**3. Management of antibacterial chemotherapeutic drugs**

The choice of antibiotics is conditioned by:


In the case of the critical patients, the early administration of an effective antibiotic treatment is essential and determining, the time until the initiation of therapy being a strong predictor of mortality. A retrospective cohort study showed that the delay of effective treatment after the onset of recurrent or persistent hypotension was associated with an increased death risk; the survival rate in patients with treatment administered during the first hour was of 79.9%, with each hour of delay in antibiotic therapy leading to a 7.6% decrease in this rate [27].

*Optimization of doses*. The antibiotic requirement is calculated depending on the characteristics of the patient (age, weight, renal function), on the pathogenic microorganism, infection site (endocarditis, pneumonia, meningitis, osteomyelitis) and the pharmacokinetic and pharmacodynamic characteristics of the drug [28].

Severe acute infections are classified as community-acquired, healthcare-associated and hospital-acquired infections. For the practical assessment of a case, Yehuda Carmeli proposed a score, which allows the stratification of risk factors for the infections with resistant or MDRO, depending on the previous contact of the patient with the health care sector, on the existence in his/her medical history of antibiotic treatments, as well as on associated factors (immune

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Risk assessment for infections with resistant or MDR pathogens:

suppression, co-morbidities):

**1.** No contact—1

**a.** Contact with the health care sector:

**b.** Previous antibiotic treatment:

**c.** Characteristics of the patient:

**1.** Young, without co-morbidities—1

**2.** Elderly, with co-morbidities—2

**1.** No antibiotics—1 **2.** With antibiotics—2

microorganism in question.

**2.** Contact without invasive procedures—2

**3.** Repeated contacts with invasive procedures—3

**3.** Immunocompromised patient (AIDS, neoplastic diseases)—3

According to this score, the value 1 corresponds to community-acquired infections, the value 2 corresponds to HCAI and the value 3 to hospital-acquired infections. The Carmeli score may only be 1, 2 or 3, and it is given by the highest value obtained from the answers to the three categories of questions [29]. This classification allows a correlation between the type of infection, the most probable aetiology and the estimation of the antibiotic susceptibility of the

The empirical or first-line treatment is especially important for the evolution of the infection; the delayed initiation of an effective antimicrobial treatment leads to increased morbidity and mortality, aggravated and generalised infections, as well as increased health care costs. If the initial treatment has not been effective, adding a new antibiotic or replacing the initial one with a broader spectrum antibiotic (escalation) will not increase the chance of favourable evolution. The adjustment of antibiotic treatment after the microbiological results become available might be tardy and ineffective, if the initial treatment has been inadequate, especially in the case of hospital-acquired infections (multivariate analysis have demonstrated that inadequate empirical treatment increased the risk of mortality). The association of antibi-

otics of different classes is useful in the initial treatment of infections with MDRO.

The loading dose is probably the most important and depends on the distribution volume of the drug and on the intended plasmatic concentration, regardless of the renal function. Antibiotics are classified according to multiple criteria, one being the criterion, which influences the dosage: the doses of hydrophilic antibiotics (beta-lactam) must be increased during the first stages of sepsis, together with the increase in the extravascular space. The doses of lipophilic antibiotics are influenced by other factors, such as obesity [7, 28].

Before establishing the rational antibiotics administration regimen, the antimicrobial activity in time must be understood, i.e., the pharmacodynamics of the drug in question (the relationship between its serum concentration and its therapeutic effect). From a pharmacodynamic perspective, antimicrobial agents may be divided into:


The time-dependent bactericidal effect is achieved by optimising the duration of bacterial exposure to antibiotics, while the dose-dependent bactericidal effect is maximal when the antibiotic concentration is maximal [7].

Polymyxins are concentration-dependent antibiotics; they are active on carbapenemase-producing bacteria, and they are increasingly kept as last therapeutic option in infections with resistant pathogens, such as *Pseudomonas aeruginosa*, *Acinetobacter baumannii* and *Klebsiella pneumoniae*. We must underline the fact that if sub-optimal doses of colistin are administered, the pathogen gains resistance.

First-line antibiotic treatment in severe acute infections.

Severe acute infections are classified as community-acquired, healthcare-associated and hospital-acquired infections. For the practical assessment of a case, Yehuda Carmeli proposed a score, which allows the stratification of risk factors for the infections with resistant or MDRO, depending on the previous contact of the patient with the health care sector, on the existence in his/her medical history of antibiotic treatments, as well as on associated factors (immune suppression, co-morbidities):

Risk assessment for infections with resistant or MDR pathogens:

	- **1.** No contact—1

(endocarditis, pneumonia, meningitis, osteomyelitis) and the pharmacokinetic and pharma-

The loading dose is probably the most important and depends on the distribution volume of the drug and on the intended plasmatic concentration, regardless of the renal function. Antibiotics are classified according to multiple criteria, one being the criterion, which influences the dosage: the doses of hydrophilic antibiotics (beta-lactam) must be increased during the first stages of sepsis, together with the increase in the extravascular space. The doses of

Before establishing the rational antibiotics administration regimen, the antimicrobial activity in time must be understood, i.e., the pharmacodynamics of the drug in question (the relationship between its serum concentration and its therapeutic effect). From a pharmacodynamic

• The bactericidal effect of beta-lactam antibiotics is independent of their concentration, as long as this exceeds the MIC and they do not possess a significant post-antibiotic effect (PAE) (The inhibition of bacterial growth continued for a variable period after the concentration of antibiotic at the infection site has dropped under the MIC.) The strategy to obtain optimal results is to increase the exposure time of microbes to plasmatic concentrations of antibiotic exceeding the MIC, which is accomplished by frequent doses, by the administra-

• The bactericidal effect of vancomycin, carbapenems, macrolides, clindamycin, azoles, linezolid is independent of their concentration, if this is higher than the MIC, but it is time dependent. The PAE is intermediate (The serum antibiotic levels may drop under the MIC for a short while.) The antibiotics in this group produce optimal results when administered

• The bactericidal effect of aminoglycosides, fluoroquinolones and metronidazole is dose dependent and has a significant post-antibiotic effect (Bacterial growth is prevented even if tissue levels decrease under the MIC for longer periods of time.) This is why higher doses, but at larger intervals, may be administered, with 2–4 h between the doses after being admitted, during which time the plasmatic concentration of these antibiotics may be

The time-dependent bactericidal effect is achieved by optimising the duration of bacterial exposure to antibiotics, while the dose-dependent bactericidal effect is maximal when the

Polymyxins are concentration-dependent antibiotics; they are active on carbapenemase-producing bacteria, and they are increasingly kept as last therapeutic option in infections with resistant pathogens, such as *Pseudomonas aeruginosa*, *Acinetobacter baumannii* and *Klebsiella pneumoniae*. We must underline the fact that if sub-optimal doses of colistin are administered,

lipophilic antibiotics are influenced by other factors, such as obesity [7, 28].

codynamic characteristics of the drug [28].

30 Current Topics in Intensive Care Medicine

perspective, antimicrobial agents may be divided into:

tion at short time intervals or by continuous infusion.

undetectable, which reduces their nephrotoxicity.

First-line antibiotic treatment in severe acute infections.

in lower but with more frequent doses.

antibiotic concentration is maximal [7].

the pathogen gains resistance.

	- **1.** No antibiotics—1
	- **2.** With antibiotics—2
	- **1.** Young, without co-morbidities—1
	- **2.** Elderly, with co-morbidities—2
	- **3.** Immunocompromised patient (AIDS, neoplastic diseases)—3

According to this score, the value 1 corresponds to community-acquired infections, the value 2 corresponds to HCAI and the value 3 to hospital-acquired infections. The Carmeli score may only be 1, 2 or 3, and it is given by the highest value obtained from the answers to the three categories of questions [29]. This classification allows a correlation between the type of infection, the most probable aetiology and the estimation of the antibiotic susceptibility of the microorganism in question.

The empirical or first-line treatment is especially important for the evolution of the infection; the delayed initiation of an effective antimicrobial treatment leads to increased morbidity and mortality, aggravated and generalised infections, as well as increased health care costs. If the initial treatment has not been effective, adding a new antibiotic or replacing the initial one with a broader spectrum antibiotic (escalation) will not increase the chance of favourable evolution. The adjustment of antibiotic treatment after the microbiological results become available might be tardy and ineffective, if the initial treatment has been inadequate, especially in the case of hospital-acquired infections (multivariate analysis have demonstrated that inadequate empirical treatment increased the risk of mortality). The association of antibiotics of different classes is useful in the initial treatment of infections with MDRO.

The Principles of de-escalation are as follows:

abscess, empyema, etc. [31].

(**Figure 2**).

**Author details**

**References**

Muntean Delia and Licker Monica\*

• identification of the aetiology within this covered period,

\*Address all correspondence to: deliacristimuntean@yahoo.com

Heidelberg: Springer-Verlag; 2007. pp. 203-205

[5] \*\*\*CDC Bacterial Pneumonia, MMWR. 1997;**46**:RR1-RR85

8e28-01aa75ed71a1/language-ro

"Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania

• administration of an ultra-broad-spectrum antibiotic for a short period of time,

If, after 48–72 h of treatment with a broad-spectrum antibiotic, the status of the patient does not improve, the available microbiological data are attentively reanalysed and the possibility of MDRO infection, a non-bacterial or even a non-infectious aetiology, are considered. The evaluation must also include the possibility of a complication, such as the formation of an

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Decreasing the risk of adverse reactions, the decreased selection pressure of resistant strains, as well as the reduction of costs represent the benefits of de-escalation and treatment cessation after a shorter time. Examples of benefits in the administration of antibiotics in short cures and/or reduction of the antibiotics spectrum include the decrease in the incidence of cases of diarrhoea with *Clostridium difficile* and of infections with resistant bacteria and *Candida* spp.

[1] Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.

[2] Marin H, Kollef MLE, Baughman RP. Health care-associated pneumonia (HCAP): A critical appraisal to improve identification, management, and outcomes-proceedings of

[3] Rello J, Kollef M, Diaz E, Rodriguez A. Infectious Diseases in Critical Care. Berlin

[4] https://publications.europa.eu/ro/publication-detail/-/publication/10ed460f-0711-11e2-

American Journal of Respiratory and Critical Care Medicine. 2005;**171**:388-416

the HCAP summit. Clinical Infectious Diseases. 2008;**46**(Supl 4):S296-S334

• replacement of the initial antibiotic with a narrow-spectrum antibiotic.

**Figure 2.** Algorithm for initiation of antibiotic therapy.

In patients with severe infections, the recommendation is to administer the antibiotic treatment during the first hour after the diagnosis, but not before collection of blood and other biological samples required for the identification of the aetiological agent and testing for its sensitivity to chemotherapeutics. Patients with meningitis will receive antibiotic treatment during the first 30 min after hospital admission, immediately after collection of blood and CSF [1, 10].

The empirical or first-line antibiotic treatment is initiated according to the most probable microbiological spectrum and consists of the administration of a broad-spectrum antibiotic (covering Gram-positive cocci, including MRSA and enterococci, as well as Gram-negative bacilli, including *Acinetobacter* spp., *Pseudomonas aeruginosa* and *Enterobacter* spp.) for a short period of time, i.e., for 2–3 days. Depending on the clinical evolution of the patient and on the results of microbiological tests, the initial treatment scheme may be modified by decreasing the number of antibiotics or reducing the spectrum (*de-escalation*). Narrowing the therapeutic regimen does not only refer to the shift from a broad-spectrum to a narrow-spectrum antibiotic, but also to adjusting (reducing) the doses and treatment duration [30].

The Principles of de-escalation are as follows:


If, after 48–72 h of treatment with a broad-spectrum antibiotic, the status of the patient does not improve, the available microbiological data are attentively reanalysed and the possibility of MDRO infection, a non-bacterial or even a non-infectious aetiology, are considered. The evaluation must also include the possibility of a complication, such as the formation of an abscess, empyema, etc. [31].

Decreasing the risk of adverse reactions, the decreased selection pressure of resistant strains, as well as the reduction of costs represent the benefits of de-escalation and treatment cessation after a shorter time. Examples of benefits in the administration of antibiotics in short cures and/or reduction of the antibiotics spectrum include the decrease in the incidence of cases of diarrhoea with *Clostridium difficile* and of infections with resistant bacteria and *Candida* spp. (**Figure 2**).
