See **Tables 2** and **3**.

(A, B, C, and D). A, C, and D enzymes utilize serine for β-lactam hydrolysis and class B metalloenzymes require zinc bivalent metal ion, usually Zn2+ ions for substrate hydrolysis [46–48].

Multidrug efflux mechanisms in bacteria contribute significantly to intrinsic and acquired resistance to many antibiotics. Whole genome sequencing has confirmed the broad distribution of these systems in Gram-negative as well as in Gram-positive bacteria. Multidrug efflux systems have given rise to high-level resistance to Gram-negatives, particularly when multiple mechanisms or resistances are simultaneously produced by a single isolate. The efflux system is mediated by transport proteins, which confer resistance antimicrobial agents. The tripartite efflux system in Gram-negative bacteria is necessary to expel the antibiotic to the outer medium. The system consists of (a) protein localized in the cytoplasmic membrane, (b) protein located in the periplasmatic space, and (c) a third protein located in the outer membrane. These active transport proteins are grouped in families, which are based on their amino acid sequences and mechanisms. The most identified and studied multidrug efflux systems

The surviving sepsis guidelines now recommend IV antibiotics to be started within 1 h of sepsis recognition and should include combination therapy (at least two classes of antibiotics to cover a known or suspected pathogen) for patients with septic shock. Combination therapy should not routinely be used for patients without shock. Many studies have demonstrated improved survival in early appropriate administration of antibiotics at the first presence of septic shock [50]. Kumar et al. concluded for each hour of delay of appropriate antimicrobials resulted in a mean increase in mortality by 7.6%, with a range 3.6–9.9% [51]. Ferrer et al. published the results of a large population, which concluded that a delay in first antibiotic administration was associated with increased in-hospital mortality in patients with severe sepsis and septic shock [45]. It was also noted that there was a linear risk increase in mortality for every hour delay in antibiotic administration. Another study by Vazquez-Guillamet concluded that improved targeting in multidrug-resistant bacteria would have the greatest impact on reducing overall mortality. In their study, they calculated the number of patients needed to treat and found for every four patients treated with appropriate antimicrobial therapy in severe sepsis and septic shock, it prevents one patient death [52]. The appropriateness of early empiric antibiotics is driven by local hospital-resistance patterns. At times,

a) Class A enzymes TEM, SHV, ESBL, CTX-M, KPC, PC1, SME, IMI/NMC, GES/IBC.

Example enzymes are as follows:

86 Contemporary Topics of Pneumonia

c) Class C enzymes AmpC, CMY.

**7. Early detection**

b) Class B enzymes MP, VIM, SIM, GIM, SPM, NDM-1.

d) Class D OXA superfamily (OXA-23, OXA-40 in US outbreaks).

among Gram-negative bacteria are *P. aeruginosa* and *E. coli* [49].

Procalcitonin (PCT) is an inflammatory biomarker that is an acute phase reactant that reflects host response to bacterial infections. PCT synthesis is up regulated in the presence of bacterial toxins and certain bacterial pro-inflammatory mediators such as TNFα (tumor necrosis factor alpha), interleukin (IL)-1b, IL-6. PCT is neutral to cytokines that are normally released for viral


**Table 2.** Rapid diagnostic testing methodologies.


**8. Treatment**

programs.

dysfunction.

defenses [50].

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

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

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

89

a) The site of infection, pathogen profile, and antimicrobial pharmacokinetics and pharmaco-

b) Prevalence of pathogens in the community, hospital, and specific hospital locations, i.e.,

c) The resistance patterns of prevalent pathogens in the form of antibiograms or surveillance

d) Status of the patient, i.e., immunocompromised patients such as HIV infection, splenectomy, neutropenia, congenital defects of immunoglobulin, complement, or leukocyte

e) Age and patient comorbidities, the presence of invasive devices that compromise the host

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

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

several factors in determining the appropriate antimicrobial regimens:

critical care unit by means of surveillance is an important determinant.

dynamics (PK/PD) as it relates to penetration at the site.

coverage for the candida infection needs to be considered [58].

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

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 unnecessary use of antibiotics [50].
