Lakhasly

1.These bacteria differentiate into "persister cells." Persister cells are a subgroup of temporarily antibiotic-tolerant bacterial cells. They often have a slow or arrested growth and can continue growing after severe stress. They are associated with recurrent persistent bacterial infections. They are linked to an increased risk of AMR [43]. It has been found that children can be exceptional hosts of biofilms. They receive medical devices. The devices range from central venous catheters to complex heart defect patches. They also include ventriculoperitoneal shunts. These devices can be a formidable breeding ground for biofilms and bacteria. Antibiotics can't reach them. These may predispose to long-term infections. Sometimes, the only definitive treatment is removing and replacing the device. Generally, many infections in children are linked to biofilms. This happens even when no medical devices are present. Biofilms have also been found in the nasopharynx of children affected with repeated upper airways and middle ear infections. This may explain the frequent lack of efficacy of antibiotic therapy in these cases [44]. In particular, biofilms have been recognized as responsible for recurrent acute otitis media. They also cause otitis media with effusion. This finding may be explained by evidence that otitis media with effusion often has a negative culture. However, molecular research for pathogens is often positive. It is often unresponsive to antibiotics and highly recurrent. Moreover, children with chronic rhinosinusitis are more likely to have biofilms. This is more common than in children without an underlying condition. It's also more common than in children with acute rhinosinusitis. Researchers found mature biofilms in 95% of adenoids removed from children with chronic rhinosinusitis (45). Chronic conditions, like cystic fibrosis (CF), cause serious illness and early death. This happens because people with these conditions frequently get long-lasting infections. These infections may result from the disease's precise cause. They may also result from frequent and prolonged hospital stays. The chronic use of multiple antibiotics raises the chance of MDR. In particular, pediatric CF patients seem to harbor different opportunistic infections compared to adults. This is because different bacteria use type VI secretion systems to compete with each other [46]. This also impacts antibiotic treatment in young and adult CF patients. It may explain the emergence of AMR. 3. Emerging Threats The WHO recently published a list of bacteria for which new antimicrobials are urgently needed [47]. This comes from observing a progressive decrease in the R&D pipeline of new antibiotics. This is in dire contrast with the concerning rise of resistant infections. Pediatric antibiotics research and development needs oral formulations for community-acquired infections with high morbidity. We need oral antibiotics for drug-resistant ESBL-producing Enterobacteriaeceae, Neisseria gonorrhoeae, and Salmonella typhi. 3.1. Resistant Staphylococcus Aureus Strains of MRSA were first identified as a threat in adult patients in the 1960s. MRSA infections were uncommon in children until the 1990s. Infections in adults and children, with no prior risk factors or healthcare contact, began to show resistant strains [48]. Thus, healthcare-acquired MRSA (HA-MRSA) began circulating together with community-acquired MRSA (CA-MRSA). [49]. Trimethoprim-sulfamethoxazole and clindamycin are often used in the treatment of CA-MRSA. Resistance to trimethoprim/sulfamethoxazole is relatively uncommon. However, clindamycin resistance has increased in the past decade [49]. Doctors often apply mupirocin ointment to the anterior nares. They often also use chlorhexidine baths. This helps to eradicate MRSA carriage and limit its spread. Since these practices started, resistance to mupirocin and chlorhexidine have emerged [50]. Vancomycin has long been considered the last resort for treating MRSA infections. However, in 1997, the first strain of vancomycin-intermediate susceptible Staphylococcus aureus (VISA) was isolated from a surgical wound of a Japanese child. The child's infection did not respond well to long-term vancomycin therapy [51]. Since then, vancomycin resistance has cast a dark shadow on anti-MRSA antibiotic treatment. This is especially true for children. Their therapeutic options remain few, including daptomycin and linezolid. Nonetheless, daptomycin is of no use in treating lung infections. It binds surfactant, which inactivates it [52]. Interestingly, ceftaroline is often overlooked. It is effective against MRSA. It maintains cephalosporin's safety. It has a wide range of uses, whether on or off label [53]. It has been approved for children older than two months of age. No widespread resistance has been identified so far. 3.2. ESBL-Producing Enterobacteriaceae (ESBL-Ent) and Carbapenem-Resistant Enterobacteriaceae (CRE) In the U.S.A., there has been a significant increase of ESBL-Ent infections in children. This increase is correlated with the spread of MDR ST131 CTX-M-producing E. coli strains [54]. The acquisition of ESBL-Ent varies greatly. It depends on country, age, healthcare exposure, organism, and ESBL genotype. International studies in hospitals show an increase in ESBL-Ent colonization. For this population, risk factors include younger gestational age, low birth weight, antibiotic use, and prolonged mechanical ventilation [55]. Outside the neonatal age, risk factors for ESBL-Ent infections are similar to those of adults. These factors include antibiotic use, chronic clinical conditions, healthcare access, and recurrent infections [56]. Neurological diseases might be a predisposing risk for the pediatric population [57]. Therapeutic options for ESBL-Ent include piperacillin-tazobactam, ceftazidime-avibactam, cefepime, fluoroquinolones, aminoglycosides, tigecycline, fosfomycin, and carbapenems. However, safety profiles and dosage guidelines often limit these options for children. Consider carbapenem-sparing strategies first to combat their overuse. When possible, use a step-down strategy after empirical therapy. There might be decreased sensitivity to carbapenems. This might be because of carbapenemases, which are ?-lactamases. They break down penicillins (cephalosporins, carbapenems, and monobactams). It might also be because of the production of ESBL or downregulated porins. Resistance to carbapenems in pediatric populations has dramatically increased in recent decades. The 2013 CDC report described this as an urgent threat. It highlighted a 50% mortality rate in hospitalized patients with bloodstream CRE infection [16]. A significant increase in CRE frequency was noted in some pediatric populations, especially for the Enterobacter species. The frequency increased from 0% in 2000 to 4.5% in 2012, particularly in ICU settings [58]. Therapeutic options for CRE are few. Pediatric options are further limited. The use of tigecycline is carefully weighed for people <18 years of age due to its safety profile. Colistin and other polymyxins have optimal dosing issues for the pediatric population. Oral fosfomycin may be used for CRE bladder infection. Dosing guidelines are available only for older children and adolescents [59]. Moreover, ESBL-Ent and carbapenemase-producing bacteria often carry other plasmid-transmitted genes. These genes also confer resistance to aminoglycosides, sulfonamides, and fluoroquinolones. This characteristic makes these bacteria true MDROs [60]. 3.3. Colistin Resistance In the mid-1990s, the rise of MDR Gram-negative bacteria pushed clinicians to reconsider old, disused antibiotics. This included fosfomycin and, more interestingly, colistin. A plunge in new antimicrobials production active towards them also played a role. [61]. After being introduced, colistin was quickly replaced in the 1970s. Newer, safer parenteral antibiotics took its place. This was because of reports of nephrotoxicity and neurotoxicity [62]. When colistin use decreased in the 1980s, resistance to it had hardly been documented, and resistance mechanisms were still unclear [63]. However, after this drug was reintroduced in clinical pediatrics as salvage therapy for difficult-to-treat MDR Gram-negative infections, resistance patterns were noticed and reported for the first time. A resistance to colistin encoded in chromosomes had been reported. Over the past decade, scientists have described intrinsic mutations and adaptive mechanisms. They also discovered an mcr-1 gene. This gene confers resistance through plasmid transfer. In conclusion, we need to preserve colistin activity. It's one of the very last few drugs that work against carbapenem-resistant Gram-negative organisms. It should be used in very few clinical cases. Keep in mind its complicated PK and narrow therapeutic window. This is especially true in pediatric patients. 4. Future Perspectives: Stepping Back from the Edge 4.1. Overcoming To control AMR, first implement an antimicrobial stewardship strategy. This is needed in acute care, long-term care, and outpatient care settings. Antimicrobial stewardship involves coordinated interventions. These are designed to improve and measure the appropriate use of antibiotic agents. It does this by promoting the selection of the best drug regimen. This includes dosing, duration of therapy, and route of administration" [65].Specifically, pharmacokinetics investigations should be conducted in addition to safety and efficacy trials to identify the optimal dose regimen for different age groups rather than assuming adult dosages.o prevalence of broad-spectrum agents use o discontinuation or de-escalation of antibiotics according to microbial culture results o rates of antibiotic use by ward, hospital or nation o early switch from parenteral to oral therapy o good documentation of the reason for prescription in the patient's medical charts o <24 h perioperative administration of antibiotics for surgical prophylaxis.Additional clinical trials are required to validate the efficaciousness of other new antibiotics, such as ceftolozane/tazobactam [71], tedizolid [72], and dalbavancin [73], which are exhibiting intriguing results in the paediatric population.Furthermore, even for outdated medications that are resurfacing in wards as a potential defence against MDR infections, the scientific community as a whole ought to be dedicated to doing pharmacokinetic studies in paediatric populations.Diverse and interconnected causes link to it. Even though Alexander Fleming warned the scientific and medical community about antibiotic overuse in 1945, an era of antibiotic abuse started after World War II. It affected agriculture, livestock, veterinary, and human medical practices.In 2012, the Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) group obtained detailed information on antibiotic use in hospitalized neonates and children from a multicenter retrospective cohort study for the first time.The scarcity of specific pediatric clinical trials on antibiotics and the common practice of complete or partial extrapolation of adult pharmacokinetic and pharmacodynamics (PD) data to the pediatric population contribute to a lack of high-evidence-level knowledge and strictly pediatric guidelines.New Antibiotics for Children A few novel antibiotics, such ceftaroline [68,69] and ceftazidime/avibactam [70], have been approved for use in paediatric patients as part of the therapeutic arsenal to combat multidrug-resistant infections.Furthermore, third-generation whole genome sequencing (WGS) technologies are available in the majority of modern diagnostic centres and can be used to quickly detect infections and screen for genes related to drug susceptibility [67].In order to attain the proper concentrations and prevent the establishment and spread of antimicrobial resistance, it is also crucial to determine the optimal antimicrobial dose based on customised pharmacokinetic characteristics.o Regular auditing and reviewing of local antimicrobial prescriptions; o Pharmacodynamics/pharmacokinetic-guided dosing, considering physiological developmental processes of the child.In 2006, the American Academy of Pediatrics (AAP) recommended using fluoroquinolones only in these three cases: (1) FDA-approved uses, (2) MDROs with no other safe or effective option, and (3) when a patient can't take oral fluoroquinolones and all other options are intravenous.Pediatric patients with gastrointestinal infections, acute otitis media, sinusitis, lower respiratory tract infections, pneumonia, or Mycobacterium infections [37] may consider them.Known mechanisms of antimicrobial resistance, such as modifying enzymes, target mutations, and efflux pumps, do not seem to protect bacteria in biofilms.Furthermore, it is imperative to firmly encourage pharmaceutical companies to involve children in clinical trials related to the pharmacological development of novel antibiotics.The Food and Drug Administration (FDA) and European Medicines Agency (EMA) Guidance Documents [30,31] provide highly detailed information on this method.Two Modern Infection-Predisposing Issues: Biofilms and Chronic Conditions Biofilms are associated with chronic subsequent infections and inherent resistance to antibiotic therapy.The EMA Guidelines on the role of pharmacokinetics in developing medicines for children recommends finding markers that show changes in drug processing as the body matures.Antibiotic Overuse and Misuse in Hospitalized Children and Outpatient Care The most important cause of the modern expansion of antibiotic resistance is the improper use of antibiotics [21,22].Additionally, antibiotics are still commonly prescribed for wrong diagnoses, such as viral infections, especially in outpatient care [23,24,25].The ARPEC study found high use of amikacin in neonates admitted to hospitals in Western Europe, Southern Europe, Asia, and Latin America.Regulatory agencies widely endorse using the population PK-PD method on this population.Another proposed approach to characterize drugs' uptake, effects, and pharmacokinetics (PK) in this population is the physiologically based pharmacokinetic (PBPK) model.A third mechanism of antibiotic resistance is when a subpopulation of bacteria in a biofilm shifts to a unique, highly protected phenotypic state.Rapid Diagnosis Empirical treatments are the culprit for antibiotic misuse and overuse.To understand the significance of the threat from AMR, WHO estimated that MDR bacteria cause 700,000 deaths globally.Antibiotic-resistant bacteria cause 66% of neonatal sepsis and meningitis in Sub-Saharan Africa [5].The prevalence of multidrug-resistant organisms (MDROs) is surging up. Affected patients experience significant illness and death.Furthermore, medical malpractice contributed to selecting MDR strains of bacteria.Researchers analyzed more than 17,000 pediatric hospital admissions in 226 hospitals from 41 countries worldwide.This may be due to a high incidence of ESBL-producing or carbapenem-resistant Gram-negative organisms.Posology and Dose Appropriateness for the Pediatric Age The pediatric population deserves pharmacological treatments that meet their needs.As knowledge on pediatric developmental physiology grows, drugs will be prescribed to children with greater accuracy, efficacy, and safety.When it's essential to use tetracycline, there's limited evidence that reducing the total dose and length of exposure may help.Most cases of antibiotic-resistant biofilm infections are not explained by conventional antibiotic resistance mechanisms.The team includes infectious disease specialists, clinical pharmacologists, microbiologists, and pediatricians.In the Middle East, 90% of newborns with sepsis have resistant bacteria when hospitalized in ICU [3].During treatment for MDR Gram-negative bacteria, 20% of pediatric patients in a U.S. study developed resistance to colistin [6].The WHO projected that, if this trend continues, drug-resistant diseases could cause 10 million deaths by 2050.The roots of improper antibiotic use are the poor knowledge of pathogens associated with different infections.However, the high level of empirical broad-spectrum antibiotic use may indicate that at least a portion of this prescribing may be inappropriate.However, a striking regional difference in antibiotic prescribing was observed among hospitalized children older than 28 days.These were mainly benzylpenicillin, sulfamethoxazole/trimethoprim, amoxicillin, and gentamicin.Children in Eastern and Southern Europe, Asia, North and Latin America received more broad-spectrum antibiotics.In conclusion, the 2016 ARPEC study identified potential quality indicators of correct antimicrobial use in pediatric populations.Strategies to optimize pediatric dosing have been proposed to prevent ethical issues and specific pediatric difficulties.It has provided more specific indications on the effects of maturation on absorption, elimination, and effects of antibiotics.Using a tetracycline with lower calcium-binding, like doxycycline, may reduce the risk of tooth discoloration.Bacteria in biofilms persist by tenacious survival, not aggressive virulence.This suggests an inherent antibiotic resistance due to the peculiar habitat created by this film of cells.A rapid diagnosis is essential for managing infectious disease correctly.For antimicrobials to be managed optimally, a fast analysis that can determine the etiological agent and provide answers for susceptibility testing is necessary.This is especially true when it comes to paediatrics, where pharmacokinetic variability needs to be carefully taken into account and intervention time is crucial.Introduction Antimicrobial resistance (AMR) is one of the most important public health threats worldwide.In parts of Southeast Asia, 83% of children have E. coli resistant to first-line antibiotics [4].In the USA alone, doctors and hospitals have spent an estimated 2.39 billion dollars treating MDR infections [11,12].Additionally, people lack understanding of the specific antibiotic classes' pharmacokinetic and pharmacodynamic characteristics.Such inappropriate use was also found by Levy et al. The authors attributed the increase to failure to stop or reduce treatment.In poorer and resource-limited settings, de-escalation is less considered.Nonetheless, successful de-escalation of carbapenems has been reported in these settings [27].In Asian hospitals, meropenem was prescribed to many newborns.Many African, Australian, Western European, and Northern European children kept getting older.It seems that resource-limited settings favor using older narrow-spectrum antibiotics.These treatments should be appropriate in prescription, safety, posology, and efficacy profiles.This is especially true when considering the great pediatric variability of pharmacokinetics (PK).It includes premature and neonates, and infants and children to adolescents.The variability in kidney function development directly correlates with highly diverse drug clearance in pediatric patients.These strategies aim to address concerns in conducting trials with this population [29].In particular, the population pharmacokinetic-pharmacodynamics method is ideal for this population.This model combines the developmental physiological processes of children with adult PK data.It also needs pediatric-specific information on the anatomical, physiological, and biochemical variables from birth to age 18.They also recommend using PBPK models in the design of pediatric clinical trials [33,34].Contraindicated in Children: Sometimes, It Is a Matter of a Lack of Options It is also relevant to note that some antibiotics have precise contraindications for children.The potential occurrence of these severe arthropathies has limited the use of fluoroquinolones in children.Fluoroquinolones have been successfully used in a variety of pediatric infections.They have also successfully treated community-acquired MRSA, malaria, and acne.Another adverse event, tetracycline-induced photosensitivity, is worth noting.The AAP recommended using tetracycline in pediatric infections.The indications include rickettsial infections, cholera, and anthrax.This is due to bacteria adhering to damaged tissue or implanted medical devices.Treatment often fails because biofilm infections require high doses of antibiotics for a long time.The first hypothesis is that the antibiotic may slowly or incompletely penetrate the biofilm [41].They can draw up local guidelines, provide advice on antimicrobial use, and implement educational interventions.Quick and accurate antimicrobial susceptibility testing (AST) is essential.This evolution favors implementing new rapid AST diagnostic tools.Researchers are validating methods and equipment that apply nucleic acid amplification.This will enable us to use the right dosage, preventing the development of new resistances and protecting the limited number of new weapons we have available.This occured through unnecessary, inappropriate, or suboptimal prescribing.Doctors have observed this in 30% to 60% of the antibiotic therapies given to outpatients.When a new antibiotic enters the market, we can observe the time until MDROs appear for that drug.The estimated annual cost for healthcare systems and gross domestic product loss is $300 billion [1,7].We looked at its emerging threats and potential strategies to overcome it. These are compelling reasons.The Roots of Antibiotic Resistance in Childhood Children receive antibiotics more often than any other type of drug.These range from common urinary tract infections to less frequent meningitis.These features highly influence and affect drug choice, correct doses, posology, and duration of a treatment course.This happened in pediatric intensive care units (PICUs) and pediatric wards.However, developed countries, including hospitals, prefer to prescribe new-generation antibiotics.It is important to extrapolate drugs' efficacy data to the pediatric population.This reduces the need for pediatric efficacy trials.However, dose-finding and safety pediatric trials are still crucial.There are not enough pediatric clinical trials on antimicrobials.It can also lead to the development of antibiotic-resistant bacterial strains.The complex variability of PK comes from the great range of pediatric age groups.The most prominent differences, compared with adults, are in neonates and infants.Moreover, tubular secretion is immature at birth.Developmental pharmacology has advanced in recent decades.However, additional studies are needed to better understand PK and PD in children.It is a promising method to support first-time dosing studies in children [32].Advocates have suggested using PBPK models to support first-time dosing in children.Recent advances in developmental pharmacology have not eliminated the strong need for more research.This research should focus on drug metabolizing enzymes, transporters, receptor systems, and disease course.These antibiotics have shown irreversible adverse events on cartilage development in young animals.They cause inflammation and disruption of weight-bearing joints [35,36].These events are clearly reported in various pediatric studies.Adults' resistance to fluoroquinolones has worsened significantly in the past 25 years.This trend may become an important concern in the pediatric population due to persistent use.Thus, this class of antibiotics is relatively contraindicated in children younger than eight years old.It usually manifests as a photosensitive rash, similar to an intense sunburn.The permanent tooth discoloration is a sufficient reason to avoid prescribing these antibiotics to young children whenever possible.They advised this when the benefits outweigh the risks of adverse events.In fact, when bacteria are dispersed from the biofilm, they usually become sensitive to antibiotics.The second hypothesis is that an altered chemical microenvironment within the biofilm is responsible [42].In pediatrics, precision dosing is extremely important, especially for antimicrobial therapy.Clinical practice should use software that predicts the correct drug dosage.They integrate mass-spectrometry and biosensor-based AST.All healthcare workers and institutions should consider it a high priority.In Europe, MDR infections in pediatric patients may represent up to 30% of the total cases [2].Infections caused by MDR bacteria are more difficult to treat.These infections raise the risk of death by up to 40% in MDR hospital-acquired infections [7,8,9,10].This abuse was the leading driver of the evolution of resistance in bacteria [13,14].It also occurs in some inpatients in some studies [15,16].These behaviors are accelerating an already quick natural selection of MDROs.Vancomycin had the longest time without resistance, 16 years.It's because MDR bacteria populations are in their gut.We must promote antimicrobial stewardship to limit this burden on our society.We conducted a review on the current pediatric AMR.They are frequent subjects of infections of various causes.They showed a high level of broad-spectrum antibiotic use in certain regions.Bacteriological cultures are performed less often.They continued to take narrow-spectrum antibiotics.Mainly, they received third-generation cephalosporins and carbapenems.The practice of extrapolation often causes antibiotic misuse.Age-related physiological development continues into childhood and adolescence.The glomerular filtration rate increases quickly through the first two weeks of life.Then, it rises steadily until adult rates are reached at 8-12 months of age [28].This will ensure that antibiotic prescriptions meet the best standards of care.It describes both the average behavior of a homogeneous population.It also describes the differences between individuals.It requires adult PK parameters.This affects the range of antibiotics available to treat infections.They compare fluoroquinolones to non-fluoroquinolone treatments.Another concern about using fluoroquinolones is that they can lead to more bacterial resistance.They are effective for treating cystic fibrosis exacerbations.However, most evidence supporting their use in children comes from small, uncontrolled studies.Benefits and risks of this antibiotic therapy must be carefully weighed.They are largely unused in the pediatric age.Some warnings for tooth discoloration in children were already reported in 1956 [38].In older children, tetracyclines have successfully treated respiratory infection.Taking it less often reduces the risk of dental staining [40].Biofilm infections can linger for months or even years.They are rarely fatal but often resist antibiotic treatment.In a pediatric context, actions must be taken to avoid AMR.For this purpose, the following steps are recommended: An institutionalized team of experts was created.It accounts for drug characteristics, developmental changes, and clinical condition.Thirteen percent of antibiotic therapies are started inappropriately.A more severe and prolonged illness leads to longer hospital stays for them.This also comes with a financial cost that affects healthcare systems.This problematic present condition threatens our future.But for penicillin, the interval drops to only two years.The more recent daptomycin and ceftaroline drop to only one year.Without urgent actions, we are heading towards a post-antibiotic era.Common infections may once again become fatal.This leads to selective antimicrobial pressure after birth.This is particularly true also for newborns younger than a week.This is probably due to exposure to bacteria in the environment.We must also halt antibiotic abuse in any field.They found that 6499 inpatients received at least one antimicrobial.These offer a broader spectrum.They use weight or body surface area as the only discerning indicator.This can lead to a relative risk of toxicity.These strains are specific to the pediatric age.It reaches adult function throughout the first year of life.Additionally, there are practical difficulties to consider when working with such a specific age group.These include child-friendly formulations and feeding regimens.It only requires a few samples per patient at flexible times [29].For instance, fluoroquinolones remain largely not used in children due to safety concerns.Tetracyclines are another class of antibiotics.This event is more likely to occur during the tooth-calcification process.Phototoxicity can represent a significant concern.They suggest prescribing doxycycline.Three main hypotheses may explain this phenomenon.This could allow for individualized dosing between people [66].It could also allow for individualized dosing within the same person over time [66].They are not correctly identifying the cause [13].It prevents the spread of AMR.To date, technologies are evolving.Around 200,000 of these are newborns [1].This is especially true for children.They often get common infections.Part of this variability is age-dependent.They offer the best standard of care to this important population.It can also lead to over- or under-dosage.This is especially true when considering kidney function.It is extremely variable and age-dependent.It is especially important for children with underlying conditions.Tetracyclines were first introduced in 1948.The process finishes by age eight.These actions should reverse the current trend.It also helps choose the right antimicrobial agent at the right time.It is a current issue.[17,18].2.2.1.2.2.2.3.2.4.4.2.4.3.

1. Introduction
   Antimicrobial resistance (AMR) is one of the most important public health threats worldwide. It is a current issue. All healthcare workers and institutions should consider it a high priority.
   To understand the significance of the threat from AMR, WHO estimated that MDR bacteria cause 700,000 deaths globally. Around 200,000 of these are newborns [1]. In Europe, MDR infections in pediatric patients may represent up to 30% of the total cases [2]. In the Middle East, 90% of newborns with sepsis have resistant bacteria when hospitalized in ICU [3]. In parts of Southeast Asia, 83% of children have E. coli resistant to first-line antibiotics [4]. Antibiotic-resistant bacteria cause 66% of neonatal sepsis and meningitis in Sub-Saharan Africa [5]. During treatment for MDR Gram-negative bacteria, 20% of pediatric patients in a U.S. study developed resistance to colistin [6].
   The prevalence of multidrug-resistant organisms (MDROs) is surging up. Affected patients experience significant illness and death. Infections caused by MDR bacteria are more difficult to treat. A more severe and prolonged illness leads to longer hospital stays for them. These infections raise the risk of death by up to 40% in MDR hospital-acquired infections [7,8,9,10]. This also comes with a financial cost that affects healthcare systems. In the USA alone, doctors and hospitals have spent an estimated 2.39 billion dollars treating MDR infections [11,12].
   This problematic present condition threatens our future. Diverse and interconnected causes link to it. Even though Alexander Fleming warned the scientific and medical community about antibiotic overuse in 1945, an era of antibiotic abuse started after World War II. It affected agriculture, livestock, veterinary, and human medical practices. This abuse was the leading driver of the evolution of resistance in bacteria [13,14]. Furthermore, medical malpractice contributed to selecting MDR strains of bacteria. This occured through unnecessary, inappropriate, or suboptimal prescribing. Doctors have observed this in 30% to 60% of the antibiotic therapies given to outpatients. It also occurs in some inpatients in some studies [15,16].
   These behaviors are accelerating an already quick natural selection of MDROs. When a new antibiotic enters the market, we can observe the time until MDROs appear for that drug. Vancomycin had the longest time without resistance, 16 years. But for penicillin, the interval drops to only two years. The more recent daptomycin and ceftaroline drop to only one year. [17,18].
   Without urgent actions, we are heading towards a post-antibiotic era. Common infections may once again become fatal. This is especially true for children. They often get common infections. This leads to selective antimicrobial pressure after birth. This is particularly true also for newborns younger than a week. It's because MDR bacteria populations are in their gut. This is probably due to exposure to bacteria in the environment. It's also from their mother during and after birth [19,20]. The WHO projected that, if this trend continues, drug-resistant diseases could cause 10 million deaths by 2050. The estimated annual cost for healthcare systems and gross domestic product loss is $300 billion [1,7]. We must promote antimicrobial stewardship to limit this burden on our society. We must also halt antibiotic abuse in any field.
   We conducted a review on the current pediatric AMR. We looked at its emerging threats and potential strategies to overcome it. These are compelling reasons.


2. The Roots of Antibiotic Resistance in Childhood
   Children receive antibiotics more often than any other type of drug. They are frequent subjects of infections of various causes. These range from common urinary tract infections to less frequent meningitis.
   2.1. Antibiotic Overuse and Misuse in Hospitalized Children and Outpatient Care
   The most important cause of the modern expansion of antibiotic resistance is the improper use of antibiotics [21,22]. The roots of improper antibiotic use are the poor knowledge of pathogens associated with different infections. Additionally, people lack understanding of the specific antibiotic classes' pharmacokinetic and pharmacodynamic characteristics. These features highly influence and affect drug choice, correct doses, posology, and duration of a treatment course. Additionally, antibiotics are still commonly prescribed for wrong diagnoses, such as viral infections, especially in outpatient care [23,24,25].
   In 2012, the Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) group obtained detailed information on antibiotic use in hospitalized neonates and children from a multicenter retrospective cohort study for the first time. Researchers analyzed more than 17,000 pediatric hospital admissions in 226 hospitals from 41 countries worldwide. They found that 6499 inpatients received at least one antimicrobial. They showed a high level of broad-spectrum antibiotic use in certain regions. This may be due to a high incidence of ESBL-producing or carbapenem-resistant Gram-negative organisms. However, the high level of empirical broad-spectrum antibiotic use may indicate that at least a portion of this prescribing may be inappropriate. Such inappropriate use was also found by Levy et al. The authors attributed the increase to failure to stop or reduce treatment. This happened in pediatric intensive care units (PICUs) and pediatric wards. In poorer and resource-limited settings, de-escalation is less considered. Bacteriological cultures are performed less often. Nonetheless, successful de-escalation of carbapenems has been reported in these settings [27]. The ARPEC study found high use of amikacin in neonates admitted to hospitals in Western Europe, Southern Europe, Asia, and Latin America. In Asian hospitals, meropenem was prescribed to many newborns.
   However, a striking regional difference in antibiotic prescribing was observed among hospitalized children older than 28 days. Many African, Australian, Western European, and Northern European children kept getting older. They continued to take narrow-spectrum antibiotics. These were mainly benzylpenicillin, sulfamethoxazole/trimethoprim, amoxicillin, and gentamicin. Children in Eastern and Southern Europe, Asia, North and Latin America received more broad-spectrum antibiotics. Mainly, they received third-generation cephalosporins and carbapenems. It seems that resource-limited settings favor using older narrow-spectrum antibiotics. However, developed countries, including hospitals, prefer to prescribe new-generation antibiotics. These offer a broader spectrum.
   In conclusion, the 2016 ARPEC study identified potential quality indicators of correct antimicrobial use in pediatric populations.
   • prevalence of broad-spectrum agents use
   • discontinuation or de-escalation of antibiotics according to microbial culture results
   • rates of antibiotic use by ward, hospital or nation
   • early switch from parenteral to oral therapy
   • good documentation of the reason for prescription in the patient’s medical charts
   •