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

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Shocking revelations about toxic shock syndrome therapy

Iona Berger December 21, 2016

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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

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

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Meet our Patient

PMHx Previously healthy MPTA None Social history From Langley Lives with mom & dad Family history

• Brother: autism spectrum disorder
• Mom: type 1 diabetes

ID history

• No sick contacts
• No recent travel history
• No recent antibiotic use

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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

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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

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Review of Systems

Site Culture Susceptibilities Dec 6 12:05 Peripheral blood culture (@ LMH)

• S. aureus (@ 18hrs)

(2/2 bottles) Pending – likely MSSA Dec 6 12:10 Peripheral blood culture (@LMH)

• S. aureus (@ 18hrs)

(2/2 bottles) Pending – likely MSSA Dec 7 Arterial line No growth Dec 7 Central line No growth

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Medical Problem List (Dec 7)

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Medical Problems Medications Methicillin-sensitive Staphylococcus aureus toxic shock syndrome Vancomycin 1g IV Q12H (=30 mg/kg/day) Cefotaxime 2 g IV Q6H (=120 mg/kg/24h) 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

ID DTPs

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• CL is experiencing S. aureus toxic shock

syndrome and requires reassessment of his antibiotic drug therapy

Staphylococcus aureus

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

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Pathogenesis of toxic shock

TSST-1, PVL a-toxin, SEA

Goals of Therapy

1. Prevent mortality 2. Prevent morbidity (=deep seeded infections, amputation, multi-

• rgan 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) 5. Alleviate signs and symptoms of sepsis (= afebrile(34.7-37.3C (ax)), ↓ WBC, ↓neuts, absence of band neutrophils, ↓ rash, -ive BCx) 6. Minimize adverse drug reactions 7. Optimize antimicrobial stewardship

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Methicillin-sensitive S. aureus Treatment Alternatives

Cell wall/membrane

• Cloxacillin
• Pip/Tazo
• Cefazolin
• Cefuroxime,

Cefprozil

• Cefotax, Ceftriax
• Cefepime
• Meropenem
• Vancomycin
• Daptomycin

DNA synthesis

• TMP/SMX
• Moxifloxacin
• Levofloxacin

Protein synthesis

• Clindamycin
• Linezolid
• Doxycycline
• Clarithromycin
• Azithromycin
• Tigecycline

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Methicillin-sensitive S. aureus Treatment Alternatives

Cell wall/membrane

• Cloxacillin
• Pip/Tazo
• Cefazolin
• Cefuroxime,

Cefprozil

• Cefotax, Ceftriax
• Cefepime
• Meropenem
• Vancomycin
• Daptomycin

DNA synthesis

• TMP/SMX
• Moxifloxacin
• Levofloxacin

Protein synthesis

• Clindamycin
• Linezolid
• Doxycycline
• Clarithromycin
• Azithromycin
• Tigecycline

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Mechanism of Action of Clindamycin and Linezolid

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Clindamycin’s role in TSS

Clindamycin-Induced Suppression of Toxic- Shock Syndrome – Associated Exotoxin Production Schlievert PM, Kelly JA. 1984

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Clindamycin’s role in TSS

• Clindamycin is capable of stopping toxin

production prior to inhibition of bacterial growth

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Log # of cells/mL Concentration of TSS exotoxin Clindamycin concentration (µg/mL) Isolate MN 8 Typical isolates Isolate MN 8 Typical isolates 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%)

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

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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

• utput and azotemia resolved.

Safety: none reported Follow up Culture results at 48 hours revealed S. aureus susceptible to oxacillin, clindamycin, erythromycin, and linezolid Was switched to IV clinda and discharged 24 hrs later with PO clinda

Stevens, et al. 2006

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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 P 56 y/o ♂ w/ toxic shock syndrome; S. aureus isolate (1 x 108 CFU/mL) I Linezolid 20 µg/mL C Vancomycin 5 µg/mL, Nafcillin 4 µg/mL, Clindamycin 0.5 µg/mL O Antibiotic effects on the growth of S. aureus and the production of toxic shock syndrome toxin (TSST-1)

Results

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• 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 µg/mL) significantly suppressed TSST-1 production

• 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

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Conclusion

Limitations

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Evidence Quality

• Case report and in-vitro study

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

Turner C, Sriskandan S. 2015

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Panton–Valentine leucocidin expression by Staphylococcus aureus exposed to common antibiotics

D In-vitro & in-vivo murine model study P Female balb/c mice infected subcutaneously with ~ 2x108 CFU S. 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

Results

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• In vitro:

– Fluclox, clinda or linezolid had either equal or ↓ levels

• f 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)

Results

• In vivo (murine abscess model):

– Little effect of abx combos on bacterial burden within abscesses

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Results

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• All combos of abx ↓ overall leucotoxin activity present in pus
• Only flucloxacillin with clindamycin ↓ this significantly compared to control

PBS treated mice

• For MSSA-PVL, combined treatment of

flucloxacillin and clindamycin would be the most effective and that additional inclusion

• f linezolid for treatment of MSSA may be

unnecessary

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Conclusion

Limitations

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Evidence Quality

• In-vitro study
• Effects of antibiotics tested up to 21 h

Generalizability

• PVL has no effect on murine neutrophils

and cannot be used to model disease

• utcomes related to PVL
• ? Extrapolation of doses used in murine

model to CL

• Unknown relevance of PVL toxin decrease

with clinical outcomes

Dumitrescu, et al. 2007

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Effect of antibiotics on Staphylococcus aureus producing Panton-Valentin Leukocidin

D In-vitro study P

• S. aureus LUG855 strain, 5 CA-MRSA strains

I Oxacillin, vancomycin, clindamycin, linezolid C No antibiotic O Amount of PVL toxin

Results

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Sub-inhibitory concentrations of clindamycin and linezolid significantly reduce PVL release.

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Conclusion

Limitations

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Evidence Quality

• In-vitro study

Generalizability

• Only 1 isolate used in-vitro
• Linezolid combination therapy with

clindamycin not assessed

• Unknown relevance of PVL toxin decrease

with clinical outcomes?

Dumitrescu, et al. 2008

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Effect of antibiotics, alone and in combination,

• n Panton-Valentine leukocidin production by

a Staphylococcus aureus reference strain

D In-vitro study P

• S. aureus LUG855 strain

I Oxacillin, clindamycin, linezolid, rifampicin, vancomycin, fusidic acid, pristinamycin, tetracycline, ofloxacin, co-trimoxazole,

• xacillin + clindamycin, oxacillin + linezolid, oxacillin + fusidic acid

C No antibiotic O Amount of PVL toxin

Results

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Results

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• PVL production started to decrease

significantly at % &

⁄ x MIC of clindamycin

and at % (

⁄ x MIC of linezolid

• Clindamycin and rifampicin both

significantly reduced PVL production in the presence of oxacillin, while linezolid had an inconsistent effect

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Conclusion

Limitations

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Evidence Quality

• In-vitro study

Generalizability

• Only 1 isolate used in-vitro
• Linezolid combination therapy with

clindamycin not assessed

• Unknown relevance of PVL toxin decrease

with clinical outcomes?

Conclusion of the evidence

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Clindamycin Linezolid Article Efficacy Safety Efficacy Safety Stevens, et al. 2006 ü In vivo & vitro N/A ü In vivo & vitro N/A Turner C, Sriskandan S. 2015 ü In vivo & vitro N/A ü In vivo only (x against use as combo) N/A Dumitrescu, et

• al. 2007

ü In vitro (monotx) N/A ü In vitro (not as efficacious as clinda) N/A Dumitrescu, et

• al. 2008

ü In vitro (monotx & combo w/ oxacillin) N/A ü In vitro (not as efficacious as clinda – either as mono or combo w/ oxacillin) N/A

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Clindamycin

Linezolid

Relating it to CL

• Recommendations:

– Continue cloxacillin 2000 mg IV Q4H – Continue clindamycin 600 mg IV Q8H – Discontinue cefotaxime – Discontinue linezolid

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Monitoring Plan

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Efficacy Frequency Safety Freq. Vitals Temp, HR, BP, RR, O2sats Q1hour (Δ to Qshift if clinically stabilized) CNS LOC Qshift Metallic taste Anytime CVS Perfusion (cap refill), pedal pulses Qshift GI/Liver Abd pain, emesis, diarrhea (bristol #, freq) Qshift ALT, AST, GGT, ALP Daily GU/Renal Urine output/CRRT Daily Hematuria Anytime HEME CBC + diff (WBC + neuts + bands) Daily DERM Rash, gangrene Daily Rash, pruritis Daily ID

• ive BCx

Daily Line infections, C. diff infection

Follow up

• Team accepted recommendations when C&S

reported next morning (Dec 8):

– S: Cloxacillin, clindamycin, vancomycin, linezolid – R: Penicillin, ampicillin

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References

• 1. Schlievert P, Kelly J. Clindamycin-Induced Suppression of Toxic Shcok Syndrome-Associated

Exotoxin Production. J Infect Dis. 1984;149(3):471.

• 2. Stevens D, Wallace R, Hamilton S, Bryant A. 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. Clin Infect Dis. 2006;42(January):729–30.

• 3. Turner CE, Sriskandan S. Pantone-Valentine leucocidin expression by Staphylococcus aureus

exposed to common antibiotics. J Infect [Internet]. 2015;71(3):338–46. Available from: http://dx.doi.org/10.1016/j.jinf.2015.05.008

• 4. Dumitrescu O, Badiou C, Bes M, Reverdy ME, Vandenesch F, Etienne J, et al. Effect of antibiotics,

alone and in combination, on Panton-Valentine leukocidin production by a Staphylococcus aureus reference strain. Clin Microbiol Infect [Internet]. 2008;14(4):384–8. Available from: http://dx.doi.org/10.1111/j.1469-0691.2007.01947.x

• 5. Dumitrescu O, Boisset S, Badiou C, Bes M, Benito Y, Reverdy ME, et al. Effect of antibiotics on

Staphylococcus aureus producing Panton-Valentine leukocidin. Antimicrob Agents Chemother. 2007;51(4):1515–9.

• 6. Pichereau S, Moran JJM, Hayney MS, Shukla SK, Sakoulas G, Rose WE. Concentration-

dependent effects of antimicrobials on staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells. J Antimicrob Chemother. 2012;67(1):123–9. 45

Questions?