Resistance to carbapenems among Acinetobacter spp., especially Acinetobacter baumannii, poses a global threat to healthcare systems due to the wide variety of antimicrobial agent resistance. Acinetobacter spp. are pathogens found in hospital settings; they pose a significant threat to hospital patients, employees, and the general public via their ability to cause pneumonia, bloodstream infections, and potentially lethal wounds. These pathogens cause infections with high mortality rates due to the presence of less effective drugs against these pathogens. Carbapenems are not effective against CRAB, and because of horizontal gene transfer (HGT), these CRAB are empowered with various carbapenem-resistant mechanisms, such as beta-lactamase production. CRAB can readily mutate, thereby developing multidrug resistance (MDR). CRAB can undergo HGT and mutations in genes involved in the production of carbapenem-hydrolyzing beta-lactamases, which are termed metallo-beta-lactamases (MBLs) and OXAs. Finally, they fortify the bacterial cell by changing the outer membrane porins in a way that renders carbapenem entry very difficult.¹ Moreover, efflux pumps limit the amount of medications that bacteria may store in their bodies. The intricate process of carbapenem-resistance involves multiple genetic alterations, making it challenging to overcome.²

Figure 1 shows the processes that lead to infections caused by CRAB.³ This emphasizes the role of genetic resistance factors in causing infections and deaths. Therefore, novel drugs and improved treatment techniques are urgently needed.⁴ Because of widespread reports of CRAB resistance, the presence of this microbe in intensive care units (ICUs) has prompted grave concerns about the spread of MDR pathogens, particularly CRAB. Anyone from the most developed nations to the least developed ones may find CRAB. The misuse of antibiotics, due to lack of knowledge on how to use them correctly, is a leading source of multidrug-resistant bacteria. The spread of CRAB is also a major concern worldwide because the resistance patterns are also found in communities and places other than hospitals.⁵ Hence, research on CRAB and how to address it has become very important before it becomes a major threat to the human race. Because carbapenem-resistant Acinetobacter is present in most of the public places, it can easily infect a person or worsen a sick person’s condition, incurring high medical bills. Once CRAB develops MDR, it can worsen a patient’s condition because of ineffective medications. Shortage of effective drugs against CRAB makes treatment difficult for the patients. Due to the lack of an effective vaccine, controlling and eradicating this Acinetobacter is difficult.⁶ To prevent MDR, effective research is needed on preventing the spread of CRAB.

Overview of Acinetobacter spp.
Soil, water, and healthcare facilities can host Acinetobacter spp. Acinetobacter spp. are aerobic coccobacilli that are oxidase-negative, non-motile, Gram-negative, and prevalent in the Earth’s ecosystem. Among the Acinetobacter spp., A. baumannii is the most hazardous. It is commonly isolated in healthcare facilities. The presence of this substance in the hospital environment poses a significant risk to patients who have already been hospitalized for other medical conditions are listed in Table 1. A. baumannii causes ventilator-associated pneumonia (VAP) and may infect the bloodstream, urinary tract, or wounds. Only a small fraction of the over 50 species with names pose any real threat to humans. The Acinetobacter baumannii, complex (ACB complex), which includes A. baumannii, Acinetobacter calcoaceticus, and Acinetobacter nosocomialis, is notoriously difficult to identify and halt mutations in using the standard and conventional procedures used by the vast majority of labs. Recently, species-level identification has been enhanced by molecular approaches, such as polymerase chain reaction (PCR) and mass spectrometry-based identification, Matrix-Assisted Laser Desorption/Ionization – Time of Flight.  (MALDI-TOF). Their presence on dry surfaces and resistance to desiccation are the most harmful and spreadable traits. Thus, it can be concluded that this trait aids them during nosocomial epidemics. From the most dangerous (Acinetobacter baumannii) to the least dangerous (Acinetobacter lwoffii and Acinetobacter calcoaceticus), all Acinetobacter species are listed in Table 2, along with the illnesses they cause and their clinical relevance. This highlights their functions in healthcare-associated infections particularly in patients with impaired immune systems.

Table (1): General characteristics of Acinetobacter spp.

Table (2): Clinically relevant Acinetobacter species and associated infections

Figure 2 illustrates the clinically relevant Acinetobacter species, highlighting their varying levels of pathogenicity and the types of infections they cause, from severe hospital-acquired infections to opportunistic infections in immunocompromised patients.⁷

Importance of carbapenem-resistance in Acinetobacter
Acinetobacter infections are treated with carbapenem antibiotics, such as imipenem and meropenem. However, Acinetobacter has recently developed significant resistance to older and more rudimentary antibiotics, and this has become a great concern for communities worldwide. Due to alterations in membrane permeability and efflux pump overexpression, as well as the production of carbapenemases, namely OXA-type beta-lactamases and MBLs, Acinetobacter has evolved significant resistance against antibiotics.

Currently, CRAB leaves very little scope for treatment as it is nearly resistant to most of the available antibiotics on the market. The combination usually used for treatment is colistin and tigecycline, which can have many side effects and can be toxic. Due to the resistance shown by CRAB, the mortality rate, hospital expenses, and healthcare costs increase.⁸ Therefore, the World Health Organization (WHO) has identified CRAB as a global health concern and is allocating substantial resources to the research and development of novel antibiotics that may play a pivotal role in the eventual eradication of Acinetobacter.

For the removal and stoppage of Acinetobacter, the world must come and work together for global surveillance, enhanced diagnostic capabilities, and advanced methods to prevent the spread of infections. There is also a need to closely monitor day-to-day advancements in the resistance of CRAB and study the molecular mechanisms of CRAB for developing more effective drugs against Acinetobacter.

Objectives of the review

1. To investigate the taxonomy, microbiological traits, and clinical relevance of Acinetobacter species, with an emphasis on A. baumannii and its function in healthcare-related illnesses.
2. To investigate the biochemical and molecular processes underlying carbapenem-resistance in Acinetobacter species, including the functions of plasmid-mediated resistance genes, carbapenemases, efflux pumps, and porin mutations.
3. To examine worldwide epidemiological trends and the transmission of Acinetobacter strains resistant to carbapenem, emphasizing geographical distribution, resistance patterns, and risk factors that contribute to the formation and spread of clones that are resistant to multiple drugs.
4. To assess new therapeutic approaches, infection control procedures, antimicrobial stewardship, and future research directions, as well as existing and developing methods for the prevention, management, and treatment of carbapenem-resistant Acinetobacter infections.

Microbiology of Acinetobacter spp.
General characteristics of Acinetobacter
The bacterium Acinetobacter spp. is characterized by its lack of motility, aerobic metabolism, oxidase resistance, and catalase activity. The important characteristic of these bacteria is that they can adapt to environmental conditions, such as low temperature, high salinity, and desiccation. Due to these, Acinetobacter can live in the hospital environment of the ICU, which can prove fatal to hospital patients. There are almost 50 species of Acinetobacter, and the most common and devastating of them is A. baumannii, which has greater resistance to antibiotics and a high power to mutate itself according to the surroundings or antibiotics, thus causing a lot of infections to human beings than with any other Acinetobacter.

The Gram-negative outer membrane, which comprises the cell wall of Acinetobacter spp. aids in the development of resistance to several anti-bacterial medications. In addition to protecting catheters and ventilators from infection, CRAB (Acinetobacter spp.) forms biofilms on these tools, thereby increasing the risk of infection in hospitalized patients. Acinetobacter acquires resistance capabilities as a consequence of the genetic material that contributes to the formation of antibiotic resistance genes, which in turn produce clinical pathogenicity.⁹

Identification and classification of Acinetobacter species
Using Gram staining, biochemical tests, and antimicrobial susceptibility patterns, the Acinetobacter species can be easily identified and classified. The aforementioned phenotypic methods are not effective for all species because many species have overlapping characteristics. Multiple molecular methods, including PCR tests, 16S rRNA gene sequencing, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), have been used to determine the species of these Acinetobacter bacteria are included in Figure 3.

Differentiating between several species of Acinetobacter, most notably the Acinetobacter calcoaceticus-baumannii (ACB) complex, using conventional techniques is impossible.¹⁰ A. baumannii is the most common cause of illness because it is the most harmful Acinetobacter species. Although less dangerous, other ACB complex species, including Acinetobacter calcoaceticus and Acinetobacter nosocomialis, are important in clinical practice. Molecular typing methods such as pulsed-field gel electrophoresis and multilocus sequence typing (MLST) are used to monitor Acinetobacter strains that have developed resistance to many drugs and to obtain a better knowledge of the epidemiology of this bacterium. The key Acinetobacter species and the clinical importance of their identification techniques (e.g., PCR, MALDI-TOF MS, and biochemical assays) are included in Table 3 and Figure 4. Although Acinetobacter lwoffii is rarely pathogenic, A. baumannii is widely recognized as a significant nosocomial pathogen. This species causes opportunistic infections and infections in the respiratory system and urinary tract.¹¹

Table (3): Key Acinetobacter species and identification methods

Beta-lactamase production (Class A, B, C, and D)
A. baumannii can render carbapenems ineffective against most CARB by hydrolyzing their beta-lactam ring via the development of beta-lactamases. Serine beta-lactamases are classified into class A, MBLs into class B, ampC-type beta-lactamases into class C, and oxacillinases into class D. Class B MBLs and class D OXA-type beta-lactamases are the most prevalent kinds of beta-lactamases. Horizontal bacterial gene transfer occurs through plasmids or transposons. Most carbapenemases are of the OXA type. For example, the MBLs of the OXA-23, OXA-24, and OXA-58 varieties hydrolyze a variety of beta-lactams with relative ease. The presence of carbapenemases reduces the efficacy of antibiotics.¹²

OXA gene expression is facilitated by insertion sequence elements (ISs), such as ISAba1, ISAba4, and ISAba125, which provide strong promoters. CRAB contains virulence factors that affect disease progression. The global distribution of A. baumannii emerged in the 1970s through ‘international clones of high risk’ (ICs), with IC1 and IC2 first identified in nosocomial infections. GenBank data on the IC1-IC9 outbreaks show IC2 was the most prevalent CRAB clone. In South America, CRAB is linked to OXA-23 carbapenemases through clones IC1 (CC1), IC4 (CC15), IC5 (CC79), and IC7 (CC25), with IC2 (ST2) present across countries.

Intrinsic resistance occurs via bacterial outer membrane-blocking drugs and chromosomal AmpC β-lactamases. Acquired resistance includes: i) production of carbapenem hydrolyzing class D β-lactamases ii) metallo-β-lactamases (NDM 1) iii) aminoglycoside modifying enzymes within Figure 5. The RND family efflux pumps expel antimicrobials, whereas resistance develops through gyrA and parC mutations. These resistance determinants spread via HGT through plasmids, integrons, and transposons, leading to MDR organisms.¹³

Porin channel mutations and reduced permeability
Porins were identified as the mechanisms responsible for carbapenem-resistance. The porin channels in the outer layer of Acinetobacter are highly permeable to small molecules and antibiotics. The Acinetobacter spp. makes the porin channels to reduce the influx of carbapenems and other antibiotics through various mutations, which causes antibacterial drug resistance and leads to a lot of infections in the human race.¹² These mutations often occur in the carO gene, which encodes a major porin protein involved in carbapenem uptake. The reduction of these porins, which leads to increased resistance to MDR and carbapenems, is a direct result of the overuse and abuse of antibiotics.

Efflux pumps and their role in resistance
The antibiotic resistance in Acinetobacter is caused by efflux pumps. Due to efflux pumps, a large number of antibiotics and carbapenems are discharged or ejected from the bacterial cell body, thus making these antibiotics of no use. The Ade family of efflux pumps, particularly the AdeABC pump, plays a significant role in monitoring various antibiotics such as carbapenems, fluoroquinolones, and aminoglycosides.¹⁴

Genetic factors contributing to resistance
Some genetic factors, such as plasmids, transposons, and integrons, are responsible for carbapenem-resistance in Acinetobacter. Due to HGT, MDR strains are rapidly formed in bacteria, making them resistant to antibiotics. Mechanisms such as beta-lactamase production, efflux pump overexpression, and porin mutations are providing the power to Acinetobacter to develop multiple resistance mechanisms. These mechanisms enable Acinetobacter to adapt to various antimicrobial agents and to survive in different environments.

Role of HGT in resistance spread
HGT is the primary cause of MDR in Acinetobacter species. Conjugation, transformation, and transduction allow the rapid transmission of resistant genes from one species to another. The presence of HGT in hospitals is the main cause of the development of MDR Acinetobacter bacteria. The presence of OXA-type beta-lactamases or MBL in Acinetobacter or CRAB is responsible for the rapid transmission of these MDR strains.¹⁵

Global trends in carbapenem-resistant Acinetobacter infections
A. baumannii is a rising threat to Indian healthcare. In India, A. baumannii has become a major healthcare pathogen, with alarming antibiotic resistance rates. Infections are more prevalent in tertiary care hospitals and ICUs. An analysis of a North Indian tertiary care facility found that Gram-negative bacteria predominantly cause nosocomial infections. In India, from 307 clinical specimens, A. baumannii was mainly isolated from endotracheal tubes (44.95%). Biofilm formation occurred in 66.78% of the isolates, correlating with MDR status. International Clone II emerged as the predominant lineage in Indian hospitals in 2023, associated with high antibiotic resistance. A literature review assessed the prevalence, resistance trends, and risk factors of A. baumannii infection. In India, A. baumannii caused 22.3% of hospital-acquired pneumonia cases, with carbapenem-resistance exceeding 70%. New Delhi Metallo-β-lactamase (NDM)-producing strains have increased the challenge, with MDR strains rising to 74.7%. In China, A. baumannii accounts for 35.7%-52.7% of hospital-acquired pneumonia cases, with carbapenem-resistance above 70% and MDR strains reaching 63.8%.¹⁶

Epidemiology of CRAB
Nosocomial pathogens, such as CRAB, cause infections in hospitalized patients and are often discovered in ICUs. From various studies, we found that the incidence of CRAB in hospitalized patients has increased manyfold in Asia and Europe. For example, the carbapenem-resistance rate in A. baumannii surpassed 50% in many European nations, according to a surveillance report from the European Centre for Disease Prevention and Control (ECDC, 2022). In nations such as China and India, the prevalence of CRAB is above 60%.¹⁵

Infections of the urinary tract and bloodstream, as well as ventilator-associated pneumonia, are the most common CRAB infections. Patients with compromised immune systems are more likely to develop infections than healthy individuals. Patients often end up paying more for their healthcare because of the increased length of stay in the hospital.¹⁷ From 2021 to 2023, the prevalence of CRAB in India is 68%, followed by China with 63%, Italy with 54%, Brazil with 48%, and the USA with 34%.

Geographic distribution of resistance
The global distribution of CRAB depends on antimicrobial usage, infection control measures, and healthcare infrastructure. In Europe, the states and countries situated in the Eastern and Southern regions have a higher percentage of MDR cases than the Western and Northern regions. For example, the percentage of patients infected with CRAB is higher in Greece and Italy,¹⁸ while countries such as Sweden and Norway have lower percentages of MDR CRAB infections.

In the USA, the CRAB presence can be seen in hospitals and nursing homes (CDC, 2021). The Southeast Asian and Middle Eastern countries have more cases of MDR due to misuse and overuse of antibiotics and the presence of less effective laws.¹⁹ The WHO has classified CRAB as a “priority 1: critical pathogen” under its global priority.²⁰

Information on the worldwide spread of CRAB is provided by the Global Antimicrobial Resistance and Use Surveillance System (GLASS), an international organization. In addition, this group has called on people worldwide to unite in the battle against CRAB.

Impact on healthcare systems and patient outcomes
The impact of CRAB on patients is increased hospital bills the length of stay in the hospital increases. Moreover, lives of patients infected with CRAB are at stake. Majority of mortality is due to the presence of CRAB in the bloodstream, accounting for almost 40% of mortality.²¹ More powerful antibiotics, such as colistin, are used for the treatment of the CRAB; however, they have various side effects associated with them.

The financial strain on patients and their families is significant, as hospital expenses increase with extended hospitalization. Mortality rates for CRAB are also elevated due to the absence of effective and safe antibiotics currently available to prevent or treat MDR. Hospitals facing CRAB outbreaks are required to implement costly infection-control measures, such as intensified disinfection, patient cohorting, and staff education, which further strain healthcare resources.²²

Clinical implications of carbapenem-resistant Acinetobacter
Resistance in hospital and community settings
Previous studies have concluded that CRAB is a pathogen that is especially found in hospitals; however, recent research suggests that CRAB is also found in community settings. Hospital ICUs are best suited for their presence because of the various invasive devices and antibiotics. The rate of spread is higher in hospitals because of the presence of contaminated and used medical equipment with which healthcare workers are constantly in touch.²³ In some of the cases, it was found that the CRAB cases are being found in individuals who do not have any hospital exposure, which suggests the presence of contamination in water and soil.²⁴ These emerging cases outside the hospital setting pose significant challenges to containment and early diagnosis.

Associated infections (e.g., Pneumonia, bloodstream infections)
Infections of the wound, blood, urinary tract, and VAP are all possible complications of catheter-associated bloodstream infections (CRAB). The death and morbidity rates are higher in patients with VAP. Because of its ability to establish biofilms on endotracheal tubes, A. baumannii is difficult to eradicate.²⁵ Some investigations have shown that CRAB infections in the bloodstream had a death rate of about 60%.²⁶ Because of immune clearance mechanisms, CRAB develop a high degree of resistance to a wide variety of antibiotics, making it very difficult to treat infections caused by these bacteria.²⁷

Table (4): Major infections caused by CRAB and clinical outcomes

Table 4 highlights major infections caused by CRAB, including VAP, BSI, UTI, and wound infections, along with their common sites. The associated mortality rates vary significantly, with bloodstream infections showing the highest fatality.²⁸

Treatment challenges and therapeutic options
A. baumannii resistance to piperacillin/tazobactam has increased to 56.8%, consistent with studies from the Asia-Pacific and the Middle East reporting 50%-60% resistance rates. Ciprofloxacin resistance surged to 68%, reflecting a global trend of 65%-70%. Colistin, as a last-line defense against MDR organisms, showed a low resistance rate of 0.8%, although increased use may lead to higher resistance. Aminoglycoside resistance also increased. These patterns significantly affect clinical practice, necessitating greater reliance on current local resistance data and emphasizing the importance of antibiotic stewardship.²⁹

Because very few antibiotics are available for the treatment of CRAB, there is an urgent need to conduct more research on CRAB and MDR. For the time being, we use colistin, tigecycline, and cefiderocol, all of which have various adverse effects associated with them. Colistin is a last-resort antibiotic; however, its nephrotoxicity limits its long-term use. Newer agents, such as cefiderocol, have shown promise; however, clinical data on their long-term efficacy remain limited.²⁸

As a last resort, doctors may prescribe a combination medication that includes colistin and either meropenem or rifampin, in a specific ratio, to treat CRAB.³⁰ In various cases, it was also found that all the methods used for the treatment of CRAB proved ineffective due to the strong resistance shown by CRAB.³¹ Some of the modes of treatment that are still in the experimental stage are bacteriophage therapy, antimicrobial peptides, and immunotherapies.³² Enhanced techniques for the elimination of illnesses caused by the Acinetobacter bacteria and other preventative measures will have to be used until a viable CRAB therapy is found.

Diagnostic approaches for carbapenem-resistant Acinetobacter
Conventional and molecular methods
Two methods are used: the conventional diagnostic approach and the molecular diagnostic approach. Under the traditional methods, we used MacConkey agar and biochemical tests (oxidase reactions and carbohydrate assimilation) for bacterial identification. The only real issue with automated systems, such as BD Phoenix and VITEK 2, is they may sometimes provide false positives when the species are very close, despite their high speed and accuracy for quick identification. Manual disc diffusion and broth microdilution are the techniques of choice for determining the minimum inhibitory concentrations against Acinetobacter spp.³³ Resistance genes such as bla_OXA-23, bla_OXA-24, bla_NDM, and bla_VIM may be detected using molecular methods such as PCR, real-time PCR, and multiplex PCR. Compared to other approaches, such as phenotypic tests, which are used to identify carbapenemase genes, the aforementioned methods tend to be more sensitive and precise. Loop-mediated isothermal amplification (LAMP) and DNA microarrays, which are advanced molecular methods, are becoming popular owing to their simple and rapid results.³⁴

According to a few studies, molecular analysis revealed a high prevalence of bla_OXA-23 in 94.4% CRAB isolates, indicating its dominant role in carbapenem-resistance. bla_NDM-1 was identified in 53% of the isolates, and all bla_{NDM 1}-positive isolates also contained bla_OXA-23, indicating the co-existence of multiple carbapenemase genes. These findings align with the evidence that OXA-type carbapenemases and MBLs are the principal mechanisms of carbapenem-resistance in A. baumannii, particularly in South/Southeast Asia. Similar co-occurrence has been reported in India, Nepal, and Algeria. Although MBLs are less common in developed countries, their prevalence in developing regions, often in combination with other carbapenemase genes, is well-documented. Since its identification in India, bla_NDM-1 has spread globally, accounting for most cases in Asia.

Sequencing analysis confirmed accurate gene amplification with high sequence identity, validating the assay reliability. Minor mismatches and deletions in the non-coding regions indicated allelic variation among the isolates. High sequence conservation suggests evolutionary pressure to maintain the functional integrity of resistance determinants. Similar conservation patterns have been reported in other regions, highlighting the need for molecular surveillance to monitor variants and support infection control.³⁵

Table (5): Comparison of diagnostic methods for crab

Table 5 compares various diagnostic methods for detecting CRAB based on principles, time, sensitivity, and specificity. Rapid molecular techniques, such as PCR and LAMP, offer high accuracy and speed, whereas traditional culture methods remain reliable but slow.³⁴

Challenges in detection
Medical professionals encounter numerous obstacles when identifying CRAB. Phenotypic methods struggle to detect low-level or novel resistance, making this a significant challenge. Advanced techniques often fail to include all pertinent carbapenemase genes in databases, leading to inaccurate results. The use of heterogeneous expression can exacerbate mixed infections. Additionally, genotypic methods require specialized equipment and expertise, which limit their use in resource-poor areas. Another significant issue for contemporary medical teams is the absence of standardized molecular protocols that are crucial for the accurate diagnosis of infections. The ongoing mutation and emergence of new variants, such as bla_OXA-235 and bla_OXA-72, further complicate diagnostic processes.³⁵ The medical community seeks diagnostic tools that are cost-effective, rapid, and capable of distinguishing between colonization and infection.

Advances in diagnostic technologies
Whole-genome sequencing (WGS) is essential to phylogenetic connections, resistance genes, and virulence factors. Because of high cost and lengthy processing time, WGS is only used for CARB monitoring and investigation.³⁷ Because of the development of MALDI-TOF MS, the detection of bacterial infections has become much easier. It takes only a minute for it to recognize many different species. Modern applications include the identification of protein biomarkers associated with resistance.³⁸ Rapid and accurate identification of resistance genes is being achieved using CRISPR-based diagnostics such as SHERLOCK and DETECTOR. Therefore, thermal cyclers are not necessary. As a portable and easily managed method, nanopore sequencing allows us to monitor CRAB in real time in hospitals.³⁹

Table (6): Emerging diagnostic technologies for CRAB

Table 6 and Figure 4 outline⁴⁰ emerging diagnostic technologies for CRAB, highlighting innovations such as WGS, MALDI-TOF MS, CRISPR-based assays, and nanopore sequencing. These methods offer advanced detection capabilities with varying advantages and limitations in terms of speed, accuracy, and accessibility.⁴⁰

Control and prevention strategies
Infection control measures in healthcare settings
Medical professionals employ infection prevention and control (IPC) technologies to prevent CRAB infections in hospitals. In this strategy, hospital personnel maintain strict hygiene by cleaning their hands properly and at regular intervals, cleaning instruments and objects present in the hospital environment, using personal protective equipment, and separating the patient from the rest of the patients and hospital staff. MDR Acinetobacter spp. has the capability to stay and live on the dry surface for a long duration of time without being damaged; hence, to stop it from spreading, the hospitals should be cleaned properly with the use of sodium hypochlorite or hydrogen peroxide.⁴⁰ Additionally, surveillance cultures and cohorting of patients help contain outbreaks effectively.⁴¹

The spread of nosocomial CRAB infections can be significantly decreased with the help of a strict precaution system and active screening. Hospital staff should be trained and educated to maintain strict hygiene within the ICU and hospital surroundings.⁴² Regular monitoring and audits of IPC adherence should further strengthen these efforts.

Antimicrobial stewardship programs
For the removal and stoppage of the infections, antimicrobial stewardship programs (ASPs) are also used. In these programs, medical professionals initially impose certain restrictions, then conduct audits and await feedback, and finally, propose prescribing based on the guidelines. During ASP, it is advised not to use carbapenems and cephalosporins, which can increase the rates of mutations and MDR in CRAB.⁴³

Medical professionals use de-escalation of empirical therapy, which involves combining pharmacokinetic and pharmacodynamic (PK/PD) approaches to treat infections to increase therapeutic effectiveness. For crucial implementation, various teams of ASP have been formulated, which are a combination of infectious disease physicians, pharmacists, and microbiologists.⁴⁴

Development of new antimicrobials and alternative therapies
Cefiderocol, a siderophore cephalosporin, is an essential component in the treatment of infections that are resistant to carbapenems.⁴⁵ The medical experts are conducting clinical trials of some of the combinations, such as sulbactam-durlocactam and meropenem-vaborbactam, to overcome resistance caused by class D carbapenemas.⁴⁶

Medical experts are investigating a range of alternative therapies, including bacteriophage therapy, antimicrobial peptides, and CRISPR. Bacteriophage therapies have shown significant effectiveness against A. baumannii.⁴⁷ Additionally, immunomodulatory therapies that focus on host-pathogen interactions are being studied.

Role of vaccines in prevention
It is a fact that we do not have any vaccines against these CRAB; however, medical researchers are trying their best to discover a vaccine against these infections. Outer membrane proteins (OMPs), such as OmpA and OmpW, have provided very good results against these CRAB.⁴⁸ To generate long-term immunity in patients and medical staff, scientists are also developing live-attenuated and conjugate vaccines.

The most important challenges faced by these vaccines are:

1) Antigenic variability and
2) Lack of strong immunity. With a successful vaccine, the rate of infection can be easily decreased.⁴⁹

Future directions in combatting carbapenem-resistant Acinetobacter
Research on new resistance mechanisms
To protect the world from the threats of A. baumannii we must develop a mechanism that can better understand the resistance mechanism of CRAB. Various studies have shown the determination of new variants, bla_OXA-235 and bal_OXA-72, which are better equipped with efflux pump overexpression and porin modifications.⁵⁰ The medical experts and researchers can decode the unrecognized resistance determinants and mobile genetic elements with the help of WGS, which makes the method easy for horizontal gene transfer. These findings highlight the need for continuous molecular monitoring in diagnosis and therapy.

Novel therapeutic approaches and drug development
Cefiderocol and sulbactam-durlobactam are two antibiotics that have shown promising outcomes in preventing CRAB infections and are currently in the penultimate stage of clinical testing. Cefiderocol and sulbactam-durlobactam are part of the Therapeutic Innovation Approaches.⁵¹ The popularity of phage therapy is also reaching a new height because of its precision and ability to easily penetrate the defense resistance mechanism of CRAB. Moreover, antimicrobial peptides and immunotherapeutics, including monoclonal antibodies targeting virulence factors such as OmpA, are being studied as adjunctive or stand-alone therapies.⁵² These approaches, combined with PK/PD-based dosing strategies, offer promising avenues for treatment.

Global collaboration for surveillance and control
Global cooperation is essential for the effective control of CRAB. The entire world must come together and combat the infections caused by CRAB. The WHO introduced GLASS to enhance global data sharing. Medical researchers have initiated collaborative research networks and public private partnerships to develop robust mechanisms for detecting and curbing the spread of CRAB.⁵³ Additionally, ensuring access to quality diagnostics and improved treatments is crucial for eradicating CRAB worldwide.