**8. Treatment**

infections such as interferon-γ. PCT concentrations are undetectable (less than 0.05 ng/mL). However, PCT is immediately released within 2–4 h upon exposure to bacterial toxins. The plasma half-life of PCT is approximately 24 h. Concentrations in the literature have varied for infected patients; however, as higher max concentrations of PCT are released during infection, this tends to correlate with a higher incidence of mortality. In the critically ill baseline PCT levels should be obtained with signs and symptoms of infection as a means of trending. A low PCT level or an ample decrease from baseline along with clinical review during the course of therapy should be interpreted to discontinue antimicrobial therapy. This methodology is part of an antimicrobial stewardship program, which reduces unnecessary antibiotics and also decreases duration. PCT has been proven to effective and safe in various critically ill patients. Many published studies have evaluated the utility of a PCT-guided strategy for determining the appropriate time to discontinue and/or de-escalate antibiotics in patients with varying severity of illnesses with documented infections. These studies have resulted in decreased

Rectal swabs Gram-negative:

unnecessary use of antibiotics [50].

**Rapid nucleic acid–based tests (molecular test)**

88 Contemporary Topics of Pneumonia

Multiplex PCR (detects 23 bacterial species, four resistance mechanisms and *Candida* spp.)

Microarray (detects 15 different Grampositive targets and 14 different Gram-negative targets (including nine resistance mechanisms)

"On demand" PCR

**Table 3.** Rapid diagnostic testing methodologies.

**Methodology Specimen type Organisms** 

Blood Other FDA Cleared Panels: Respiratory, GI, Meningitis

Blood Other FDA Cleared Panels: Respiratory, GI

**identified**

Gram-positives: *Staph/Strep/ Enterococcus/ Listeria* Gram-negatives: *Enterobacteriaceae*, *Pseudomonas aeruginosa*, and *Acinetobacter* species. Fungus: *Candida spp*.

Gram-positives: *Staph/Strep/ Enterococcus/ Listeria* Gram-negatives: *Enterobacteriaceae, Pseudomonas aeruginosa*, and *Acinetobacter* species

*Enterobacteriaceae*, *Pseudomonas aeruginosa*, and *Acinetobacter* species

**Resistance mechanisms identified**

*mecA vanA/vanB blaKPC*

*mecA vanA/vanB* IMP/KPC/NDM OXA/VIM/ CTX-M ESBLs

IMP/KPC/NDM/ OXA\*/VIM \*(Includes OXA-48, OXA-181, OXA-232)

**Turnaround time**

1 h (after blood culture positivity, ~8–24 h)

2.5 h (after blood culture positivity, ~8–24 h)

48 min (can test directly from clinical specimen)

**Manufacturer/ product name**

BioFire Diagnostics LLC/ Film Array® Blood Culture Identification Panel (BCID)

Nanosphere/ Verigene®

Cepheid GeneXpert Carba R

As described earlier, prompt administration with appropriate empiric broad-spectrum antibiotics within 1 h of recognizing sepsis or septic shock has shown to improve survival. The surviving sepsis guidelines recommend initial selection of antimicrobial therapy to broad or "shot gun" approach. This approach ensures that the likely pathogen will be covered. If not, survival may decrease as much as fivefold for septic shock if the initial empiric regimen fails to cover the offending pathogen [50]. The choice of empiric antimicrobial therapy depends on factors related to clinical status, the patient's history, and local epidemiologic factors (see below). Due to the high mortality associated with inappropriate initial therapy, empiric treatment choices should be broad initially, with constant evaluation to de-escalate the regimen once cultures and results have been determined. The guidelines also address several factors in determining the appropriate antimicrobial regimens:


Since majority of the patients with severe sepsis do have some form of immunocompromised status, the broad-spectrum antibiotics should be initiated [50]. Clinicians should assess these statuses of β-lactam and carbapenem resistance in their local communities. Physicians should also consider adding another Gram-negative coverage to cover *Pseudomonas* or *Acinetobacter* infections [57]. It holds true for covering for MRSA infections in patients with suspicion or risk factors for those infections. In patients who are immunocompromised with immunosuppressive medications, neutropenia, liver or renal failure, on total parenteral nutrition the coverage for the candida infection needs to be considered [58].

Dosing patients with severe sepsis and septic shock should be centered on pharmacokinetics/ pharmacodynamics (PK/PD) and drug properties as per the recommendation of surviving sepsis committee [50]. In most instances, the inability to achieve a therapeutic response can be attributed to the failure of optimizing PK/PD, i.e., failure of target attainment by means of reduced initial dosing or inadequate achievable troughs with subsequent dosing [59]. For optimum dosing for fluoroquinolones and aminoglycoside, it requires to optimize the peak plasma level. For aminoglycoside, it can be achieved by 5–7 mg/kg daily gentamicin dose or equivalent. For fluoroquinolones, one should consider dosing for ciprofloxacin at 600 mg, every 12 hourly and for levofloxacin at 750 mg Q 24 hourly [60–62].

For vancomycin, trough levels of 15–20 mg/L have been advocated. In addition, drugs with a low volume of distribution such as vancomycin and colistin, a higher loading dose is suggested [63–65]. For the β-lactams, it is the time when the plasma concentration of the drug should be above the pathogen minimum inhibitory concentration (MIC) level. It is suggested to have the T > MIC (time above the minimum inhibitory concentration) of 60% and greater to have good efficacy, but among patients with sepsis a level of T > MIC of 100% may be needed. This is achieved by prolonging the infusion either as an extended or continuous infusion [50, 66].

In regard to the duration of antimicrobial therapy, per surviving sepsis guidelines, the duration of 7–10 days is adequate for most serious infections associated with sepsis and septic shock. In the 2016, management of adults with hospital-acquired and ventilator-associated pneumonia, 7 days are appropriate for those patients that respond to therapy early on and show clinical improvement (see below). Longer courses can be appropriate for patients who are slow responders or immunocompromised patients, and patients with MDR organisms, some fungal, or viral infections or MRSA [50]. Patients with endocarditis, osteomyelitis and larger abscesses may also require longer duration of therapy [50].

Multidrug-resistant pathogens are associated with increased morbidity and mortality and are certainly challenging to treat. We have described the surviving sepsis guidelines and recently published the 2016 Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: Clinical Practice Guidelines by the Infectious Diseases Society of America. These guidelines make recommendations for the diagnosis and treatment of Hospital-acquired pneumonia (HAP) and Ventilator-associated pneumonia (VAP) and are evidence-based derived from systematic literature reviews (**Table 4**).

Detailed pathogen recommendation is beyond the scope of this chapter, but we included an extensive review on Minocin IV. Minocin IV has an FDA approved indication for *Acinetobacte*r *spp*. and not referenced in the guidelines above, but it has been used with success against *Acinetobacte*r, including MDR and XDR strains. MINOCIN® (minocycline) [67] IV has been reformulated, the new formulation contains magnesium sulfate heptahydrate and can be infused in as low as 100 mL to as high as 1000 mL over 60 min. It has a new pH of 4.5–6.0 when diluted.

Resistance to β-lactams has resulted in the resurrection of shelf toxic agents, i.e., the polymyxins. Tigecycline and sulbactam are not FDA approved for treatment of infections due to *Acinetobacter*. A recent meta-analysis evaluating the use of tigecycline against *Acinetobacter* infections disfavor its use due to an associated higher in-hospital mortality (OR = 1.57, 95% CI 1.04–2.35; *P* = 0.03) [68].

CLSI recommends separate *Acinetobacter* susceptibility results for minocycline since surrogate testing with other tetracyclines will underestimate susceptibility. Several retrospective studies have documented that lower mortality rates seen with combination therapy are used

**Table 5.** Clinical and Laboratory Standards Institute MIC and disk breakpoints available for minocycline and *Acinetobacter* 

**B. Gram-negative antibiotics with antipseudomonal activity: β-lactam–**

OR OR

Notes: Please refer to these guidelines for the compete table, HAP recommendations and detailed pathogen recommendations that can be found at: https://www.thoracic.org/statements/resources/tb-opi/hap-vap-guidelines-2016.

**Table 4.** Summary of recommendations for suggested empiric treatment options for clinically suspected ventilator-

Antipseudomonal penicillins Piperacillin-tazobactam 4.5 g IV q6h **C. Gram-negative antibiotics with antipseudomonal activity: non–β-**

http://dx.doi.org/10.5772/intechopen.69377

91

**lactam–based agents**

Ciprofloxacin 400 mg IV q8h Levofloxacin 750 mg IV q24h

Amikacin 15–20 mg/kg IV q24h Gentamicin 5–7 mg/kg IV q24h Tobramycin 5–7 mg/kg IV q24h

Colistin 5 mg/kg IV × 1 (loading dose) followed by 2.5 mg × (1.5 × CrCl + 30) IV q12h (maintenance

Polymyxin B 2.5–3.0 mg/kg/d divided

Fluoroquinolones

Multidrug-Resistant Gram-Negative Pneumonia and Infection in Intensive Care Unit

Aminoglycosides

Polymyxins

in 2 daily IV doses

dose)

**based agents**

Cephalosporins Cefepime 2 g IV q8h Ceftazidime 2 g IV q8h

Carbapenems

Monobactams Aztreonam 2 g IV q8h

Imipenem 500 mg IV q6hd Meropenem 1 g IV q8h

OR OR OR

OR

**MIC (µg/mL) Interpretation** ≤4.0 Susceptible (S) 8.0 Intermediate (I) ≥16.0 Resistant (R)

Minocycline IV has been used in combination therapy to achieve synergistic activity and to maximize antimicrobial activity in severely ill patients, or to prevent emergence of resistance [74]. Minocycline and colistin combinations demonstrated bactericidal and synergistic

against MDR *A. baumannii* infections.

**A. Gram-positive antibiotics with** 

Vancomycin 15 mg/kg IV q8-12h (Consider a loading dose of 25–30 mg/kg × 1 for severe illness)

**MRSA activity**

Glycopeptides

Oxazolidinones Linezolid 600 mg IV q12h

pdf

*spp*.

associated pneumonia.

Tetracyclines, as a class, have shown consistent *in vitro* activity against *Acinetobacte*r [20, 21]. Increasing levels of multidrug resistance with *Acinetobacter* have led clinicians to reevaluate certain tetracyclines with good *in vitro* activity. Studies of minocycline in *Acinetobacter* infections have shown clinical success ranging from 67 to 88% [21, 69–73]. Minocycline has approved breakpoints for *Acinetobacter* set forth by the Clinical and Laboratory Standards Institute (CLSI) [54]. These breakpoints are shown in **Table 5**.


equivalent. For fluoroquinolones, one should consider dosing for ciprofloxacin at 600 mg,

For vancomycin, trough levels of 15–20 mg/L have been advocated. In addition, drugs with a low volume of distribution such as vancomycin and colistin, a higher loading dose is suggested [63–65]. For the β-lactams, it is the time when the plasma concentration of the drug should be above the pathogen minimum inhibitory concentration (MIC) level. It is suggested to have the T > MIC (time above the minimum inhibitory concentration) of 60% and greater to have good efficacy, but among patients with sepsis a level of T > MIC of 100% may be needed. This is achieved by prolonging the infusion either as an extended or continuous infusion [50, 66]. In regard to the duration of antimicrobial therapy, per surviving sepsis guidelines, the duration of 7–10 days is adequate for most serious infections associated with sepsis and septic shock. In the 2016, management of adults with hospital-acquired and ventilator-associated pneumonia, 7 days are appropriate for those patients that respond to therapy early on and show clinical improvement (see below). Longer courses can be appropriate for patients who are slow responders or immunocompromised patients, and patients with MDR organisms, some fungal, or viral infections or MRSA [50]. Patients with endocarditis, osteomyelitis and

Multidrug-resistant pathogens are associated with increased morbidity and mortality and are certainly challenging to treat. We have described the surviving sepsis guidelines and recently published the 2016 Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: Clinical Practice Guidelines by the Infectious Diseases Society of America. These guidelines make recommendations for the diagnosis and treatment of Hospital-acquired pneumonia (HAP) and Ventilator-associated pneumonia (VAP) and are evidence-based

Detailed pathogen recommendation is beyond the scope of this chapter, but we included an extensive review on Minocin IV. Minocin IV has an FDA approved indication for *Acinetobacte*r *spp*. and not referenced in the guidelines above, but it has been used with success against *Acinetobacte*r, including MDR and XDR strains. MINOCIN® (minocycline) [67] IV has been reformulated, the new formulation contains magnesium sulfate heptahydrate and can be infused in as low as 100 mL to as high as 1000 mL over 60 min. It has a new pH of 4.5–6.0 when diluted.

Resistance to β-lactams has resulted in the resurrection of shelf toxic agents, i.e., the polymyxins. Tigecycline and sulbactam are not FDA approved for treatment of infections due to *Acinetobacter*. A recent meta-analysis evaluating the use of tigecycline against *Acinetobacter* infections disfavor its use due to an associated higher in-hospital mortality (OR = 1.57, 95% CI

Tetracyclines, as a class, have shown consistent *in vitro* activity against *Acinetobacte*r [20, 21]. Increasing levels of multidrug resistance with *Acinetobacter* have led clinicians to reevaluate certain tetracyclines with good *in vitro* activity. Studies of minocycline in *Acinetobacter* infections have shown clinical success ranging from 67 to 88% [21, 69–73]. Minocycline has approved breakpoints for *Acinetobacter* set forth by the Clinical and Laboratory Standards

every 12 hourly and for levofloxacin at 750 mg Q 24 hourly [60–62].

90 Contemporary Topics of Pneumonia

larger abscesses may also require longer duration of therapy [50].

derived from systematic literature reviews (**Table 4**).

Institute (CLSI) [54]. These breakpoints are shown in **Table 5**.

1.04–2.35; *P* = 0.03) [68].

Notes: Please refer to these guidelines for the compete table, HAP recommendations and detailed pathogen recommendations that can be found at: https://www.thoracic.org/statements/resources/tb-opi/hap-vap-guidelines-2016. pdf

**Table 4.** Summary of recommendations for suggested empiric treatment options for clinically suspected ventilatorassociated pneumonia.


**Table 5.** Clinical and Laboratory Standards Institute MIC and disk breakpoints available for minocycline and *Acinetobacter spp*.

CLSI recommends separate *Acinetobacter* susceptibility results for minocycline since surrogate testing with other tetracyclines will underestimate susceptibility. Several retrospective studies have documented that lower mortality rates seen with combination therapy are used against MDR *A. baumannii* infections.

Minocycline IV has been used in combination therapy to achieve synergistic activity and to maximize antimicrobial activity in severely ill patients, or to prevent emergence of resistance [74]. Minocycline and colistin combinations demonstrated bactericidal and synergistic activity against imipenem-resistant *A. baumannii* and MDR *A. baumannii* clinical isolates [75]. Combinations of minocycline plus meropenem and minocycline plus colistin were found to be synergistic *in vitro* against XDR *A. baumannii*. The package insert (PI) has an initial dose of 200 mg, with subsequent doses of 100 mg administered over 60 min every 12 h. Minocycline is very lipophilic compared to other tetracyclines. It has a very unique pharmacokinetic/pharmacodynamic profile (PK/PD) [67]:

Official Publication of Joint Commission Requirements New Antimicrobial Stewardship Standard

scientific literature.

• Budget plans

• Strategic plans

PC.02.03.01)

*stewardship program are as follows:* • Accountability documents

• Infection prevention plans • Performance improvement plans

crobial stewardship data

**1**. Leaders establish antimicrobial stewardship as an organizational priority. (*See also* LD.01.03.01, EP 5) **Note:** *Examples of leadership commitment to an antimicrobial* 

• Using the electronic health record to collect antimi-

**3**. The critical access hospital educates patients, and their families as needed, regarding the appropriate use of antimicrobial medications, including antibiotics. (For more information on patient education, refer to Standard

**Note:** *An example of an educational tool that can be used for patients and families includes the Centers for Disease Control and Prevention's Get Smart document, "Viruses or Bacteria— What's got you sick? At https://www.cdc.gov/antibiotic-use/ community/pdfs/Viruses-or-Bacteria-Factsheet-Eng.pdf*

grams shows that a physician leader is effective.

prescribing and resistance patterns.

period of initial treatment (for example, "antibiotic time out" after 48 h).

mation on antibiotic use and resistance, to doctors, nurses, and relevant staff.

*Stewardship Programs (https://www.cdc.gov/antibiotic-use/healthcare/pdfs/core-elements.pdf)*

Applicable to Hospitals and Critical Access Hospitals Effective January 1, 2017 Medication Management (MM) Standard MM.09.01.01 The critical access hospital has an antimicrobial stewardship program based on current

> **2**. The critical access hospital educates staff and licensed independent practitioners involved in antimicrobial ordering, dispensing, administration, and monitoring about antimicrobial resistance and antimicrobial stewardship practices. Education occurs upon hire or granting of initial privileges and periodically thereafter,

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93

**4**. The critical access hospital has an antimicrobial

multidisciplinary team that includes the following

**Note 1:** *Part-time or consultant staff are acceptable as members of the antimicrobial stewardship multidisciplinary* 

**Note 2:** *Telehealth staffs are acceptable as members of the antimicrobial stewardship multidisciplinary team*

members, when available in the setting:

• Infectious disease physician • Infection preventionist(s)

based on organizational need

Multidrug-Resistant Gram-Negative Pneumonia and Infection in Intensive Care Unit

stewardship

• Pharmacist(s) • Practitioner

*team*

**5. The critical access hospital's antimicrobial stewardship program includes the following CDC core elements:** • Leadership commitment: Dedicating necessary human, financial, and information technology resources. • Accountability: Appointing a single leader responsible for program outcomes. Experience with successful pro-

• Drug expertise: Appointing a single pharmacist leader responsible for working to improve antibiotic use.

• Tracking: Monitoring the antimicrobial stewardship program, which may include information on antibiotic

• Action: Implementing recommended actions, such as systemic evaluation of on-going treatment need, after a set

• Reporting: Regularly reporting information on the antimicrobial stewardship program, which may include infor-

• Education: Educating practitioners, staff, and patients on the antimicrobial program, which may include informa-

**Note:** *These core elements were cited from the Centers for Disease Control and Prevention's Core Elements of Hospital Antibiotic* 

tion about resistance and optimal prescribing. (*See also* IC.02.01.01, EP 1 and NPSG.07.03.01, EP 5)

