~ 2x10 8 CFU S. P aureus MSSA isolates (n=27) to form an abscess I 12.5 mg/kg flucloxacillin (fluclox) 12.5 mg/kg fluclox+ 10 mg/kg clindamycin (clinda) 12.5 mg/kg fluclox+ 10 mg/kg clinda + 10mg/kg linezolid C Phosphate buffered saline (PBS) O Total leucotoxin activity (LukF-PV protein) lukF -PV transcription 25

Results • In vitro: – Fluclox, clinda or linezolid had either equal or ↓ levels of lukF-PV transcript vs. PBS at all time points and concentrations of abx – ↓ in LukF-PV protein observed following 3 h exposure to either fluclox or clinda significant for: • Clinda; 5xMIC at 4, 5 & 21 h • Fluclox; MIC at 3 h, ½MIC &¼MIC at 5 h – Linezolid had little effect on LukF-PV protein levels – Addition of fluclox ↑ total protein content in culture media (after 21 h) 26

Results • In vivo (murine abscess model): – Little effect of abx combos on bacterial burden within abscesses 27

Results All combos of abx ↓ overall leucotoxin activity present in pus - Only flucloxacillin with clindamycin ↓ this significantly compared to control - PBS treated mice 28

Conclusion • For MSSA-PVL, combined treatment of flucloxacillin and clindamycin would be the most effective and that additional inclusion of linezolid for treatment of MSSA may be unnecessary 29

Limitations Evidence • In-vitro study Quality • Effects of antibiotics tested up to 21 h Generalizability • PVL has no effect on murine neutrophils and cannot be used to model disease outcomes related to PVL • ? Extrapolation of doses used in murine model to CL • Unknown relevance of PVL toxin decrease with clinical outcomes 30