**3. Empiric antimicrobial therapy (EAT)**

Initial selection of particular antimicrobial agents is empiric and is based on an assessment of the patient's underlying host defenses, the potential sources of infection, and the most likely pathogens depending on the locally epidemiological data. EAT is preferably administered within the first hour.

#### **3.1 Times to antibiotics**

Once a presumed diagnosis of sepsis or septic shock has been made, optimal doses of appropriate intravenous antibiotic therapy should be initiated, preferably within one hour of presentation and after cultures have been obtained. The Infectious Diseases society of America (IDSA) opts to that prompt administration of antibiotics is recommended once a presumed diagnosis of sepsis or shock has been made by the treating clinician [7]. The Surviving Sepsis Campaign recommends immediate antibiotics for all patients with suspected sepsis and septic shock, ideally within 1 hour of recognition.

The literature review does not find a clinical trials evaluating specially the target time of one hour to start antimicrobials. That is understandable given the enormous ethical concern that results. But almost all observational studies agree that a delay exceeding one hour is related to poor outcomes; as well as inadequate doses and inappropriate antibiotic therapy [8–14]. Ferrer R, et al. in a large population of patients with severe sepsis and septic shock (17,990 patients) demonstrated a linear increase in the risk of mortality for each hour delay in antibiotic administration [9]. In a retrospective study of 35,000 patients treated in emergency department, the increase in absolute mortality associated with an hour's delay in antibiotic administration was 0.3% (p = 0.04) for sepsis, 0.4% (p = 0.02) for severe sepsis, and 1.8% (p = 0.001) for shock [11].

In a large database study comparing patients with sepsis and septic shock treated with various types of protocolized treatment bundles (that included fluids and antibiotics, blood cultures, and serum lactate) versus those in whom a three-hour bundle (blood cultures before broad spectrum antibiotics and serum lactate level) was completed within the three-hour time frame [12]. Each 3-hour bundle delay achievement increased in-hospital mortality by 1.04 per hour [12]. In addition, a delayed completion of a fluid bolus did not increase mortality significantly (OR = 1.04) as the delay of antimicrobials [12].

#### **3.2 Identification of suspected source/responsible pathogens**

Establishing an accurate diagnosis of the infection site is a priority objective that must be fulfilled as soon as possible.

Sometimes the patient arrives with a visible source of infection (e.g. infected wound, cellulitis etc). In the case where the source is unclear, the process of its identification is based on a good anamnesis for collecting the medical and surgical history and a careful and exhaustive physical examination looking for local inflammatory signs or function loss. If the source is identified, targeted imaging and microbiological sampling should be done and therefore empiric antibiotic therapy should be initiated.

In the case where the source remains unclear, it is necessary to complete by an exhaustive imaging or even a whole body CT scan and extensive sampling.

**Table 1** summarizes the most common sources of infection with a potential risk of progress to a sepsis and septic shock and the additional tests to be performed.

Additional diagnostic testing or interventions may be required to identify the anatomic site(s) of infection. In particular, in addition to antibiotics, closed space infections should be promptly drained or debrided (eg, empyema, abscess) for effective source control.

Besides bacteriological examinations, imaging is often essential to recognize sites of infection (chest radiography, ultrasound, tomography and MRI).

Sometimes in structures with limited resources, imaging is not always available, as are interventional radiology techniques. In this case, blood cultures before the administration of antibiotics becomes an essential measure and ideally that should be obtained from two sites.

#### **3.3 Regimen to choose**

The choice of empirical antibiotic therapy is not a simple attitude and must be reasoned upon the presumed primary focus, the history of the patient ((eg, recent antibiotics received, previous organisms) and its co-morbidities (eg, diabetes, organ failures, immune defect..), invasive devices, nosology (eg, community- or hospital-acquired) and the bacterial ecology and resistance patterns of the unit where the patient is hospitalized [13, 14, 16–18]. It must be preceded by directed bacteriological samples.

Also, the choice of the molecule is made according to its spectrum of action and its pharmacodynamics/pharmacokinetics (PK/PD) properties and the spectrum of the selected combination must be efficient against gram-positive, gram-negative, and anaerobic bacteria because all of these classes of organisms produce similar clinical presentations.

Regarding the administration route and dosing, it is recommended that the intravenous is mandatory and at high doses to achieve bactericidal serum levels. This later correlated with clinical improvement rather than the number of antibiotics prescribed.


*PCR: polymerase chain reaction, SARS CoV2: severe acute respiratory syndrome coronavirus 2, CSF: cerebrospinal fluid; PD: peritoneal dialysis; MRI: magnetic resonance imaging. Source: Reference [15]*

#### **Table 1.**

*Identification of sources of sepsis and additional tests.*

The regimen to choose should consider antipseudomonal in patients with neutropenia or burns and anti-anaerobes in intra-abdominal/perineal infections.

Antimicrobial choice should be tailored to each individual. In any case, appropriate cultures should be obtained which include two sets of blood cultures obtained before antibiotics are started and cultures of other suspected sites of infection (sputum, urine, etc.) obtained as soon as possible.

For most patients with sepsis without shock, antimicrobials may be administered in monotherapy or in combination. Anyway, the empiric chosen regimen must cover all the maximum number of pathogens most likely involved (ie grampositive and gram-negative bacteria, fungi if presence of invasive candidiasis factors or immune-compromised for aim *Pneumocystis jirovecii*, and rarely viruses (eg, influenza, Cytomégalovirus (CMV)). For SARS CoV2, all the therapeutic means tried so far (chloroquine, macrolides, tocilizumab, remdesivir, monoclonal antibody, colchicine ...) are designed for immunomodulatory purposes and no treatment is directed specifically against COVID-19.

Patients with septic shock, in whom gram negative bacilli are suspected, must be treated with at least two antimicrobials from two different classes according to the considered likely organisms and local antibiotic susceptibilities. That is commonly called combination therapy defined as more than one antimicrobial agent given in the aim to improve efficiency against a known or suspected pathogen.

*Escherichia coli*, *Staphylococcus aureus, Klebsiella pneumoniae,* and *Streptococcus pneumoniae,* are the most common isolated organisms from patients with sepsis. Thus, these organisms should be taken into account when choosing empiric regimen [19]. Betalactams such carbapenem, piperacillin-tazobactam, in combination or not with aminosides or quinolones are a good alternative to cover a large batch of gram negative and positive organisms.

When nosocomial nature of sepsis or septic shock is suspected, the multiresistant profile of microorganisms (mainly non fermenting gram negative bacilli including *Acinetobacter Baumannii*) should be covered [20, 21].

Otherwise, the following pathogens must be included in the spectrum of antibiotics to be chosen and this according to the risk factors for their presence:

	- Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or
	- Antipseudomonal carbapenem (eg, imipenem, meropenem), or
	- Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillintazobactam, or Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or Aminoglycoside (eg, gentamicin, amikacin), or Monobactam (eg, aztreonam)

*Empiric Antimicrobial Therapy in Critically Ill Septic Patients DOI: http://dx.doi.org/10.5772/intechopen.98327*

0,70–1,32), indicating no mortality benefit with combination therapy compared to monotherapy with a third generation cephalosporin or a carbapenem [24]. Furthermore, the combination to an amino-glycoside was related to an increase of nephrotoxicity [24].

Therefore, it is recommended to administer a single antimicrobial agent known to have proven efficacy and the least possible toxicity. Patients with neutropenia or in whom *Pseudomonas* is suspected are to exclude from this rule and combination therpay should be contemplated.

• **Carbapenemase-producing** *Enterobacteriaceae* **(CPE)** are becoming an emerging concern worldwide. Infections caused by these pathogens are associated with high morbidity, mortality and costs while they are difficult to treat since only a small number of therapeutic options are available. Only a few clinical studies, often size-limited and retrospective, have been conducted mainly on infections caused by KPC - producing *Klebsiella pneumoniae* whereas there are more in vitro and animal data. In some cases, β-lactams can be used, such as carbapenems (if MIC ≤8 mg/L), aztreonam or ceftazidime. A doublecarbapenem regimen also seems to be promising, with ertapenem. Polymyxins and tigecyline (with a loading dose and high dosages) are possible alternatives in combination. Aminoglycosides (especially gentamicin) in monotherapy are choice options for the treatment of urinary tract infections. Fosfomycin may be used in combination but there is a risk of emergence of resistant mutants during therapy. For the treatment of severe infections (bacteremia and pneumonia), combination therapy should be used since risks of clinical failure and mortality are significantly lower than with monotherapies in the majority of studies. The most frequent combinations are polymyxins-carbapenems, tigecycline-carbapenems and polymyxins-tigecycline, knowing that carbapenem-based regimens (if MIC ≤8 mg/L) must be favored [25].

**Acinetobacter Baumannii:** *Acinetobacter* are opportunistic and ubiquitous bacteria that occur in the form of Gram-negative coccobacilli. Among the species of this genus, *Acinetobacter baumannii* is the most implicated in nosocomial infections, especially in ICU [26]. This bacterium is involved in a wide range of infections such as VAP, bacteremia, CRI, urinary tract infections, secondary wound infections or postoperative meningitis. *A.baumannii* exhibits a remarkable ability to acquire mechanisms of resistance to antibiotics, rapidly leading to multi-resistance to almost all commercially available antibiotics and sometimes to therapeutic dead ends [27]. *Acinetobacter baumannii* is one of the ESCAPE organisms (*Enterococcus faecium*, *Staphylococcus aureus*, *Clostridium difficile*, *Pseudomonas aeruginosa*, and Enterobacteriaceae), a group of clinically important, predominantly health care-associated organisms that have the potential for substantial antimicrobial resistance [28].

Independent risk factors for colonization or infection with resistant strains of *Acinetobacter* include the following [29–32]: prior colonization with MRSA, prior beta-lactam (particularly carbapenems) or fluoroquinolone use, bedridden status, current or prior ICU admission, presence of a CVC, recent surgery, Mechanical ventilation, Hemodialysis, malignancy, steroids therapy.

Empiric antibiotic therapy for *Acinetobacter*, before results of antimicrobial susceptibility testing are available, should be selected based on local susceptibility patterns. In general, it should consist of a broad spectrum cephalosporin, a combination beta-lactam/beta-lactamase inhibitor (eg, a combination including sulbactam), or a carbapenem. An additional agent may be warranted if local resistance rates to the chosen antibiotic class are high (eg, greater than 10 to 15%).

When rates of resistance to the selected antimicrobial agent are low (ie, below 10 to 15 percent), monotherapy is likely adequate as there are no data to clearly demonstrate that combination therapy improves outcomes through synergistic effect. However, when rates of resistance are higher, it is reasonable to use one of the agents above in combination with an antipseudomonal fluoroquinolone, an aminoglycoside, or colistin to improve the likelihood of administering an antibiotic agent that retains activity. While there are no clear clinical data to support this practice for *Acinetobacter* infections, many experts favor empiric combination therapy for serious infections with these and other potentially resistant gram-negative organisms because of the increased mortality associated with inappropriate empiric therapy.

A prospective cohort study was made in 70 ICU patients with nosocomial sepsis/ septic shock in whom imipenem/colistin was prescribed as first line antibiotic therapy [33]. The main findings were: this regimen was only appropriate in 52% of cases and inappropriateness was associated with an increased ICU mortality risk (OR = 6.27, 95% CI [1.83–21], p = 0.003) [33].


Susceptibility testing for these agents should be performed as well prior to their use given the possibility of resistance.

We generally favor using a second agent, such as a carbapenem, tigecycline, or rifampin, in addition to polymyxins for serious infections (eg, bacteremia, pneumonia, critical illness) with resistant isolates.

There are no definitive clinical data that demonstrate improved outcomes with combination versus monotherapy, and some randomized trials have suggested that certain combinations (colistin and rifampin or colistin and meropenem or fosfomycin) resulted in comparable clinical outcomes as monotherapy with colistin [34, 35]. Nevertheless, infections with multidrug-resistant *Acinetobacter* are associated with high mortality rates, and we are concerned that the use of a single agent is not adequate, particularly since resistance can develop during therapy, leaving no therapeutic alternatives. The synergistic pharmacological tests are a great contribution to the choice of treatment and consultation with an expert in the management of such infections is advised.

In case of ventilator acquired pneumonia (VAP) caused by *Acinetobacter,* additional considerations include the possible use of adjunctive inhaled antibiotics. Inhaled colistin may be beneficial in select patients [36–38], although not all studies suggest a benefit [39]. We favor use of inhaled colistin among patients with severe pneumonia due to *Acinetobacter* only sensitive to colistin, since intravenous colistin yields low lung concentration. The optimal dose of inhaled colistin is uncertain and ranges from 75 to 150 mg colistin base activity (2.25 to 4.5 million international units CMS) twice daily. Higher doses, up to 5 million international units colistimethate sodium (approximately 167 mg colistin base) every eight hours, have also been used for VAP with *Acinetobacter* [40].

• **Invasive fungal infections:** Fungal infections are a feared complication in ICU patients. Their epidemiology has deeply changed linked to major changes in medical practices (induced immunosuppression, organ transplants, cytotoxic chemotherapy, ICU invasive procedures, parenteral nutrition, and prolonged antimicrobial). Moreover, several factors depend on patient's morbidities (chronic liver or renal failure, diabetes, surgery, septic shock or multisite *Candida* colonization).

The Arsenal antifungal therapy has also broadened considerably with new molecules, such echinocandins, well tolerated than amphotericin B. The use of an empiric antifungal in patients exhibiting sepsis and septic shock has been widely debated with a rather converging towards the absence of a favorable effect on mortality [41–44]:

Cortegiani A, et al. in a meta-analysis including 22 studies (total of 2761 participants) concluded that the use of untargeted antifungal is not associated with a significant reduction in all-cause mortality and may be associated with a reduction of invasive fungal infection among ICU patients [41]. Empiric antifungal treatment (mostly fluconazole) not decreased risk of mortality or occurrence of invasive candidiasis in ICU patients receiving mechanical ventilation for at least five days [42]. In addition, the multicenter randomized trial conducted in ICU (known as EMPIRICUS, n = 260 patients colonized with *Candida* and having sepsis), micafungin administered for 14 days did not improve 28 day-survival without infection [43].

In a 8-years retrospective double cohort (empiric antifungal group, n = 125 versus no empiric antifungal group, n = 122), no improvement of 28-day survival was found. Moreover, no preventing effect on a new episode of candidemia. Nevertheless, a beneficial effect of empiric antifungal on survival was found in patients with an Acute Physiology and Chronic Health (APACHE) II score < 16: OR = 0.68; CI 95% [0.53–0.87]; p = 0.002 [44]. That means; it is the less severe patients who can benefit from an empiric fungal.

However, if *Candida* or *Aspergillus* is strongly suspected or if neutropenia is present, echinocandin (for *Candida*) or voriconazole (for *Aspergillus*) are often appropriate [45].

Even if our focus here is the empirical choice of antibiotic therapy in septic ICU patients, but it would be wise to suggest a list of the more common potential pathogens that would need to be treated. The main pathogens to be considered in **community infections** depending on the infected site are:

**Community acquired pneumonia (CAP**): *Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophyla, Haemophilus influenzae, Enterobacteria, anaerobies, Staphylococcus aureus.*

**Community meningitides:** *Streptococcus pneumoniae, Nesseria meningitis, Listeria monocytogenes Haemophilus influenzae, Enterobacteria, Streptococcus sp.*

**Urinary tract infections:** *Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Staphylococcus saprophyticus, Enterobacter sp, Enterococcus sp.*

**Skin and soft tissues infections:** *Streptococcus pyogenes, Staphylococcus aureus, anaerobies.*

**Intrabdominal infections**: *Escherichia coli, Klebsiella pneumonia, anaerobies (Bacteroides fragilis) Enterobacter sp, Enterococcus sp, Streptococcus pneumoniae, Pseudomonas sp.*

**For nosocomial infections,** Gram-negative bacilli are mostly involved followed by Gram-positive cocci. The main multidrug-resistant bacteria (MDRs) to be considered are: Methicillin-resistant *Staphylococcus aureus* (MRSA), *Enterobacteriaceae* producing Extended spectrum beta-lactamases (ESBL) or hyperproducing cephalosporinases (HPCase), *Pseudomonas æruginosa, Acinetobacter Baumannii* and *Enterococci* Vancomycin Resistant (EVR).


*\*Vancomycin dosed per pharmacy consult. Typically with loaded with 20–25 mg/kg dose initially (max 2 g initial dose).*

*MDR GNB: multi drug resistant gram negative bacilli, ESBL: Extended spectrum betalactamases, MRSA: Methicillin-resistant Staphylococcus aureus, CAP: Community Acquired Pneumonia***,** *HCAP: healthcare acquired pneumonia, HAP: hospital acquired pneumonia, VAP: ventilator acquired pneumonia.*

#### **Table 2.**

*Suggested regimens for empiric antimicrobials in sepsis/septic shock.*

**Table 2** displays suggested regimens for empiric antimicrobials in sepsis and septic shock according to the suspected Source (all antibiotics are to be administered intravenously).
