Infectious Diseases

[Pharmacotherapy] Pneumonia

September 6, 2016 Infectious Diseases, Pulmonary Medicine No comments , , , , , , , ,

Pneumonia is inflammation of the lung with consolidation. The cause of the inflammation is infection, which can be caused by a wide range of organisms. There are five classifications of pneumonia: community acquired, aspiration, hospital-acquired, ventilator-associated, and healthcare-associated. Patients who develop pneumonia in the outpatient setting and have not been in any healthcare facilities, which include wound care and hemodialysis clinics, have community-acquired pneumonia (CAP). Pneumonia can be caused by aspiration of either oropharyngeal or gastrointestinal contents. Hospital-acquired pneumonia (HAP) is defined as pneumonia that occurs 48 hours or more after admission. Ventilator-associated pneumonia (VAP) requires endotracheal intubation for at least 48 to 72 hours before the onset of pneumonia. The newest category is healthcare-associated pneumonia (HCAP), which is defined as pneumonia occuring in any patient hospitalized for at least 2 days within 90 days of the onset of the infection; residing in a nursing home or long-term care facility; received IV antibiotic therapy, wound care, or chemotherapy within the last 30 days prior to the onset of the infection; or having attended a hemodialysis clinic.

Complications

Potential complications secondary to pneumonia include further decline in pulmonary function in patients with underlying pulmonary disease, prolonged mechanical ventilation, bacteremia/sepsis/septic shock, and death.

Goals

The goal of antibiotic therapy is to eliminate the patient's symptoms, minimize or prevent complications, and decrease mortality. Use of an antimicrobial agent with the narrowest spectrum of activity that covers the suspected pathogen(s) without having activity against organisms not involved in the infection is preferred to minimize the development of resistance.

General Approach to Treatment

Designing a therapeutic regimen for any patient with any type of pneumonia begins with three general categories of consideration:

  1. Patient specific factors that will impact therapy (e.g., age, renal function, drug allergies and/or drug intolerances, immune status [diabetes, neutropenia, or immunocompromised host], cardiopulmonary disease, pregnancy, medical insurance and prescription coverage, exposure to resistant organisms, and prior antibiotic exposure(s) [what agents and when]).
  2. The top one to three organisms likely causing the infection and resistance issues associated with each organism.
  3. The antimicrobials that will cover these organisms. The spectrum should not be too broad or narrow; they should penetrate into the site of infection and be the most cost effective.

Factors influencing infection from a resistant organism:

  • Antimicrobial therapy in preceding 90 days
  • Current hospitalization of at least 5 days
  • High occurrence of antibiotic resistance in the community or in the specific hospital unit
  • Immunosuppressive disease and/or therapy
  • Presence of risk factors for HCAP:

     

     

    • Hospitalization for 2 days or more in the preceding 90 days
    • Resience in a nursing home or extended-care facility
    • Peritoneal or hemodialysis within 30 days
    • Home wound care
    • Close contact family member with MDR pathogen

State of Art

CAP

Treatment of CAP is predominantly empiric, that is, treatment is started without knowing the causative pathogen. The approach to patient care is based on the classification of patients into two broad categories, outpatient and inpatient, and then further dividing the groups by comorbid conditions and location in the hospital, respectively. These guidelines use patient-specific data along with predominant pathogen information to design appropriate empirical antimicrobial regimens.

Adult outpatient previously healthy

First-line therapeutic options for treating previously healthy adults include use of a macrolide or an azalide or doxycycline. If a patient has failed therapy with a macrolide, azalide, or doxycycline, one has to consider why the patient failed. The most common reasons are either medication adherence issues or the presence of resistance organisms.If a resistant organism is suspected, then use of one of the respiratory fluoroquinolones active against S. pneumoniae (gemifloxacin, levofloxacin, or moxifloxacin) is warranted.

Adult outpatient with comorbid conditions

The comorbid conditions that can impact therapy and outcomes in patients with CAP inlcude diabetes mellitus; COPD; chronic heart, liver, or renal disease; alcoholism; malignancy; asplenia; and immunosuppressive condition or use of immunosuppressive drugs. If the patient did not receive antibiotics in the last 3 months, then either a respiratory fluoroquinolone alone or a combination of an oral beta-lactam agent plus a macrolide or azalide is recommended. If the patient received an antibiotic in the last 3 months, the recommendation is to use an agent from a different class. Doxycycline is an acceptable alternative to a macrolide or azalide.

Adult inpatient not in the ICU

For patients admitted to the hospital with CAP, the severity of illness is generally increased (caused either by the organism itself or underlying comorbidities in the patient), and the pathogens are essentially the same as in the outpatient setting. Recommendations are to use either a respiratory fluoroquinolone alone or a combination of an IV beta-lactam agent plus an advanced macrolide/azalide (clarithromycin/azithromycin) or doxycycline. Therapy should be initiated in the emergency room; however, due to the controversy with a first antibiotic dose time of less than 4 or 8 hours, no recommendations have been made regarding time to the first antibiotic dose. Conversion to oral therapy should occur when the patient is hemodynamically stable, improving clinically, and able to take oral medications, which often is within 48 to 72 hours for most patients. Discharge from the hospital should be as soon as the patient is stable and without  other medical complications. The need to observe the patient in the hospital on their oral antibiotic is not necessary.

Adult inpatient in the ICU

Patients admitted to the ICU have severe pneumoniae, and the likely etiology includes S. pneumoniae and H. influenzae as in the other categories; however, the incidence of L. pneumophila increases in this setting and should be considered a potential pathogen. In addition, enteric gram-negative bacilli and S. aureus are more frequently the cause of the pneumonia in these apteints. The recommendations are to treat with an IV beta-lactam plus either azithromycin or a respiratory fluoroquinolone. This combination therapy minimizes the risk of treatment failure due to resistant pathogen as well as provides coverage against all of the potential pathogens.

Aspiration

Anaerobes and Streptococcus spp. are the primary pathogens if a patient aspirates his or her oral contents and develops pneumonia. Antibiotics active against these organisms include penicillin G, amicillin/sulbactam, and clindamycin. If the patient aspirates oral and gastric contents, then anaerobes and gram-negative bacilli are the primary pathogens.

HCAP/HAP/VAP

Empirical selection of antimicrobial therapy for ventilator-, healthcare-, and hospital-associated pneumonia is broad spectrum; however, once culture and susceptibility information are available, the therapy should be narrowed to cover teh identified pathogen(s). Two factors important to the empirical selection of antibioics for these types of pneumonia are onset time after admission and risk factors for MDR organisms. If it is early onset (less than or equal to 5 days since admission), and there are no risk factors for MDR organisms, then the most frequent pathogens include S. pneumoniae, H. influenzae, methicillin-susceptible Staphylococcus aureus, and enteric gram-negative bacilli. If it is late-onset pneumonia and/or there are risk factors for MDR organisms, then the pathogen list includes P. aeruginosa, extended-spectrum beta-lactamase-producing K. pneumoniae, Acinetobacter spp., and MRSA. Empirical antibiotic selection must cover P. aeruginosa, which often then covers the other gram-negative pathogens.

Duration of Antimicrobial Therapy

The duration of therapy for pneumonia should be kept as short as possible and depends on several factors: type of pneumonia, inpatient or outpatient status, patient comorbidities, bactermia/sepsis, and the antibiotic chosen. If the duration of therapy is too prolonged, then it can have a negative impact on the patient's normal flora in the respirator and gastrointestinal tracts, vaginal tract of women, and on the skin. This can result in colonization with resistant pathogens, Clostridium difficile colitis, or overgrowth of yeast. In addition, the longer antibiotics are administered, the greater the chance for toxicity from the agent, as well as an increase in cost.

For treating adult outpatient CAP, two antibiotics are approved for a 5-day duration of therapy, levofloxacin (the 750-mg dose) and azithromycin. The recommended duration of therapy for all other therapies is 7 to 10 days. For treatment of CAP in adult patients admitted to the hospital, the duration is dependent on whether or not blood cultures were positive. In the absence of positive blood cultures, the duration of therapy is 7 to 10 days. If blood cultures were positive, the duration of therapy should be 2 weeks from the day blood cultures first became negative.

The duration of therapy cited in the literature for HCAP, HAP, or VAP ranges from 10 to 21 days. Efforts should be made to shorten the duration of therapy from the traditional 14 to 21 days to periods as short as 7 days, provided that the etiologic pathogen is not P. aeruginosa and that the patient has a good clinical response with resolution of clinical features of infection. Shortening the duration of therapy is acknowledged as beneficial because of the colonization, toxicity, and cost issues. Several studies evaluated mortality, clinical success, recurrence, or the development of resistance with shorter courses of therapy for VAP and found no differences when compared with longer courses of therapy.

The TDM of Vancomycin

August 16, 2016 Critical Care, Infectious Diseases, Pharmacokinetics No comments , , , , ,

Question #1. B.C., a 65-year old, 45-kg man with a serum creatinine concentration of 2.2 mg/dL, is being treated for a presumed hospital-acquired, MRSA infection. Design a dosing regimen that will produce peak concentration less than 40 to 50 mg/L and through concentrations of 5 to 15 mg/L.

Target Plasma Concentration

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Clearance and Volume of Distribution

The first step in calculating an appropriate dosing regimen for B.C. is to estimate his pharmacokinetic parameters (i.e., volume of distribution, clearance, elimination rate constant, and half-life).

The volume of distribution for B.C. can be calculated by using Equation 13.1.

V (L) = 0.17 (age in years) + 0.22 (TBW in kg) + 15

So, B.C.'s expected volume of distribution would be: V (L) = 0.17 (65 yrs) + 0.22 (45 kg) + 15 = 36.0 L [Equation 13.1]

Using Equation 13.2 and Equation 13.4 to calculated B.C.'s expected creatinine clearance and vancomycin clearance.

Clcr for males (mL/min) = (140 – Age)(Weight in kg) / [(72)(SCrss)] [Equation 13.2]

Vancomycin Cl ≈ Clcr [Equation 13.4]

For B.C. the vancomycin Cl ≈ (140 – 65 yrs)(45 kg) / [(72)(2.2 mg/dL)] = 21.3 mL/min = 1.28 L/hr

The calculated vancomycin clearance of 1.28 L/hr and the volume of distribution of 36.0 L then can be used to estimate the elimination rate constant of 0.036 hr-1. And the corresponding vancomycin half-life can be calculated, which equals (0.693)(V) / Cl = 19.5 hr.

Loading Dose

In clinical practice, loading doses of vancomycin are seldom administered. This is probably because most clinicians prescribe about 15 mg/kg as their maintenance dose.

C0 = (S)(F)(Loading Dose) / V = (1)(1)(15 mg/kg x 45 kg) / 36 L = 18.8 mg/L ≈ 20 mg/L (Equation 13.8)

If you want to administer a loading dose, the loading dose = (V)(C) / [(S)(F)] = (36.0 L)(30 mg/L) / [(1)(1)] = 1080 mg or ≈ 1000 mg.

Steady-State

During the steady-state, Css max = Css min + [(S)(F)(Dose) / V] (Equation 13.5). This equation is based on several conditions including: 1) Steady state has been achieved; 2) the measured plasma concentration is a trough concentration; and 3) the bolus dose is an acceptable model (infusion time <1/6 half-life).

In the clinical setting, trough concentrations are often obtained slightly before the true trough. Because vancomycin has a realtive long half-life, most plasma concentrations obtained within 1 hour of the true trough can be assumed to have met condition 2 above.

Since vancomycin follows a multicompartmental model, it is difficult to avoid the distribution phase when obtaining peak plamsa concentrations. If peak levels are to be measured, samples should be obtained at least 1 or possibly 2 hours after the end of the infusion period. It is difficult to evaluate the appropriateness of a dosing regimen that is based on plasma samples obtained before steady state. Additional plasma concentrations are required to more accurately estimate a paient's apparent clearance and half-life, and to ensure that any dosing adjustments based on a non-steady-state trough concentration actually achieve the targeted steady-state concentrations.

Maintenance Dose

The maintenance dose can be calculated by a number of methods. One approach might be to first approximate the hourly infusion rate required to maintain the desired average concentration. Then, the hourly infusion rate can be multiplied by an appropriate dosing interval to calculate a reasonable dose to be given on an intermittent basis. For example, if an average concentraion of 20 mg/L is selected (approximately halfway between the desired peak concentration of ≈ 30 mg/L and trough concentration of ≈ 10 mg/L), the hourly administration rate would be 25.6 mg/hr.

Maintenance Dose = (Cl)(Css ave)(tau) / [(S)(F)] 

For this patient the 24 hour dose should be (1.28 L/hr)(20 mg/L)(24 hr) / [(1)(1)] = 614 mg ≈ 600 mg

– or –

Maintenance delivery rate = Dose/tau = (Cl)(Css ave) / [(S)(F)]

For this patient the maintenance deliver rate = (1.28 L/hr)(20 mg/L) / [(1)(1)] = 25.6 mg/hr

The second approach that can be used to calculate the maintenance dose is to select a desired peak and trough concentration that is consistent with the therapeutic range and B.C.'s vancomcin half-life. For example, it steady-state peak concentrations of 30 mg/L are desired, it would take approximately two half-lives for that peak level to fall to 7.5 mg/L. Since the vancomycin half-life in B.C. is approximately 1 day, the dosing interval would be 48 hours. The dose to be administered every 48 hours can be calculated as follows using Equation 13.5:

Dose = (V)(Css max – Css min) / [(S)(F)] = (36.0 L)(30 mg/L – 7.5 mg/L) / [(1)(1)] = 810 mg ≈ 800 mg

The peak and trough concentrations that are expected using this dosing regimen can be calcualted by using Equations 13.12 and 13.14, respectively.

Css max = (S)(F)(Dose) / {V x [1- e(-k*tau)]} = 27.0 mg/L (Equation 13.12)

Note that although 27 mg/L is an acceptable peak, the actual clinical peak would normally be obtained approximately 1 hour after the end of a 1-hour infusion, or 2 hours after this calculated peak concentration, and would be about 25 mg/L, as calculated by Equation 13.13.

C2 = C1[e(-k*t)] = 25.1 mg/L (Equation 13.13)

The calculated trough concentration would be about 5 mg/L.

Css min = (S)(F)(Dose / V)[e(-k*tau)] / [1 – e(-k*tau)] = (Css max)[e(-k*tau)] = 4.8 mg/L (Equation 13.14 and 13.15)

This process of checking the expected peak and trough concentrations is most appropriate when the dose or the dosing interval has been changed from a calculated value (e.g., twice the half-life) to a practical value (e.g., 8, 12, 18, 24, 36, or 48 hours). Many institutions generally prefer not to use dosing intervals of 18 or 36 hours because the time of day whent the next dose is to be given changes, potentially resulting in dosing errors. If different plasma vancomycin concentrations are desired, Equations 13.12 and 13.14 can be used target specific vancomycin concentrations by adjusting the dose and/or the dosing interval.

A third alternative is to rearrange Equation 13.14, such that the dose can be calculated:

Dose = (Css min)(V)[1 – e(-k*tau)] / {(S)(F)[e(-k*tau)]} (Equation 13.16)

Specific Immunosuppressive Therapy

July 20, 2016 Hematology, Immunology, Infectious Diseases, Oncology, Pharmacology, Transplantation No comments , , , , , , , , , , , , , , , ,

The ideal immunosuppressant would be antigen-specific, inhibiting the immune response to the alloantigens present in the graft (or vice versa alloantigens present in recipient in GVHD) while preserving the recipient's ability to respond to other foreign antigens. Although this goal has not yet been achieved, several more targeted immunosuppressive agents have been developed. Most involve the use of monoclonal antibodies (mAbs) or soluble ligands that bind specific cell-surface molecules. On limitation of most first-generation of mAbs came from their origin in animals. Recipients of these frequently developed an immune response to the nonhuman epitopes, rapidly clearing the mAbs from the body. This limitation has been overcome by the construction of humanized mAbs and mouse-human chimeric antibodies.

Many different mAbs have been tested in transplantation settings, and the majority work by either depleting the recipient of a particular cell population or by blocking a key step in immune signaling. Antithymocyte globulin (ATG), prepared from animals exposed to human lymphocytes, can be used to deplete lymphocytes in patients prior to transplantation, but has significant side effects. A more subset-specific strategy uses a mAb to the CD3 molecule of the TCR, called OKT3, and rapidly depletes mature T cells from the circulation. This depletion appears to be caused by binding of antibody-coated T cells to Fc receptors on phagocytic cells, which then phagocytose and clear the T cells from the circulation. In a further refinement of this strategy, a cytotoxic agent such as diphtheria toxin is coupled with the mAb. Antibody-bound cells then internalize the toxin and die. Another technique uses mAbs specific for the high-affinity IL-2 receptor CD25. Since this receptor is expressed only on activated T cells, this treatment specifically blocks proliferation of T cells activated in response to the alloantigens of the graft. However, since TREG cells also express CD25 and may aid in alloantigen tolerance, this strategy may have drawbacks. More recently, a mAb against CD20 has been used to deplete mature B cells and is aimed at suppressing AMR (antibody-mediated rejection) responses. Finally, in cases of bone marrow transplantation, mAbs against T-cell-specific markers have been used to pretreat the donor's bone marrow to destory immunocompetent T cells that may react with the recipient tissues, causing GVHD.

Because cytokines appear to play an important role in allograft rejection, these compounds can also be specifically targeted. Animal studies have explored the use of mAbs specific for the cytokines implicated in transplant rejection, particularly TNF-alpha, IFN-gamma, and IL-2. In mice, anti-TNF-alpha mAbs prolong bone marrow transplants and reduce the incidence of GVHD. Antibodies to IFN-gamma and to IL-2 have each been reported in some cases to prolong cardiac transplants in rats.

TH-cell activation requires a costimulatory signal in addition to the signal mediated by the TCR. The interaction between CD80/86 on the membrane of APCs and the CD28 or CTLA-4 molecule on T cells provides one such signal. Without this costimulatory signal, antigen-activated T cells become anergic. CD28 is expressed on both resting and activated T cells, while CTLA-4 is expressed only on activated T cells and binds CD80/86 with a 20-fold-higher affinity. In mice, D. J. Lenschow, J. A. Bluestone, and colleagues demonstrated prolonged graft survival by blocking CD80/86 signaling with a soluble fusion protein consisting of the extracellular domain of CTLA-4 fused to human IgG1 heavy chain. This new drug, belatacept, was shown to induce anergy in T cells directed against the graft tissue and has been approved by the FDA for prevention of organ rejection in adult kidney transplant pateints.

Residents Series – Inflammatory Shock Syndromes

November 14, 2015 Cardiology, Critical Care, Infectious Diseases No comments , , , , , , , , , , ,

Grim-ReaperDefinitions and Impactions

SIRS/Systemic inflammatory response syndrome is a condition that is characterized by signs of systemic inflammation (e.g., fever, leukocytosis). The diagnosis of SIRS requires at least 2 of the following:

1.Temperature >38 C or <36 C

2.Heart rate >90 beats/min

3.Respiratory rate >20 breaths/min, or arterial PCO2 <32 mm Hg

4.WBC count >12,000/mm3 or <4000/mm3, or >10% immature neutrophils (band forms)

Sepsis is a kind of SIRS caused by an infection.

Severe sepsis is a sepsis condition accompanied by dysfunction in one or more vital organs, or an elevated blood lactate level (>4 mM/L).

Septic shock is a severe sepsis accompanied by hypotension that is refractory to volume infusion.

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Inflammatory injury involving more than one vital organ is called multiorgan dysfunction syndrome (MODS), and the subsequent failure of more than one organ system is called multiorgan failure (MOF).

The organs most often damaged by systemic inflammation are the lungs, kidneys, cardiovascular system, and central nervous system. The most common manifestation of inflammatory organ injury is the acute respiratory distress syndrome (ARDS), which has been reported in 40% of patients with severe sepsis, and is one of the leading causes of acute respiratory failure in critical ill patients.

The number of organs that are damaged by inflammatory injury has important prognostic implications. There is a direct relationship between the mortality rate and the number of organ failures related to inflammation. This demonstrates the lethal potential of uncontrolled systemic inflammation.

The Physiologic Characteristics of Septic Shock

Severe sepsis and septic shock have been implicated in one of every four deaths worldwide, and the incidence of these conditions is steadily rising. The mortality rate averages about 30-50%, and varies with age and the number of associated organ failures. The mortality rate is not related to the site of infection or the causative organism, including multidrug-resistant organisms. This observation is evidence that inflammation, not infection, is the principal determinant of outcome in severe sepsis and septic shock.

Hemodynamic Alterations

  • The principal hemodynamic problem is systemic vasodilatation (involving both arteries and veins), which reduces ventricular preload and ventricular afterload. The vascular changes are attributed to the enhanced production of nitric oxide (a free radical) in vascular endothelial cells.
  • Oxidant injury in the vascular endothelium (from neutrophil attachment and degranulation) leads to fluid extravasation and hypovolemia, which adds to the decreased ventricular filling from venodilation.
  • Proinflammatory cytokines promote cardiac dysfunction (both systolic and diastolic dysfunction); however, the cardiac output is usually increased as a result of tachycardia and volume resuscitation.
  • Despite the increased cardiac output, splanchnic blood flow is typically reduced in septic shock. This can lead to disruption of the intestinal mucosa, thereby creating a risk for translocation of enteric pathogens and endotoxin across the bowel mucosa and into the systemic circulation. This, of course, will only aggravate the inciting condition.

The typical hemodynamic pattern in septic shock includes low cardiac filling pressure (CVP or wedge pressure), a high cardiac output, and a low systemic vascular resistance (SVR). Because of the high cardiac output and peripheral vasodilatation, septic shock is also known as hyperdynamic shock or warm shock. In the advanced stages of septic shock, cardiac dysfunction is more prominent and the cardiac output is reduced, resulting in a hemodynamic pattern that resembles cardiogenic shock (i.e., high CVP, low CO, high SVR). A declining cardiac output in septic shock usually indicates a poor prognosis.

Tissue Oxygenation

The impaired energy metabolism in septic shock is not the result of inadequate tissue oxygenation, but is caused by a defect in oxygen utilization in mitochondria. This condiditon is known as cytopathic hypoxia, and the culprit is oxidant-induced inhibition of cytochrome oxidase and other proteins in the electron transport chain. A decrease in oxygen utilization would explain the observation that the PO2 in skeletal muscle is increased in patients with severe sepsis.

The proposed decrease in oxygen utilization in sepsis is not consistent with the increase in whole-body O2 consumption that is often observed in sepsis. This discrepancy can be resolved by proposing that the increased O2 consumption in sepsis is not a reflection of aerobic metabolism, but is a manifestation of the increased O2 consumption that occurs during neutrophil activation (i.e., the respiratory burst).

The discovery that tissue oxygenation is (more than) adequate in severe sepsis and septic shock has important implications because it means that efforts to improve tissue oxygenation in these conditions (e.g., with blood transfusions) are not justified.

Serum Lactate Levels

The increase in serum lactate levels in severe sepsis and septic shock is not the result of inadequate tissue oxygenation, but instead appears to be the result of enhanced production of pyruvate and inhibition of pyruvate dehydrogenase, the enzyme that converts pyruvate to acetyl coenzyme A in mitochondria. Endotoxin and other bacterial cell wall components have been implicated in the inhibition of this enzyme. This mechanism of lactate accumulation is consistent with the notion that tissue oxygenation is not impaired in severe sepsis and septic shock.

Management

The management of septic shock is outlined in Table 14-3, and is organized in "bundles", which are sets of instructions that must be followed without deviation to provide a survival benefit. The acute sepsis bundle is considered the most important, and must be completed within 6 hours after the diagnosis of septic shock. Screen Shot 2015-11-14 at 8.15.07 PM

Volume Resuscitation

Volume resuscitation is often necessary in septic shock because cardiac filling pressures are reduced from venodilatation and fluid extravasation. The volume resuscitation requires the insertion of a central venous catheter to monitor the central venous pressure (CVP).

1.Infuse 500-1,000 mL of crystalloid fluid or 300-500 mL of colloid fluid over 30 minutes.

2.Repeat as needed until the CVP reaches 8 mm Hg, or 12 mm Hg in ventilator-dependent patients.

If CVP measurements are not available, a volume of at least 20 mL/kg (crystalloid fluid) can be used for the volume resuscitation.

After the initial period of volume resuscitation, the infusion rate of intravenous fluids should be reduced to avoid unnecessary fluid accumulation. A positive fluid balance is associated with increased mortality in septic shock, so attention to avoid fluid accumulation will improve the chances of a favorable outcome.

Vasopressors

If hypotension persists after the initial volume resuscitation, infusion of a vasoconstrictor drug (vasopressor) like norepinephrine or dopamine should begin. Vasoconstrictor drugs must be infused through a central venous catheter, and the goal is to achieve a mean arterial pressure (MAP) >=65 mm Hg.

Norepinephrine is favored by many because it is more likely to raise the blood pressure than dopamine, and is less likely to promote arrhythmias. However, neither agent has proven superior to the other for improving the outcome in septic shock.

When hypotension is refractory to norepinephrine and dopamine, vasopressin may be effective in raising the blood pressure (Vasopressin is used as an additional pressor rather than a replacement for norepinephrine or dopamine). Vasopressin is a pure vasoconstrictor that can promote splanchnic and digital ischemia, especially at high dose rates. Although vasopressin may help in raising the blood pressure, the accumulated experience with vasopressin shows no influence on outcomes in septic shock.

Corticosteroids

Corticosteroids have two actions that are potentially beneficial in septic shock: they have antiinflammatory activity, and they magnify the vasoconstrictor response to catecholamines. Unfortunately, after more than 50 years of investigations, there is no convincing evidence that steroids provide any benefit in the treatment of septic shock. Yet steroids therapy continues to be popular in septic shock. The following comments reflect the current recommendations regarding steroid therapy in spetic shcok.

1.Steroid therapy should be considered in cases of septic shock where the blood pressure is poorly responsive to intravenous fluids and vasopressor therapy. Evidence of adrenal insufficiency (by the rapid ACTH stimulation test) is not required.

2.Intravenous hydrocortisone is preferred to dexamethasone (because of the mineralocorticoid effects of hydrocortisone), and the dose should not exceed 300 mg daily (to limit the risk of infection).

3.Steroid therapy should be continued as long as vasopressor therapy is required.

Antimicrobial Therapy

For the pharmacotherapy of antimicrobial therapy please view the thread of Systematic Approach for Selection of Antimicrobials at http://www.tomhsiung.com/wordpress/2014/03/systematic-approach-for-selection-of-antimicrobials/

The Barriers, The Innate Immune System, and Correlations to Inflammation

October 27, 2015 Immunology, Infectious Diseases No comments , , , , , ,


11th_Annual_Randy_Oler_Memorial_Operation_Toy_Drop_at_Fort_Bragg_N.C.,_Dec._6,_2008Defenses of the skin and Mucosa

Epidermis

The epidermis consists of stratified squamous cells, most of which are keratinocytes. Keratinocytes produce the protein keratin, which is not readily degraded by most microorganisms. As cells from the dermis are pushed outward into the epidermal region, they produce copious amounts of keratin and then die. This layer of dead keratinized cells forms the surface of the skin. The dead cells of the epidermis are continuously shed (desquamation). Thus, bacteria that manage to bind to epidermal cells are constantly being removed from the body.

Skin is dry and has an acidic pH (pH 5), two features that inhibit the growth of many pathogenic bacteria, which prefer a wet environment with a neutral pH (pH 7). The temperature of the skin (34 C to 35 C) is lower than that of body interior. Accordingly, bacteria that succeed in colonizing the skin must be able to adapt to the very different internal environment of the body if they manage to reach underlying tissue.

Hair follicles, sebaceous (fat) glands, and sweat glands are composed of simple epithelial cells and offer sites for potential breaches in the skin that could be used by some bacteria to move past the skin surface. These sites are protected by the peptidoglycan-degrading lysozyme and by lipids that are toxic to many bacteria.

The defenses of the skin do not completely prevent bacterial growth, as is evident from the fact that there are bacteria capable of colonizing the surface of the skin. The consist primarily of gram-positive bacteria, a mixture of cocci and rods. The commensal microbiota of the skin helps to protect against pathogenic bacteria by occupying sites that might be colonized by pathogenic bacteria. It also competes with incoming pathogens for essential nutrients. Some resident bacteria also produce bactericidal compounds which target other bacteria. The commensal microbiota does not completely prevent colonization of the skin by potential pathogens but hampers it enough so that the colonization by pathogenic bacteria is usually transient.

Mucosal Surfaces

The respiratory tract, gastrointestinal tract, and urogenital tract are topologically “inside” the body, but they are exposed constantly to the outer environment and foreign materials.

Internal surface areas/mucosal epithelia are comprised of only one epithelial layer. Mucosal epithelia have a temperature of around 37 C and a pH of 7.0 to 7.4. Mucosal epithelia are continuously bathed in fluids.

Mucosal cells are regularly replaced and old cells are ejected into the lumen. Thus, bacteria that manage to reach and colonize a mucosal surface are constantly being eliminated from the mucosal surface and can remain in the area only if they can grow rapidly enough to colonize newly produced cells.

Chemical and other innate defenses help to reduce the growth rates of bacteria sufficiently to allow ejection of mucus blobs and sloughing of mucosal cells to clear the bacteria from the area.

Mucus is an important defense that protect mucosal from bacteria. Mucus is a mixture of glycoproteins produced by goblet cells, a specialized cell type incorporated into the epithelial layer. Mucus has a viscous, slimy consistency, which allows it to act as a lubricant. Mucus plays a protective role because it traps bacteria and prevents them from reaching the surfaces of the mucosal. Mucus is constantly being produced, and excess mucus is shed in blobs that are expelled. Bacteria trapped in mucus are thus eliminated from the site.

In the gastrointestinal and urinary tracts, peristalsis and the rapid flow of liquids through the area remove the mucus blobs, along with the lumen contents.

In the respiratory tract and in the fallopian tubes, there are specialized cells, ciliated columnar cells, whose elongated protrusions (cilia) are continuously waving in the same direction. The waving action of the cilia propels mucus blob out of the area. Mucus has proteins that have antibacterial activity and these proteins include lysozyme, lactoperoxidase, toxic antimicrobial peptides (defensins, cathelicidins, histatins). Lactoferrin sequesters iron and deprives bacteria of this essential nutrient.

Most mucosal surfaces are protected by a normal resident microbiota, except uterus and upper female genital tract and the urinary tract. Resident microbiota on mucosal surface predominately consists of gram-positive bacteria.

Special defenses of the gastrointestinal tract

The lumen of the stomach is an extremely acidic environment (pH ~2), which acts as a protective barrier to prevent bacteria from reaching more vulnerable areas, such as the small intestine and colon, where conditions are more favorable for bacterial growth. Bacteria ingested in foods are probably protected somewhat from the full impact of stomach acid by the buffering capacity of the food. Food increase the chance that some of the bacteria might survive long enough in the stomach to reach the small intestine.

Bile salts are steroids with detergent-like properties that are produced in the liver, stored in the gall bladder, and then released through the bile duct into the intestine.  The detergent-like properties of bile salts help to disrupt bacterial membranes, especially those of gram-negative bacteria.

Defenses of The Innate Immune System

Skin and mucosal surfaces (barriers) are highly effective in preventing pathogenic bacteria from entering tissue and blood, but from time to time, bacteria succeed in breaching these surfaces. Bacteria that get this far encounter a formidable defense force, the phagocytic cells (neutrophils, monocytes, macrophages, and dendritic cells), natural killer cells, and the proteins that help organize their activity. These cells, together with a set of blood proteins called complement and another set of proteins called cytokines are called the innate immune system. Innate immune system plays a key role in the defence reactions against foreign invaders and correlates with inflammation.

The Firepower of Innate Immune System

The firepower of the innate immune system is very effective in killing bacteria. The phagocyte first forms pseudopods that engulf the bacterium. After engulfment, the bacterium is encased in an endocytic vesicle called phagosome. Various lysosomal enzymes, antimicrobial peptides, membrane-permeabilizing proteins, and degrading proteins mediate nonoxidative killing. Oxidative killing occurs through the formation of toxic reactive oxygen species.

Unlike phagocytic cells, NK cells do not ingest their targets, although their mode of killing resembles that of phagocytes in many respects. NK cells store their toxic substances in granules. Binding to an infected human target cell stimulates the release of these granules. To distinguish a infected cell from a healthy cell, the NK cell use the MHC-I molecule. Healthy cells express MHC-I protein on their surfaces, and MHC-I binds to a second inhibitory receptor on the NK cell surface and halts the activation of the cytotoxic response. In contrast, infected cells express much less MHC-I on their surfaces than normal cells, and the activation response of the NK cell proceeds, leading to an attack on the infected cell. Thus, instead of ingesting a bacterium or infected cell, the innate cytotoxic NK cells bombard infected cells. Cytotoxic-cell granules contain a protein called perforin that insets into the membrane of a target cell and causes channels to form. These channels allow other granule proteins, a set of proteases called granzymes, to enter the target cell. One effect of this assult appears to be forcing the target cell to initiate apoptosis.

C3a and C5a are proinflammatory molecules that stimulate mast cells to release their granules, which contain vasoactive substance that increase the permeability of blood vessels and thus facilitate the movement of phagocytes from blood vessels into tissue. C5a also acts together with cytokines to signal phagocytes to leave the bloodstream and to guide them to the infection site. Once PMNs or monocytes have left the bloodstream, they move along a gradient of C5a to find the locus of infection. At the site of infection, C3b binds to the surface of the invading bacterium and makes it easier for phagocytes to ingest the bacterium. This activity is called opsonization.

Another role of activated complement components is direct killing of the bacterium. Activated components C5b recruits C6, C7, C8, and C9 to form a membrane-damaging complex in the membranes of some types of microorganisms. This complex is called the membrane attack complex (MAC). Formation of the MAC inactivates enveloped viruses and kills bacteria by punching holes in their membranes.

Correlations Between Innate Immune System and Inflammation

Inflammation is one imporant response of vascular tissues to harmful stimuli, such as damaged tissues and the release of irritants, caused by infection. The inflammatory response recruits innate-immune cells from the blood vessels to the site of infection. Proinflammatory cytokines are induced by the complement cascade (C3a and C5a, phagocytes have receptors for C3b on their surface) and by mast cells (mast cells secrete vasoactive amines including histamine and serotonin) and activated phagocytes.