This document discusses gram positive sepsis and toxic shock syndrome. It begins by differentiating between gram positive and gram negative bacteria, noting that gram positive bacteria have a thicker peptidoglycan cell wall. It then discusses epidemiology of gram positive infections, evaluation and management of suspected sepsis, initial resuscitative therapy including IV fluids and antibiotics, monitoring response to therapy, identifying infection sources, and managing patients who fail or respond to initial therapy. It concludes by describing toxic shock syndrome caused by Staphylococcus aureus.

1. GRAM POSITIVE SEPSIS

2. INTRODUCTION
• Health professionals need to understand the important
difference between gram-positive and gram-negative
bacteria.
• Gram-positive bacteria are bacteria classified by the
color they turn in the staining method.
• Hans Christian Gram developed the staining method in
1884.
• The staining method uses crystal violet dye which is
retained by the thick peptidoglycan cell wall found in
gram-positive organisms. This gives gram-positive
organisms a blue color when viewed under a
microscope.

4. GRAM POSITIVE BACTERIA
• Gram-positive
bacteria are bacteria that give a
positive result in the Gram stain test,
which is traditionally used to quickly
classify bacteria into two broad
categories according to their cell wall.
• Gram-positive organisms have a
thicker peptidoglycan cell wall
compared with gram-negative
bacteria.
• It is a 20-80nm thick polymer while
the peptidoglycan layer of the gram-
negative cell wall is 2 to 3nm thick
and covered with an outer lipid bilayer
membran.

6. EPIDEMIOLOGY
• Bloodstream infection mortality rates have increased by
78% in just two decades[1].
• Gram-positive organisms have a highly variable growth
and resistance patterns.
• The SCOPE project (Surveillance and Control of
Pathogens of Epidemiologic Importance) found that
gram-positive organisms in those with an underlying
malignancy accounted for 62% of all bloodstream
infections in 1995 and for 76% in 2000 while gram-
negative organisms accounted for 22% and 14% of
infections for these year.

7. EVALUATION AND MANAGEMENT
OF SUSPECTED SEPSIS AND SEPTIC
SHOCK IN ADULTS

8. INTRODUCTION
• Sepsis is a clinical syndrome characterized by systemic
inflammation due to infection.
• There is a continuum of severity ranging from sepsis to
septic shock.
• Although wide-ranging and dependent upon the
population studied, mortality has been estimated to be
≥10 percent and ≥40 percent when shock is present

9. IMMEDIATE EVALUATION AND
MANAGEMENT
• Securing the airway (if indicated) and correcting hypoxemia,
and establishing venous access for the early administration of
fluids and antibiotics are priorities in the management of
patients with sepsis and septic shock.
• Stabilize respiration — Supplemental oxygen should be
supplied to all patients with sepsis and oxygenation should be
monitored continuously with pulse oximetry. Intubation and
mechanical ventilation may be required to support the
increased work of breathing that typically accompanies
sepsis, or for airway protection since encephalopathy and a
depressed level of consciousness frequently complicate
sepsis

10. • Establish venous access — the insertion of a central
line should not delay the administration of resuscitative
fluids and antibiotics.
• A central venous catheter (CVC) can be used to infuse
intravenous fluids, medications (particularly
vasopressors), and blood products, as well as to draw
blood for frequent laboratory studies.
• While a CVC can be used to monitor the therapeutic
response by measuring the central venous pressure
(CVP) and the central venous oxyhemoglobin saturation
(ScvO2).

11. • Initial investigations — An initial brief history and
examination, as well as laboratory, microbiologic, and
imaging studies are often obtained simultaneously while
access is being established and the airway stabilized.
This brief assessment yields clues to the suspected
source and complications of sepsis, and therefore, helps
guide empiric therapy and additional testing.

13. Quickly obtaining the following is preferable (within 45
minutes of presentation) but should not delay the
administration of fluids and antibiotics:
●Complete blood counts with differential, chemistries, liver
function tests, and coagulation studies including D-dimer
level
●Serum lactate
●Arterial blood gas (ABG) analysis

14. ●Peripheral blood cultures (aerobic and anaerobic cultures from
at least two different sites), urinalysis, and microbiologic
cultures from suspected sources (eg, sputum, urine,
intravascular catheter, wound or surgical site, body fluids) from
readily accessible sites. For patients with a central vascular
catheter(s) suspected to be the source, blood should be
obtained both from the catheter(s) and from peripheral sites.
●Imaging targeted at the suspected site of infection is
warranted (eg, chest radiography, computed tomography of
chest and/or abdomen).
●Procalcitonin

15. INITIAL RESUSITATIVE THERAPY
a) rapid restoration of
perfusion
• Tissue perfusion is
predominantly achieved by the
aggressive administration of
intravenous fluids (IVF), usually
crystalloids (balanced
crystalloids or normal saline)
• given at 30 mL/kg (actual body
weight) within the
first three hours following
presentation
c) Location of admission
b) early administration of
antibiotics
• Empiric antibiotic therapy
is targeted at the
suspected organism(s)
and site(s) of infection
and preferably
administered within
the first hour

16. Intravenous fluids
(first three hours)
Volume
Choice of fluid
Treating metabolic
acidosis
Empiric antibiotic therapy
(first hour)
Identification of
suspected source
Timing
Choosing a regimen
Dosing

17. • Choosing a regimen — The choice of antimicrobials
can be complex and should consider the patient's history
(eg, recent antibiotics received, previous organisms),
comorbidities (eg, diabetes, organ failures), immune
defects (eg, human immune deficiency virus), clinical
context (eg, community- or hospital-acquired), suspected
site of infection, presence of invasive devices, Gram
stain data, and local prevalence and resistance patterns
[46-50].
• antimicrobial choice should be tailored to each
individual.

18. • For most patients with sepsis without shock, we recommend empiric
broad spectrum therapy with one or more antimicrobials to cover all
likely pathogens.
• Coverage should be directed against both gram-positive and gram-
negative bacteria and, if indicated, against fungi (eg, Candida) and
rarely viruses (eg, influenza). Broad spectrum is defined as
therapeutic agent(s) with sufficient activity to cover a range of gram
negative and positive organisms (eg, carbapenem, piperacillin-
tazobactam).
• Many patients with septic shock, particularly those suspected to
have gram negative sepsis, should receive combination therapy with
at least two antimicrobials from two different classes (ie,
combination therapy) depending on the organisms that are
considered likely pathogens and local antibiotic susceptibilities

19. • Methicillin-resistant S. aureus – There is growing recognition
that methicillin-resistant S. aureus (MRSA) is a cause of
sepsis not only in hospitalized patients, but also in community
dwelling individuals without recent hospitalization [52,53]. For
these reasons, we suggest empiric
intravenous vancomycin (adjusted for renal function) be
added to empiric regimens, particularly in those with shock or
those at risk for MRSA. Potential alternative agents to
vancomycin (eg, daptomycin for non-pulmonary
MRSA, linezolid) should be considered for patients with
refractory or virulent MRSA, or with a contraindication to
vancomycin

20. In our practice, if Pseudomonas is an unlikely pathogen, we favor combining vancomycin with
one of the following:
•Cephalosporin, 3rd generation (eg, ceftriaxone or cefotaxime) or 4th generation (cefepime),
or
•Beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate), or
•Carbapenem (eg, imipenem or meropenem)
Pseudomonas – Alternatively, if Pseudomonas is a likely pathogen, we favor
combining vancomycin with two of the following, depending on local antibiotic susceptibility
patterns :
•Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or
•Antipseudomonal carbapenem (eg, imipenem, meropenem), or
•Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillin-
tazobactam, ticarcillin-clavulanate), or
•Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or
•Aminoglycoside (eg, gentamicin, amikacin), or
•Monobactam (eg, aztreonam)

21. MONITOR RESPONSE
Monitoring catheters
Clinical
Hemodynamic
Laboratory

22. SEPTIC FOCUS IDENTIFICATION AND
SOURCE CONTROL
A focused history and examination is the most valuable
method.
Following initial investigations and empiric antimicrobial
therapy, further efforts aimed at identifying and
controlling the source(s) of infection should be performed
in all patients with sepsis.
Adequacy of the antimicrobial regimen or nosocomial
super infection should be considered.

24. PATIENTS WHO FAIL INITIAL
THERAPY
• Patients having persistent hypoperfusion despite
adequate fluid resuscitation and antimicrobial treatment
should be reassessed for fluid responsiveness,
adequacy of the antimicrobial regimen and septic focus
control as well as the accuracy of the diagnosis and the
possibility that unexpected complications or coexisting
problems have occurred (eg, pneumothorax following
CVC insertion).

25. OTHER OPTIONS
Vasopressors
Glucocorticoids
inotropic therapy
blood transfusion

28. PATIENTS WHO RESPOND TO
THERAPY
• Identification and control of the septic focus
• De-escalation fluids
• De-escalation and duration of antibiotics

29. DE-ESCALATION FLUIDS
• Patients who respond to therapy (ie, clinical hemodynamic
and laboratory targets are met; usually hours to days) should
have the rate of fluid administration reduced or stopped,
vasopressor support weaned, and, if necessary, diuretics
administered.
• While early fluid therapy is appropriate in sepsis, fluids may
be unhelpful or harmful when the circulation is no longer fluid
responsive.
• Careful and frequent monitoring is essential because patients
with sepsis may develop cardiogenic and noncardiogenic
pulmonary edema (ie, acute respiratory distress syndrome
[ARDS]).

30. DE-ESCALATION
• t is appropriate that de-escalation and duration of antimicrobial agents
be assessed daily
• Once pathogen identification and susceptibility data
return and/or patients clinically improve, we recommend that
antimicrobial therapy be narrowed (typically a few days).
• When possible, antimicrobial therapy should also be pathogen- and
susceptibility-directed (also known as targeted/definitive therapy).
• However, since no pathogen is identified in approximately 50 percent of
patients, de-escalation of empiric therapy requires a component of
clinical judgement. For example, vancomycin is typically discontinued, if
no Staphylococcus is cultured.
• While there is no consensus on de-escalation criteria, most experts use
follow-up clinical (improved vital signs), laboratory and imaging data,
and a fixed course of broad-spectrum therapy (eg, 3 to 5 days).

31. • Duration – The duration of antibiotics should be
individualized. For most patients, the duration of therapy is
typically 7 to 10 day
• However, longer courses are appropriate in patients who have
a slow clinical response, an undrainable focus of infection,
bacteremia with S. aureus, some fungal (eg,
deep Candida infections) or viral infections (eg, herpes or
cytomegalovirus), endocarditis, osteomyelitis, large
abscesses, highly resistant gram-negative pathogens with
marginal or limited sensitivities, neutropenia, or immunologic
deficiencies
• Similarly, shorter courses may be acceptable in patients with
negative cultures and rapid resolution of sepsis and laboratory
studie

32. TOXIC SHOCK SYNDROME

33. INTRODUCTION
• Staphylococcal toxic shock syndrome (TSS) is a clinical
illness characterized by rapid onset of fever, rash,
hypotension, and multiorgan system involvement.
• TSS due to Staphylococcus aureus was initially
described in 1978; the disease came to public attention
in 1980 with the occurrence of a series of menstrual-
associated cases

34. EPIDEMIOLOGY
Menstrual cases
- Clinical illness arose during menstruation and was
associated with use of absorbent tampons.
Nonmenstrual cases
- can occur in a variety of clinical circumstances, including
surgical and postpartum wound infections, mastitis,
septorhinoplasty, sinusitis, osteomyelitis, arthritis, burns,
cutaneous and subcutaneous lesions (especially of the
extremities, perianal area, and axillae), respiratory
infections following influenza, and enterocolitis.

35. CLINICAL MANIFESTATIONS
• Hypotension
• Dermatologic manifestations
• Multiorgan systems invovlement

38. RECURRENT ILLNESS
• Recurrent TSS tends to occur in patients who have not
been treated with appropriate antimicrobial
therapy and/or who fail to develop an appropriate
antibody response to staphylococcal toxins. Recurrence
can occur days to months after the initial episode

39. LABORATORY FINDINGS
• Laboratory abnormalities reflect shock and organ failure: elevated
blood urea nitrogen and creatinine, elevated liver function tests, and
an elevated CPK.
• Leukocytosis may be absent, but the total number of mature and
immature neutrophils usually exceeds 90 percent (with immature
neutrophils accounting for 25 to 50 percent of the total number of
neutrophils).
• Thrombocytopenia and anemia are present during the first few days,
frequently accompanied by prolonged prothrombin and partial
thromboplastin times.
• Disseminated intravascular coagulation may be present.
• Most laboratory tests normalize 7 to 10 days after onset of illness.

40. DIAGNOSIS
• The diagnosis of staphylococcal TSS is established based on
clinical and laboratory criteria
• Detection of S. aureus in culture is not required for the diagnosis of
staphylococcal TSS.
• S. aureus is recovered from blood cultures in approximately 5
percent of cases [24]; it is recovered from wound or mucosal sites in
80 to 90 percent of cases [62].
• According to the United States Centers for Disease Control and
Prevention (CDC), a confirmed case is a case that meets the
following clinical criteria: fever, hypotension, diffuse erythroderma,
desquamation (unless the patient dies before desquamation can
occur), and involvement of at least three organ systems, with
cultures negative for alternative pathogens and serologic tests
negative for other conditions (if obtained). A patient who is missing
one of the above clinical criteria may be considered a probable
case.

41. DIFFERENTIAL DIAGNOSIS
• Streptococcal TSS
• Sepsis or septic shock due to other pathogens
• Drug reaction
• Kawasaki disease
• Meningococcal infection
• Rocky Mountain spotted fever (RMSF
• Leptospirosis
• Dengue fever
• Enteric fever

42. MANAGEMENT
• Treatment of shock
• Surgical debridement
• Antibiotic therapy

43. ANTIBIOTIC THERAPY
• Empiric therapy — For empiric treatment of sepsis of unknown cause that
might represent staphylococcal TSS, we favor the following regimen (pending
culture results):
• ●Vancomycin (adults: 15 to 20 mg/kg/dose intravenously [IV] every 8 to 12
hours, not to exceed 2 g per dose; children: 60 mg/kg per day IV in four divided
doses)
• PLUS
• ●Clindamycin (adults: 900 mg IV every eight hours; children: 25 to 40 mg/kg IV
per day in three divided doses)
• PLUS one of the following:
• ●A combination drug containing a penicillin plus beta-lactamase inhibitor
(adults: piperacillin-tazobactam 4.5 g IV every six hours; children
300 mg/kg/day IV in four divided doses)
• ●A carbapenem (adults: imipenem 500 mg IV every six hours or meropenem 1 g
IV every eight hours; children: imipenem 15 to 25 mg/kg/dose every 6 hours
[maximum 4 g per day] or meropenem 25 mg/kg/dose every 8 hours)

44. Tailored therapy — For treatment of TSS due to methicillin-susceptible S.
aureus (MSSA), we favor the following regimen:
• ●Oxacillin or nafcillin (adults: 2 g IV every four hours; children: 150 to
200 mg/kg per 24 hours IV in four divided doses). A first-generation
cephalosporin such as cefazolin (2 g IV every eight hours) is an acceptable
alternative in patients with hypersensitivity to the preceding agents.
• PLUS
• ●Clindamycin (if susceptible; adults: 900 mg IV every eight hours; children: 25 to
40 mg/kg per day in three divided doses)
For treatment of TSS due to methicillin-resistant S. aureus (MRSA), we favor the
following regimen:
• ●Vancomycin (adults: 15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2
g per dose; children: 60 mg/kg per day IV in four divided doses)
• PLUS
• ●Clindamycin (if susceptible; adults: 900 mg IV every eight hours; children: 30 to
40 mg/kg per day in three divided doses)

45. • For patients with deep-seated infections and/or bacteremia,
we favor combination therapy with clindamycin and an
antistaphylococcal penicillin (eg, oxacillin or nafcillin)
or vancomycin, until hemodynamics have stabilized.
• The duration of therapy for S. aureus infection depends on the
underlying etiology.
• There are no clinical studies to inform duration of therapy for
staphylococcal TSS. In the absence of bacteremia or a
distinct focus of infection, we typically treat with a 10- to 14-
day course of an antistaphylococcal agent plus clindamycin.

46. INTRAVENOUS IMMUNE GLOBULIN
• In general, we do not favor use of intravenous immune
globulin (IVIG) for treatment of staphylococcal TSS,
given the lack of substantive clinical data to suggest a
benefit with IVIG in staphylococcal TSS and the potential
for adverse effects.
• Use of IVIG may be considered in patients with severe
staphylococcal TSS who are unresponsive to other
therapeutic measures.
• It has been proposed that IVIG may be beneficial for
patients with staphylococcal TSS in the setting of
diminished antibody production to toxin

47. • In one case report of a 39-year-old man with HIV
infection and diffuse erythema of the arms and legs,
desquamation (of the arms, hands, feet, and eyebrows),
pharyngeal erythema, and a lesion that grew a TSST-1-
producing S. aureus, IVIG (200 mg/kg per day) was
administered for five days after failing antibiotic therapy;
symptoms subsequently resolved [63].
• ●In a retrospective study of patients with necrotizing
fasciitis and shock associated with group
A Streptococcus or S. aureus, adjunctive IVIG has no
apparent impact in mortality.

48. PROGNOSIS
• Death associated with TSS usually occurs within the first
few days of hospitalization but may occur as late as two
weeks after admission. Fatalities have been attributed to
refractory cardiac arrhythmias, cardiomyopathy,
irreversible respiratory failure, and, rarely, bleeding
caused by coagulation defects

49. REFERENCE
• https://www.uptodate.com/contents/evaluation-and-
management-of-suspected-sepsis-and-septic-shock-in-
adults?search=gram%20positive%20sepsis&source=sea
rch_result&selectedTitle=1~150&usage_type=default&di
splay_rank=1

50. Thank you