Colistin

In 1949, Y. Koyama fermented colistin (Polymyxin E) from Bacillus species, and after one decade in 1959, it was first used for clinical purposes9, 10. It has significant activity against Gram-negative bacterial infections caused by and carbapenem-resistant Enterobacteriaceae11, 12. Due to the lower availability of antibacterial agents for the treatment of MDR, XDR, PDR, and CRE, colistin is considered for treatment with more effective bactericidal activity1, 13. Colistin attacks and binds to the lipopolysaccharide (LPS) section of the exterior membrane of gram-ve rods and damages it as a magnitude14. For the last few years, colistin has been used as a first-line therapeutic agent in CRE- and carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA)15. The International Network for Optimal Resistance Monitoring (INFORM) monitoring the novel combination of colistin and ceftazidime and avibactam (CAZ-AVI) in Enterobacteriaceae. CAZ-AVI is a more potent and vigorous agent with a greater than 94% susceptibility rate, and Colistin was 82%16. Mostly colistin and carbapenem are both used as combination therapy for combating resistance. In patients with low-risk blood stream infections, monotherapy with colistin is acceptable17.

The adverse effect of colistin is related to organ toxicity, such as eyelid ptosis, hearing dysfunction, visual abnormalities, vertigo, misperception, hallucinations, attacks, any body part effect or loss of function, and rarely neuromuscular barrier leading to lung failure and is essential for ventilator care18, 19, 20. There is a higher risk of nephrotoxicity from colistin, which is a more serious adverse effect19, 21, 22. Kalin and his coworkers included 45 patients in their study, of whom 15 received a greater dose of colistin (2.5 mg/kg every 6 h), 20 received a normal dose (2.5 mg/kg every 12 h), and 10 received a small dose, as determined by creatine clearance. For high, normal, and low doses of colistin, the nephrotoxicity rates were 40%, 35%, and 20%, respectively23. Proteinuria andoliguria may also be observed in patients with colistin nephrotoxicity18, 24.

TIGECYCLINE

Tigecycline is a protein synthesis inhibitor and belongs to the tetracycline modification of a new class known as a glycylcycline antibiotic. Tigecycline works on ribosomal unit 30s to inhibit the activity and disrupt the microbe activity, but it is inherited resistance against the most notorious gram-negative pathogen 25. Tigecycline is indicated in cIAIs, cSSSTIs, and community-acquired pneumonia (CAP). In 2011, Karaiskos reported that the susceptibility ratio of tigecycline was near 100% in 22005 isolates of carbapenem-resistant gram-ve rod isolates, but resistance is on the upsurge, as evaluations now show that practically 50% of isolates are nonsusceptible to tigecycline26. Currently, the usage of this antibacterial agent daily decreases because the emergence of resistance is increasing and the susceptibility ratio is decreasing in comparison to colistin, but tigecycline is still recommended in critically ill patients due to its renal-friendly property27, 28.

CRE is treated with a high dose of colistin, tigecycline, and fosfomycin as a combination regimen, these produce therapeutic effects29. In cases where alternatives are not available and tigecycline is used as a target therapy, high doses should be used to achieve adequate PK/PD results against polymicrobial infections30.

Fosfomycin

Fosfomycin was invented in 1969 and is active against gram +ve and gram –ve microbes with cell wall synthesis inhibitors. The mechanism of action of this antibiotic is the same as penicillin. Fosfomycin has excellent results against gram +ve (MRSA) and gram –ve (ESBL) pathogen causes. UTIs and LRTIs have excellent tissue penetration, such as lungs and cerebrospinal fluid3, 31. Fosfomycin is not tremendously cast off against MDR infections and bloodstream infections by CRE, and in patients receiving anti-XDR treatment, fosfomycin is still considered a recoup treatment for CR infections or a breakthrough infection treatment32, 33.

In a limited study of 48 critically ill patients with MDR infections who received fosfomycin at a dose of 8 g every 8 h for 14 days (mostly in a combination regime with tigecycline or colistin), the all-cause 28-day death rate was 37.5%32. When used to treat severe or systemic infections beyond the urinary tract, intravenous fosfomycin will most likely be combined with an antibiotic drug from another class (fluoroquinolones, glycopeptides, or glycolipopeptides). The intravenous fosfomycin combination partner was chosen based on the indication and the patient's particular clinical state. According to the kind of infections and microorganisms, fosfomycin can be coupled with any other antibiotic class. The primary reason for combining fosfomycin with a second antibiotic is to avoid the establishment of fosfomycin resistance and to expand the antibacterial spectrum. Combination treatment may potentially provide additive or synergistic activity/efficacy as well as appealing pharmacokinetic features for hard-to-reach compartments34, 35.

Ceftazidime and Avibactam (CAZ/AVI)

MDR-negative pathogens are a serious universal public health alarm. Carbapenem has become more widely used and reliant, as ESBL-producing pathogens are becoming more prevalent. There is a growing concern about carbapenemase-producing pathogens (gram –ve) and a near need for new antimicrobials36, 37, 38.

According to in vitro experiments, avibactam (novel beta-lactam inhibitor) can restore ceftazidime (third generation cephalosporin) antimicrobial activity against numerous Enterobacteriaceae that produce ESBL, AmpC, KPC, and OXA-48 and drug-resistant P. aeruginosa isolates39. Caz/Avi is intravenously administered in HAP, VAP, cIAI, cUTI, acute pyelonephritis, and LTO40. The biological activity of avibactam is broad, barring Ambler class A (TEM-1, CTX-M-15, KPC-2, KPC-3), C (AmpC), and D (OXA-10). It is not active against class B enzymes such as MBL41, 42, 43, 44, 45.

Caz/Avi was tested alongside isolates of and . . There were 99% inhibition rates for 36,380 isolates of Enterobacteriaceae species. MDR isolates accounted for 99.2%, and XDR isolates accounted for 97.8%. isolates, including MDR and XDR strains, were inhibited in 97.1% of cases46. In 2013, the REPRISE clinical phase 3 trial was conducted and monitored the therapeutic effects of CAZ/AVI in the field of different organ infections resistant to ceftazidime-resistant and , and the combination therapy showed the best therapeutic yield against these resistant pathogens47.

In the case of critically ill patients such as HAP and VAP, CAZ/AVI has been approved for treating pneumonia caused by gram-negative pathogens6. CAZ/AVI have linear PK/PD, and human protein binding is nearly 8 to 10%48. We consider CAZ-AVI to be the most important addition to our arsenal since it is the first stationary combination to be marketed with activity in contrast to KPC and OXA producers. Safety, clinical response, and survivability reports derived from genuine use are very encouraging in life-threatening and nonthreatening conditions. CAZ/AVI must be used as combination therapy and as monotherapy49, 50, 51.

In patients with a high hazard of MDR infections, CAZ-AVI is strong in empiric regimens since it also covers ESBL-producing and has substantial magnitudes against . On the basis of local epidemiological data, the presence of MBL-producing agents should be balanced with other antibiotics (colistin and tigecycline). To avoid irrational use, CAZ-AVI empiric use should be kept for patients with greater risk influences for infection by KPC- or OXA-48 fabricators.

Role of ASPs in the prevention of antimicrobial resistance

Antibiotic policies, antibiotic management programs, and antibiotic control policies are some of the terminology used to define antimicrobial steward programs (ASPs). Overall, these all narrate the healthcare institution's continual attempt to improve antibiotic usage among hospitalized patients to enhance patient outcomes, assure cost-effective therapy, and prevent undesirable consequences associated with antibacterial agent usage, such as antimicrobial resistance52. A collaborative strategy is needed, with an infectious disease physician and a clinical pharmacist with infectious disease training serving as key team members. It is necessary to work closely with a clinical microbiologist, an information system specialist, an infection control professional, and a hospital epidemiologist. The IDSA also created a recommendation for the development and operation of antimicrobial stewardship programs (ASP) in public sector hospitals53, 54.

According to ASPs after diagnosing the infection severity with the result and choosing the right antibiotic, complete treatment of duration with strong follow-up may reduce the hospital stay along with minimizing the antibiotic resistance.