*Bactericidal and Bacteriostatic Antibiotics DOI: http://dx.doi.org/10.5772/intechopen.99546*


#### **Table 17.**

*3A X carbapenems.*


*Toxicity/Adverse effects* Dose-related nephrotoxicity is frequent with colistin than polymyxin B seen as renal impairment often reversible on stopping the medication. Dose-related neurotoxicity manifesting as neuromuscular blockade resulting in muscular weakness, apnea, and respiratory failure. This effect can be augmented on concurrent administration with aminoglycosides. Peripheral neuropathy of extremities and perioral paraesthesia [202].

#### **Table 18.**

*3A XI polymixins.*


#### **Table 19.**

*3A XII epoxide (fosfomycin).*


#### **Table 20.**

*3A XIII pleuromutilin (lefamulin).*

Plazomicin is a semisynthetic aminoglycoside derived from sisomicin. It is potent against MDR GNB, especially the ones with carbapenemase. It has been approved currently for the treatment of complicated UTI (cUTI) by aerobic

### *Bactericidal and Bacteriostatic Antibiotics DOI: http://dx.doi.org/10.5772/intechopen.99546*


**Table 21.** *3A XIV rifamycins.*

gram-negative bacilli. It is synergistic with other beta-lactams, especially zosyn cefepime and doripenem [234]. The main side effects are tinnitus, headache, dizziness, and mild to moderate drowsiness.

Delafloxacin, a newer quinolone, has MRSA activity and can be used in native and prosthetic joint infections as an oral pill.


#### **Table 22.**

*3A XV metronidazole.*

PCN skin tests are inaccurate in predicting skin reactions. In PCN or cephalosporin allergy patients, the clinical decision to use a different cephalosporin is decided by the severity of the reaction and the cephalosporin to be used. In patients with no severe reactions, a cephalosporin with a different side chain can be used. It is recommended not to use a cephalosporin in case of a severe reaction [235]. Cephalosporins are not active against atypical organisms responsible for CABP. An initial study disclosed increased mortality with cefepime than other cephalosporins compared to a beta-lactam plus beta-lactamase inhibitor (BLI), which was not observed in a more extensive meta-analysis [236, 237]. Cefepime is not recommended to be used in ESBL infections [238]. Siderophore cephalosporins Cefiderocol are active against all beta-lactamases and carbapenemase enzymes [239]. It is also active against the GNB lactose-non fermenters by its affinity for the PBP3.

Zosyn should not be used to treat ESBL infections with bacteremia due to higher mortality observed in trials compared to meropenem [240, 241].

Most *Burkholderia cepacia, Stenotrophomas maltophilia*, *Acinetobacter baumannii* strains are resistant to aztreonam.

Lactose-non fermenters such as *Stenotrophomonas maltophilia, B. cepacia,* and *Elizabethkingia meningoseptica* are intrinsically resistant to all carbapenems due to intrinsic MBL synthesis. Similarly, *Enterobacteriaceae* containing KPC (*Klebsiella pneumoniae*), OXA (*A. baumannii*), or acquired MBL are resistant to carbapenems. They are an ideal choice for polymicrobial infections as they also cover MSSA. *Pseudomonas aeruginosa* resistance to carbapenems is primarily due to porin

#### *Bactericidal and Bacteriostatic Antibiotics DOI: http://dx.doi.org/10.5772/intechopen.99546*

mutations and efflux pumps than the carbapenemase. Porin mutations affect the imipenem, whereas the efflux pumps affect the meropenem and doripenem [242, 243]. The duration of therapy for lactose-non fermenters causing VAP is controversial, as a shorter duration of seven days is associated with an increased recurrence rate [244].

Compared to other antimicrobial classes, polymixins have been associated with poorer outcomes, but this appears to be a poor application of prior suboptimal dose adjustments based on the newer pharmacokinetics and pharmacodynamics data [245, 246]. Polymixin combination regimens should be used as a last resort in the absence of any alternative antimicrobial regimen.

Extreme consideration should be given to the possible drug interactions when rifamycins are used clinically due to their ability to induce the hepatic cytochrome system.

## **4. Antibiotics in ICU**

Antimicrobial prescription in the intensive care unit has three essential ideals to be followed: the correct time when to initiate the antimicrobial, what dose to be used, and how long the antimicrobial should be used. Initiate empirical regimen as early as possible once the infection is suspected to prevent poor clinical outcomes [247]. Trials reveal a positive association between earlier antimicrobial use and mortality in sepsis and septic shock [248]. 2016 surviving sepsis guidelines recommend administering appropriate antimicrobial therapy within one hour of sepsis and septic shock recognition based on the moderate quality of evidence [249]. The empirical regimen should be based on the clinical presentation and associated risk factors. The dose used should be based on the antimicrobial pharmacokinetics, and antibiotics are labeled as either time-dependent (beta-lactams), concentrationdependent (aminoglycosides and daptomycin), and concentration-dependent with time dependence (fluoroquinolones, linezolid) [250].

For time-dependent antimicrobials, the best way to achieve efficacy is a continuous infusion to keep the drug levels above the MIC for a longer time [251]. For concentration-dependent antimicrobials, once-daily higher doses are adequate as they demonstrate postantibiotic effect with reduced adverse events [252]. It is prudent to increase the antimicrobial dosage in patients with augmented renal clearance (burns, trauma, febrile neutropenia) to increase the antimicrobial dosage to achieve the target drug levels [253]. De-escalation of antibiotics is done via three different methods. First, once empirical therapy is initiated, follow the pending culture results, and on day three, when the antimicrobials have reached adequate therapeutic levels, the regimen can be de-escalated to a narrower spectrum based on the patient's culture results and clinical diagnosis. Second, in patients with negative culture results, which is a common finding in ICU patients, the de-escalation process is unclear. For example, in patients treated for HAP who are clinically improving with negative sputum cultures for MRSA and *P. aeruginosa*, antibiotics covering these organisms can be stopped as per guidelines [254]. The third mechanism uses the empirical regimen for the shortest duration possible for a better clinical outcome [255]. This recommendation is based on expert opinion than clinical data.

Recent guidelines based on multiple trials conducted on the VAP antimicrobial therapy duration suggest using the treatment for seven days than 14 days [256]. However, they also recommend following the improvement in clinical, imaging, and laboratory parameters to decide the duration of therapy judiciously. Seven days of VAP therapy was associated with an increased recurrence of infections among lactose-non fermenter GNB such as Pseudomonas and Acinetobacter spp. [244].

Similarly, in MRSA and MSSA pneumonia, the duration is decided by the clinical picture, and most often, it is more than seven days and closer to 14 days.

Antibiotic use in the intensive care unit (ICU) usually follows two different thought processes. One way is to use a single or limited number of antimicrobials as workhorse agents as empirical therapy for infections which carries an inherent risk of resistance emergence via selective pressure (antibiotic homogeneity). This was initiated to control resistance. Another way is to select the antibiotics based on clinical presentation and comorbid risk factors associated with decreased resistance (antibiotic heterogeneity). This is a newer initiation in managing resistance. It is recommended to use antibiotic heterogeneity as much as possible to prevent antimicrobial resistance emergence [257]. Antibiotic stewardship is a must in this modern era for better clinical outcomes, prevent antibiotic adverse events and resistance using local data, reduce the costs by selecting the correct antibiotic dose duration and route. An ideal stewardship team should include an infectious disease consultant, clinical microbiologist, infectious disease trained clinical pharmacist. The current guidelines recommend two strategies to attain this objective. First, reduce the future antibiotic use by auditing institutional antimicrobial usage with feedback to the prescribers. Second, it is ideal to restrict certain antimicrobials to prevent inappropriate usage and decrease institutions' economic burden. Measures taken to enhance the ICU staff education boosts the stewardship process and increases its acceptance among health care workers.

#### **5. Conclusion**

Antibiotic resources are finite and need to be managed judiciously with principles based on antimicrobial stewardship. Management of sick patients in ICU will need timely appropriate antimicrobial adjustments based on new laboratory results and clinical parameters. It seems reasonable to utilize a stewardship team to support the intensivist in the ICU for better outcomes. It seems appropriate to extend the stewardship program to progressive care units or step-down units where antimicrobial utilization is greater than the floors. Education of the ICU staff and positive feedback to antibiotic prescribers can change prescription behavior from antibiotic homogeneity to antibiotic heterogeneity to prevent the emergence of MDR organisms.

#### **Acknowledgements**

"None, this manuscript preparation did not need external funds."

#### **Conflict of interest**

"We, the authors declare no conflict of interest."

#### **Notes/thanks/other declarations**

"A special thanks to the editor for allowing us to author this manuscript.

*Bactericidal and Bacteriostatic Antibiotics DOI: http://dx.doi.org/10.5772/intechopen.99546*
