Consensus Recommendations.

Neonatal meningitis constitutes a health emergency, and as soon as it is suspected, empirical antibiotic treatment should be indicated. A large part of the reviews and consensuses maintain the ampicillin plus an aminoglycoside regimen as the first management alternative in early-onset meningitis, based on the involvement of GBS, Escherichia coli, and Listeria monocytogenes. However, due to the difficulty in achieving adequate concentrations in the tissue of the central nervous system, the use of aminoglycosides is increasingly questioned. Level of evidence II-2, Degree of recommendation A

The late-onset presentation should cover organisms from the nosocomial setting, especially those in neonatal intensive care units, including multidrug-resistant Klebsiella, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. Level of evidence II-2, II-3 and III, Degree of recommendation A

Since the eighth edition of the book “Infectious Diseases of the Fetus and Newborn Infant” by Remington and Klein [73], it is recommended that the empirical use of cefotaxime or meropenem in neonates should be restricted to cases of meningitis or isolation of Gram-negative bacteria. This situation has given rise to a shift in management recommendations, especially in countries where Gram-negatives are predominantly the cause of sepsis and meningitis. Level of evidence III, Degree of recommendation A

In cases of suspected late-onset nosocomial meningitis, where the participation of methicillin-resistant Staphylococcus aureus, as well as negative-coagulase Staphylococcus and the Enterococcus genus, in addition to Gram-negatives such as Klebsiella / Enterobacter spp, and Pseudomonas, among other pathogens, the regimen of vancomycin plus cefotaxime or meropenem is recommended as an adequate alternative. Level of evidence I, II- 2, III. Degree of recommendation A

A significant number of other rare agents reported each year worldwide as causative agents of meningitis in newborns, including Salmonella spp, Elizabethkingia meningoseptica, Serratia marcescens, among others [74-77], should be analyzed individually, and if possible, with the advice from an expert in infectious diseases or microbiology to determine treatment. The latter must be adjusted based on the same reported sensitivity profile or on the analysis of the published international experience. Level of evidence II-2, III. Degree of recommendation A

Antibiotics must be administered as soon as possible. Prior to starting antibiotics, blood cultures and lumbar punctures should be performed for both culture and cytochemical study, with the intention of having elements to corroborate the diagnosis or adjust the antimicrobial regimen specifically to the isolated microorganism.

Regarding the time that antimicrobials should be mantained, the various studies agree that the management time for Gramnegative meningeal infections should be maintained for a minimum period of three weeks. Despite the latter, a retrospective review study in China showed that the use of third-generation cephalosporins with an average of 19 days, only had a success of 77.1%. Therefore, each case must be studied individually, and both microbiological and clinical responses must be evaluated before withdrawing the treatment [78]. In the case of some Gram-positive strains such as Streptococcus, the schemes can be shortened to 14 days. There is evidence that schemes shorter than these present a greater risk of complications or relapses. Level of evidence III Degree of recommendation A

Question 7. What is the recommended antibiotic treatment for cases of bacterial neonatal pneumonia?

Neonatal pneumonia is an infection that affects the lung parenchyma of the newborn and is associated with significant morbidity and mortality. Its incidence is variable, depending on the conditions of each institution and country [79].>

Its presentation can be congenital, as well as identified as early or late. Congenital or early-onset pneumonia usually presents within the first 72 hours of life, and is acquired from the mother through the following mechanisms:

• Intrauterine aspiration of infected amniotic fluid, transplacental transmission from the maternal circulation.

• Aspiration during or immediately after delivery of amniotic fluid and/or infected vaginal secretions.

• Organisms present in vaginal secretions can colonize the newborn and, depending on the conditions of the newborn, invade the lower respiratory tract and cause pneumonia.

Late-onset pneumonia presents after 3 days of life and can occur during hospitalization or after hospital discharge. It is generally caused by microorganisms present in the hospital environment (nosocomial) and transmitted by infected newborns, infected personnel, or contaminated ventilation equipment. Microorganisms can enter through solutions of the rupture of the defense mechanisms in the tracheal or bronchial mucosa, the use of assisted ventilation devices, or through the bloodstream [80].

Its clinical presentation generally presents with data of earlyonset respiratory distress, which can be associated with lethargy, apnea, tachycardia, dysthermia, and poor tissue perfusion. In late-onset pneumonia, the clinic is characterized by deterioration of the newborn’s baseline condition, which includes nonspecific signs such as apnea, tachypnea, anorexia, abdominal distension, jaundice, vomiting, respiratory distress, and signs of shock.

Patients who are ventilated may present a deterioration in their respiratory condition with an increase in oxygen requirements and ventilatory parameters, associated with mucopurulent secretions in bronchial aspiration [79-82].

The etiology may depend on various factors such as maternal colonization, the season (community pneumonia), as well as the hospital microbiota.

In countries such as the US, the main causal agent of early pneumonia continues to be Streptococcus agalactiae, based on the high levels of maternal vaginal colonization by this pathogen. In Mexico, enterobacteria such as Escherichia coli and Klebsiella spp. Are the main pathogens responsible for early pneumonia, although some cases of infection by Streptoccocus agalatiae, Streptococcus pneumoniae, and Listeria monocytogenes, have been reported sporadically [70,71,83,84].

In cases of late-onset pneumonia, S. aureus, S. epidermidis, K. pneumoniae, P. aeruginosa, among other pathogens, should be considered as the possible etiological agents.

In neonatal pneumonia, there is a component of early infection with the late presentation, usually after the second week of birth, which includes Chlamydia trachomatis and mycoplasma infections [80].

There are few randomized clinical studies of treatment for neonatal pneumonia., Therefore, there is a need to establish an empirical antibiotic regimen in situations of clinical suspicion, without microbiological or radiological confirmation since the appearance of consolidations can be delayed until the following 72 hours of clinical onset [86].

The decision should be based on the isolation patterns and antimicrobial resistance known locally or regionally in each population or institution, associated with the clinical data presented by each patient [87].

In cases where the pathogen is detected in blood cultures or in bronchial aspirates, the antibiotic scheme should be adjusted according to the antibiogram report.

In cases of early pneumonia, the regimen is the one that covers the most common germs (ampicillin association) and an aminoglycoside (gentamicin or amikacin) as the first choice.

In late infections of nosocomial origin, the ideal is to prescribe a combination of antibiotics for which the most frequent germs of each service are sensitive. In these cases, the use of cefotaxime plus vancomycin may be considered, mainly for coverage against methicillin-resistant S. aureus or coagulase-negative Staphylococcus. Nonetheless, in cases in which the participation of agents with resistance to third-generation cephalosporins is suspected, the adjustment must be carried out under the supervision of an expert in infectious diseases and based on the known evidence on the microbiological profile of each unit.

In relation to the recommended time for the antibiotic management of neonatal pneumonia, these times have been managed arbitrarily most of the time, using 10 to 14 days [88].

In cases of mild community-acquired pneumonia (CAP) in newborns, a controlled clinical trial compared the effect of a 4-day course (testing group) with a 7-day course (control group) of antibiotic regimen on the treatment success rate. The infants were randomized to receive a total of 4 days of antibiotics (Group 1) or 7 days of antibiotics (Group 2). The outcome measure was treatment failure in each group within 3 days of discharge. This study reported that the treatment success rate of both groups was 100%, concluding that for infants who become clinically asymptomatic within 48 h of antibiotic therapy, the 4-day schedule of antibiotic therapy is effective and safe as 7 days, with a significant reduction in hospital length-of-stay, antibiotic use, and cost [88].

Concerning to pneumonia due to “atypical” microorganisms, a randomized placebo-controlled study found that the use of clarithromycin resulted in the eradication of Ureaplasma urealyticum [89]. Therefore, in patients treated with suspected or diagnosed infection by Ureaplasma urealyticum, other mycoplasmas, or Chlamydia trachomatis, it is recommended to start intravenous treatment with Clarithromycin at a dose of 7.5 mg/kg/dose/12 hours.

Consensus Recommendations

In cases of early pneumonia, when the recommended antibiotic regimen as the first option is ampicillin + aminoglycoside (gentamicin or amikacin, preferably in a daily dose), and when the response is adequate, its recommended duration should not exceed 7 days. Level of evidence II-3, III Degree of recommendation A

In late infections of nosocomial origin, the ideal is to prescribe a combination of antibiotics for which the most frequent microorganisms are sensitive.

Daily or routine tracheal aspirate cultures and chest radiographs are not recommended for neonates with pneumonia. The case should be individualized based on clinical symptoms and risk factors, and the results should be interpreted with caution.

Level of evidence III, Degree of recommendation D

In patients with suspected or diagnosed infection by Ureaplasma urealyticum, or Chlamydia trachomatis, it is recommended to start intravenous treatment with Clarithromycin. Level of evidence I. Degree of recommendation B.

Question 8. What is the recommended antibiotic treatment for necrotizing enterocolitis in newborns, and what is the ideal time of treatment?

Between 2 to 5% of all infants admitted to the NICU develop necrotizing enterocolitis (NEC), with 90% of them being premature. This disease occurs in 2% to 8% of very low birth weight (VLBW) infants.

Approximately 20% to 40% of these neonates may require surgical intervention. The mortality rate varies from 20% to 35%, and 25% of survivors experience long-term sequelae, such as poor growth, bowel syndrome, and intestinal stricture [90].

The most widely used definition in the field is through the modified Bell scale. Nonetheless, it is not a definition, but a staging based on an already made diagnosis; with the problem being that the criteria include signs and symptoms with variations in sensitivity and specificity that are not consistent with the importance of the diagnosis (e.g. feeding intolerance and blood in stools). The latter causes the over or underestimation of the disease [91,92].

In VLBW newborns, Bell scale grade I symptoms such as oral intolerance and abdominal distention are common normal findings, or they are part of other conditions such as sepsis. For this reason and purposes of this consensus, we recommend the use of antibiotics in NEC using the modified Bell scale, from stage ≥ II [93].

The clinical manifestations associated with NEC are food intolerance, abdominal distension, and bloody stools after 8 to 10 days of age. The first imaging signs that should lead to suspicion of necrotizing enterocolitis include dilated intestinal loops and gas shortage. Pathogmonomic findings on abdominal radiography are pneumatosis intestinalis, portal venous gas, or both.

In diagnostic aids, thrombocytopenia stands out with a rapid decrease as a sign of progression to a poor prognosis, alterations in the blood count (leukopenia or leukocytosis), elevation fo acute phase reactants C-reactive protein and procalcitonin, as well as peripheral blood cultures that can be positive in 30% to 35%. Furthermore, glycemic changes, hyponatremia, alterations in coagulation times (PT and PTT), and arterial blood gases (metabolic acidosis) can be added [94].

The infectious etiology of NEC usually have a polymicrobial component, where the microorganisms involved are the microbiota found in the large intestine, including Escherichiacoli, Klebsiella/ Enterobacter, Citrobacter, Serratia, Acinetobacter, Pseudomonas, Salmonella, coagulase-negative Staphylococcus and Staphylococcus aureus. Moreover, anaerobes such as Clostridia, Bacteroides, some mycoplasmas and viruses have also been described for this pathology, as well as the participation of fungi [95].

Medical management includes medical care with empiric antibiotic therapy to prevent disease progression and surgical intervention. However, there is no evidence-based consensus regarding empiric therapy or timing surgery. In a systematic review, no antibiotic regimen was found to be superior to ampicillin and gentamicin in decreasing mortality or preventing clinical deterioration, among 3,161 patients from 2 controlled and 3 observational studies, in which 3 studies evaluated the addition of anaerobic coverage, and one observational study included the comparison with cefotaxime and vancomycin [96].

In another Cochrane systematic review, where the efficacy of different antibiotic schemes on mortality, and the need for surgery in neonates with NEC was compared, selecting all randomized and quasi-randomized clinical trials where antibiotics were used for the treatment of NEC. We found that, in one of the trials, 42 preterm infants received IV ampicillin & gentamicin or ampicillin, gentamicin and clindamycin. The results found no statistically significant difference in mortality (RR 1.10; CI 95%, 0.32 to 3.83), or bowel perforation (RR 2.20; CI 95% 0.45 to 10.74) between both groups, but there was a greater tendency towards stenosis in the group that received clindamycin. In another trial, 20 neonates received intravenous ampicillin and gentamicin with or without gentamicin, with no significant difference in mortality, intestinal perforation, or development of stenosis [97].

The empiric antibiotic regimen should provide coverage for the common pathogens of late-onset neonatal sepsis. In addition, in events of peritonitis or pneumoperitoneum suggestive of intestinal perforation, coverage should be provided to anaerobes.

Consensus Recommendations

The recommended treatment guidelines are as follows:

• Stage I Necrotizing Enterocolitis: Do not administer antibiotic treatment.

• Stage II A-B Necrotizing Enterocolitis: A-B coverage for gram-negative and positive bacteria (Ampicillin and gentamicin for 7 days).4 Level of evidence II-1 Degree of recommendation A

• Stage III A-B Necrotizing Enterocolitis or proven perforation: Add a third antibiotic with anaerobic coverage. Level of evidence II-1 Degree of recommendation A

• Option 1: Ampicillin, gentamicin, and metronidazole for 7 to 10 days or 3 to 5 days after surgical resolution. Level of evidence II-1

• Option 2: Piperacillin/Tazobactam monotherapy; consider in patients without evidence of shock. Level of evidence II-1

• Limit the use of carbapenems to situations of: necrotizing enterocolitis with septic shock in patients with extended-spectrum beta-lactamase-(ESBL) producing Enterobacteriaceae. Level of evidence I Degree of recommendation A

• In those cases, in which the clinical evolution is favorable, the blood culture is negative, the tests are of low infectious risk, and the symptoms can be attributed to other non-infectious causes: the antibiotics will be withdrawn after 48-72 hours.

• When microbiological isolation is achieved by cultures, treatment should be directed according to the sensitivity profile and, where appropriate and possible, de-escalate the antibiotic. Level of evidence I Degree of recommendation A

Question 9 What antifungal must be recommended, based on the best evidence, for the empirical treatment of patients suspected of invasive fungal infections in the neonatal stage?

Invasive fungal infections in NICUs are the second leading cause of infection-related mortality in critically ill newborns, especially in premature infants, and those with very low birth weight (<1500 g), presenting also a health problem due to the associated morbidity. Nearly 50% of surviving neonates will have serious long-term neurodevelopmental deficits, including cerebral palsy, hearing or cognitive impairment, eye damage, or periventricular leukomalacia; especially among the lowest gestational age and lowest weight at birth [98-100].

Neonatal invasive fungal infection is largely synonymous with invasive Candida infection; however, cases due to other fungi such as Malassezia, Aspergillus and Zygomycetes are being increasingly reported [98-100].

Invasive candidiasis is the third most common cause of late-onset sepsis in patients with very low birth weight, and a significant cause of morbidity and mortality in NICU. Its incidence varies from 0.5% to 20% and is inversely correlated with birth weight [101].

The most common species of neonatal candidemia is Candida albicans, being isolated in 60 to 75% of infections, followed by Candida parapsilosis, with 14 to 30% of isolates. Other species like C. tropicalis, C. lusitaniae, C. glabratay C. kruseison are much less frequent [98-101].

The main risk factors for the development of neonatal invasive fungal infections are those linked to premature birth and low weight, such as: gestational age <28 weeks, and weight <1500g, the use of parenteral nutrition, prolonged use of a central venous catheter, mechanical ventilation, prolonged length-of-stay in the NICU, use of corticosteroids, delay in enteral feeding, and biological factors such as the presence of persistent neutropenia, hyperglycemia, and thrombocytopenia, but are particularly associated with the use of broad-spectrum antibiotics in multiple schemes or prolonged periods [102-104].

The clinical features of invasive candidiasis in the newborn are nonspecific, indistinguishable from those caused by late-onset neonatal sepsis. They may include lethargy, apnea, respiratory distress, cardiovascular instability and/or feeding intolerance. It can present as candidemia, urinary tract infection, and/or as the compromise of any other tissue. A syndrome particularly unique to preterm infants is Hematogenous Candida Meningoencephalitis (HCME). Up to 25% of invasive candidiasis in premature newborns are associated with meningoencephalitis, even if they do not present obvious neurological symptoms. Although the latter condition is the most frequent, central nervous system diseases caused by Candida can also present in the form of brain abscesses, ventriculitis, and vasculitis [103,104].

PERSISTENT CANDIDEMIA AND NEURODEVELOPMENTAL IMPAIRMENT

Neonates frequently present with persistent candidemia (positive blood cultures for more than 72 hours in a patient receiving specific therapy). Candidemia, especially when present for more than 5 days, can spread to multiple organs such as kidneys (5-30%), heart (5-15%), eyes (3-50%), bones, joints, skin, and lungs. What favors the appearance of serious complications is the dissemination to different organs and systems. When the central nervous system is affected, studies have shown that up to 73% of low birth weight infants die or show signs of impaired neurodevelopment up to 18 to 22 months of follow-up [105-107].

The proper use of antifungals in the neonatal population is important for both the prevention and treatment of Invasive Fungal Infection (IFI). To maximize the activity of antifungal agents and minimize toxicity in this vulnerable population, the isolation, location, hemodynamic, stability, and extension of the infection should be assessed when choosing treatment. Because central nervous system involvement is common in newborns, a drug that crosses the blood-brain barrier and with fungicidal activity must be selected. It is also important to know if there is a urinary tract infection, which is a frequent situation in newborns and that will condition the optimal use of a drug with good diffusion in urine [108,109].

Studies of the extension of the infection are recommended: lumbar puncture, eye fundus examination, echocardiography, and abdominal ultrasound in all cases of candidemia and also renal ultrasound in the case of candiduria. Replacement of the intravascular catheter is also recommended [106,109,110].

Antifungals that have been used for the management of invasive fungal infections in newborns are grouped into four categories [110] (Table 4). Unlike in adults and non-neonatal pediatric patients, newborns tolerate these quite well, including drugs such as Amphotericin-B Deoxycholate, without significant nephrotoxic effects. On the other hand, drugs such as echinocandins do not easily reach therapeutic concentrations, mainly in the urinary tract and the central nervous system [98,109,111].

In any premature neonate with clinical suspicion or microbiological evidence of invasive candidiasis, a disseminated disease should be assumed and therefore a thorough clinical examination should be carried out. Particularly, it is of the utmost importance to consider the possibility of HCME, so in antifungal therapy, central nervous system coverage should be considered [112].

The epidemiology files of the Maternal and Perinatal Hospital “Mónica Pretelini Sáenz” and the Children’s Hospital of the State of Mexico show an increase in the number of cases of fungal infection in the neonatal period in the last two years (Tables 4 & 5)

Source: Epidemiology files of the Perinatal Hospital “Mónica Pretelini Sáenz” and the Children’s Hospital of the State of Mexico.

Source: Epidemiology files of the Perinatal Hospital “Mónica Pretelini Sáenz” and the Children’s Hospital of the State of Mexico.

Consensus Recommendations

Most of the revised guidelines suggest the use of Amphotericin B-Deoxycholate as first-line and two drugs as second-line with their respective considerations: Liposomal Amphotericin B (in the presence of urinary tract involvement it is not recommended) and Fluconazole which is recommended in patients in whom azole prophylaxis has not been administered, and not first-line if the patient has hemodynamic instability [106,109,111]. Level of Evidence I Degree of Recommendation A

Echinocandins are increasingly used in these patients. Nonetheless, they should be used with caution and generally as rescue therapy. Especially in situations where the use of Amphotericin B Deoxycholate or Fluconazole is not possible due to toxicity or resistance. Level of Evidence II-3 Degree of Recommendation B

Micafungin, although it is a drug recommended for the treatment of neonatal IC, its penetration into the central nervous system is known to be dose-dependent. Thus, high doses of 10mg/ kg/day should be used if it is decided to use in suspected HCME [111,112]. Level of Evidence I, II-3 Degree of Recommendation A

Prophylaxis of Candida infection in newborns.

Not all newborns need prophylaxis for invasive candidiasis. As mentioned above, it is known that different risk factors impact the incidence of this entity in NICU. According to revised guidelines [105,106,112-114] (Table 6) the recommendations are as follows:

1. Newborns weighing <1000 g. Fluconazole prophylaxis.

2. Newborns weighing <1500 g. Nystatin prophylaxis, as an alternative when fluconazole is not available. (Consider the potential risk of developing Necrotizing Enterocolitis)

3. Fluconazole prophylaxis when the incidence of invasive Candidiasis in NICU is ≥5%

4. European guidelines recommend, the use of lactoferrin 100mg/day ± Lactobacillus rhamnosus, a dose of 10⁶ CFU/day from the third day of life until the end of the sixth week of life or until discharge from the NICU in newborns weighing <1500 g.

5. Miconazole is contraindicated since its use may favor the appearance of azole resistance. Level of Evidence I Degree of Recommendation A

Question 10. Is it advisable to implement pharmacovigilance programs in newborns treated with antibiotics?

During intrauterine life, the fetus can be exposed to a series of drugs and toxic substances whose effects can be immediate and cause fetal death or cause damage that can manifest at birth or even weeks, months, or years later [3,115-117]. (Level of Evidence III Degree of Recommendation B)

55-65% of pregnant women and more than 70% of newborns admitted to NICU receive antibiotics during their hospitalizations [3,117,118]. (Level of Evidence III Degree of Recommendation B)

Pharmacovigilance is the science and activities related to the detection, evaluation, understanding, and prevention of Adverse Drug Reactions (ADRs) or any other potential drug-related problem.

The specific objectives of pharmacovigilance are:

• Improve patient care and safety in relation to the use of medications and all medical interventions.

• Improve public health and safety in relation to the use of medicines.

• Contribute to the evaluation of the benefits, harms, efficacy, and risk of medicines, as well as promoting their safe, rational, and more efficient (and even more profitable) use.

The success or failure of any spontaneous notification system depends on participation. Health professionals have been the main providers of notifications of suspected ADR cases throughout the history of pharmacovigilance.

Wherever medicines are used, they must be willing to observe and report unwanted adverse events [119].

To achieve something closer to ideal practices, more attention should be paid to training health professionals in the diagnosis, management, and prevention of ADRs. Not all signs are so specific or dramatic to be easily diagnosed, as were phocomelia and micromyelia caused by thalidomide [120].

The implementation of a pharmacovigilance program must be carried out in accordance with the current applicable regulations, such as the Official Mexican Normative NOM-220-SSA1-2016, Installation and operation of pharmacovigilance [121]. The latter serves as a great reference to achieve the correct implementation of a pharmacovigilance program. Since it establishes the guidelines for the installation and operation of pharmacovigilance in the national territory, it highlights everything related to: the types of notification criteria, criteria to determine the degree of information, criteria to determine the seriousness of a case, criteria to determine the severity of a case, the classification of reactions, the sending times of notifications, the reception channels, the notification forms, and the requirements for the receipt of notifications [122,123].

To carry out pharmacovigilance, some points are listed that will be informative but not limited to:

Identification of signs suggesting ADRs

• Performs the required investigation and collects the necessary information to fill out the report format for the Notice of Suspected Adverse Drug Reactions issued by COFEPRIS, by reviewing the clinical file, interviewing the doctor, the nurse, or the patient himself.

• Verifies the consistency of the ADR suspicion data, taking into account the evaluation of the causality of said event.

• Fills out the Notice of Suspected Adverse Drug Reactions forms, in accordance with the current COFEPRIS guidelines.

• Classifies ADR based on severity and evaluates its causality.

• Reviews the evolution of the patient after presenting the clinical manifestation of ADR.

• Carry out the ADR notification to the corresponding authority (Table 7) [115].

Conclusion

Based on the recommendations of this consensus, this collaborative group concluded the need to establish policies of prudent and standardized use under the best evidence regarding the of antibiotics in NICUs of the hospitals of the Institute of Health of the State of Mexico. Under these guidelines, the integration of a common manual for the use of antibiotics and antifungals must be reviewed periodically, in addition to strengthening antibiotic pharmacovigilance programs in the NICUs.

Declaration of Conflict of Interest

The authors declare that there is no known competing financial interest or personal relationships that could have appeared to influence the work reported in this consensus.

References

1. Sutherland JM, Keller WH (1961) Novobiocin and Neonatal Hyperbilirubinemia: An Investigation of the Relationship in an Epidemic of Neonatal Hyperbilirubinemia. Am J Dis Child 101(4): 447-453.
2. Sutherland JM (1959) Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. AMA journal diseases of children 97(6): 761-767.
3. Cardetti M, Rodríguez S, Sola A (2020) Uso (y abuso) de antibióticos en la medicina perinatal. Anales de Pediatría 93(3): 207.e1-207.e7.
4. Ferrario C, Califano G, Durán P, Maccarone M, Miceli I, et al. (2012) Lineamientos para la elaboración de consensos. Arch Argent Pediatr 110(2): 163-167.
5. The AGREE Collaboration Appraisal of Guidelines for Research & Evaluation (AGREE) Instrument.
6. Birtwhistle R, Pottie K, Shaw E, Dickinson JA, Brauer P, et al. (2012) Canadian task forcé on preventive health care: Can Fam Physician 58 (1): 13-15.
7. Manterola C, Asenjo-Lobos C, Otzen T (2014) Jerarquización de la evidencia. Niveles de evidencia y grados de recomendación de uso actual. Rev Chilena Infectol 31(6): 705-718.
8. Wynn J, Wong H, Shanley TP, Bizzarro MJ, Saiman L, et al. (2014) Time for a neonatal consensus definition of sepsis. Pediatr Crit Med Care 15(6): 523-528.
9. McGovern M, Giannoni E, Kuester H, Turner MA, Hoogen A, et al. (2020) Challenges in developing a consensus definition of neonatal sepsis. Pediatr Res 88(1): 14-26.
10. Wynn J (2016) Defining Neonatal Sepsis. Curr Opin Pediatric 28(2): 135-140.
11. Hofer N, Müller W, Resch B (2012) Definition of SIRS and sepsis in correlation with early and late onset neonatal sepsis J Pediatr Intensive Care 1(1): 17-23.
12. Glaser MA, Hughes LM, Jnah A, Newberry D (2020) Neonatal sepsis. Adv Neonatal Care 21(1): 49-60.
13. Shane, Sanchez P, Stoll B (2017) Neonatal sepsis. Lancet 390(10104): 1770-1780.
14. Reyna-Figueroa J, Yuri-Toala E, Ortiz-Ibarra FJ, Rodríguez-Ramírez E, Limón-Rojas AE (2006) Disparidad en los criterios para incluir pacientes con sepsis neonatal en estudios médicos científicos. ¿Nadamos en un mar sin límites? Anales de Pediatría; 65(6): 536-540.
15. Goldstein B, Giroir B, Randolph A (2005) International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6(1): 2–8.
16. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, et al. (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315(8): 801–810.
17. Hornik CP, Fort P, Clark RH, Watt K, Benjamin DK, et al. (2012) Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. Early Hum Dev 88(Suppl 2): S69–S74.
18. Hofer N, Zacharias E, Muller W, Resch B (2012) Performance of the definitions of the systemic inflammatory response syndrome and sepsis in neonates. J Perinat Med 40(5): 587–590.
19. Mohsen AH, Kamel BA (2015) Predictive values for procalcitonin in the diagnosis of neonatal sepsis. Electron Physician 7(4): 1190-1195.
20. Park IH, Lee SH, Yu ST, Oh YK (2014) Serum procalcitonin as a diagnostic marker of neonatal sepsis. Korean J Pediatr 57(10): 451-456.
21. Eschborn S, Weitkamp JH (2019) Procalcitonin versus C-reactive protein: review of kinetics and performance for diagnosis of neonatal sepsis. J Perinatol 39(7): 893-903.
22. Bunduki GK, Adu-Sarkodie Y (2020) The usefulness of C-reactive protein as a biomarker in predicting neonatal sepsis in a sub-Saharan African region. BMC Res Notes 13(1): 194.
23. Xu L, Li Q, Mo Z, You P (2016) Diagnostic value of C-reactive protein in neonatal sepsis: A meta-analysis. European Journal of Inflammation 14(2): 100-108.
24. Sola A, Mir R, Lemus L, Fariña D, Ortiz J, et al. (2020) Suspected Neonatal Sepsis: Tenth Clinical Consensus of the Ibero-American Society of Neonatology (SIBEN). Neoreviews 21(8): e505-e534.
25. Husada, P Chanthavanich, U Chotigeat, Sunttarattiwong P, Sirivichayakul C, et. al. (2020) Predictive model for bacterial late-onset sepsis in a tertiary care hospital in Thailand. BMC Infect Dis 20(1): 151.
26. Das A, Shukla S, Rahman N, Gunzler D, Abughali N (2016) Clinical indicators of Late-onset sepsis workup in very Low-Birth-Weight Infants in the neonatal intensive care unit. Am J Perinatol 33(9): 856-860.
27. Kayange N, Kamugisha E, Mwizamholya DL, Jeremiah S, Mshana SE (2010) Predictors of positive blood culture and deaths among neonates with suspected neonatal sepsis in a tertiary hospital, Mwanza- Tanzania. BMC Pediatr 10: 39.
28. Weber MW, Carlin JB, Gatchalian S, Lehmann D, Muhe L, et al. (2003) Predictors of neonatal sepsis in developing countries. Pediatr Infect Dis J 22(8): 711-717.
29. Verstraete EH, Blot K, Mahieu L, Vogelaers D, Blot S (2014) Prediction models for neonatal health care-associated sepsis: a meta-analysis. Pediatrics 135(4): e1002-e1014.
30. Benitz WE, Gould JB, Druzin ML (1999) Risk factors for early-onset group B streptococcal sepsis: estimation of odds ratios by critical literature review. Pediatrics 103(6): e77.
31. Masanja PP, Kibusi SM, Mkhoi ML (2020) Predictors of Early Onset Neonatal Sepsis among Neonates in Dodoma, Tanzania: A Case Control Study. J Trop Pediatr 66(3): 257-266.
32. Fell DB, Hawken S, Wong CA, Wilson LA, Murphy MSQ, et al. (2017) Using newborn screening analytes to identify cases of neonatal sepsis. Sci Rep 7(1): 18020.
33. Hershkovich O, Friedlander A, Gordon B, Arzi H, Derazne E, et al. (2013) Associations of body mass index and body height with low back pain in 829,791 adolescents. Am J Epidemiol 178(4): 603-609.
34. Pettinger KJ, Mayers K, McKechnie L, Phillips B (2019) Sensitivity of the Kaiser Permanente early-onset sepsis calculator: A systematic review and meta-analysis. E Clinical Medicine 19: 100227.
35. Deshmukh M, Mehta S, Patole S (2021) Sepsis calculator for neonatal early onset sepsis - a systematic review and meta-analysis. J Matern Fetal Neonatal Med 34(11): 1832-1840.
36. Achten NB, Klingenberg C, Benitz WE, Stocker M, Schlapbach LJ, et. al. (2019) Association of use of the Neonatal Early-Onset Sepsis Calculator with Reduction in Antibiotic Therapy and Safety. JAMA Pediatr 173(11): 1032-1040.
37. Klingenberg C, Kornelisse RF, Buonocore G, Maier RF, Stocker M. (2018) Culture-Negative Early-Onset Neonatal Sepsis-At the crossroad between efficient sepsis care and antimicrobial stewardship. Front. Pediatr 6: 285.
38. Schelonka RL, M K Chai, Yoder A, Hensley D, Brockett RM, et al. (1996) Volume of blood required to detect comon neonatal pathogens. J Pediatrics 129(2): 275-278.
39. Yaacobi N, Bar-Meir M, Shchors I, Bromiker R (2015) A prospective controlled trial of the optimal volume for neonatal blood cultures. Pediatr Infect Dis J 34(4): 351-354.
40. Tomar P, Garg A, Gupta R, Singh A, Gupta NK, et al. (2017) Simultaneous two-site blood culture for giagnosis of Neonatal sepsis. Indian Pediatr 54(3): 199-203.
41. Ortiz–Ibarra FJ, Oliva-Marín JE, Reyna-Figueroa J, Soriano-Becerril DM (2005) Evaluación controlada del volumen de sangre necesario para la detección de bacteriemia o fungemia en recién nacidos. Revista de Enfermedades Infecciosas en Pediatría 73: 1-7.
42. Ortiz Ibarra J, Trevino Valdez P, Valenzuela Méndez E, Rojas LA, Flores GL, et al. (2015) Evaluation of the Light-Cycler® SeptiFast Test in Newborns With Suspicion of Nosocomial Sepsis. Iran J Pediatr 25(1): e253.
43. Celik IH, Hanna M, Canpolat FE, Pammi M (2022) Diagnosis of neonatal sepsis: the past, present and future. Pediatr Res 91(2): 337-350.
44. Johnson CE, Whitwell JK, Pethe K, Saxena K, Super DM (1997) Term newborns who are at risk for sepsis: are lumbar punctures necessary? Pediatrics 99(4): E10.
45. Weiss MG, Ionides SP, Anderson CL (1991) Meningitis in premature infants with respiratory distress: role of admission lumbar puncture. J Pediatr 119(6): 973–975.
46. Smith PB, Garges HP, Cotton CM, Walsh TJ, Clark RH, et al. (2008) Meningitis in preterm neonates: importance of cerebrospinal fluid parameters. Am J Perinatol 25(7): 421-426.
47. Ansong AK, Smith PB, Benjamin DK, Clark RH, Li JS, et al. (2009) Group B streptococcal meningitis: cerebrospinal fluid parameters in the era of intrapartum antibiotic prophylaxis. Early Hum Dev 85(10 Suppl): S5-S7.
48. Kaul V, Harish R, Ganjoo S, Mahajan B, Raina SK, et al. (2013) Importance of obtaining lumbar puncture in neonates with late onset septicemia a hospital based observational study from north-west India. J Clin Neonatol 2(2): 83-87.
49. Tamim MM, Alesseh H, Aziz H (2003) Analysis of the efficacy of urine culture as part of sepsis evaluation in the premature infant. Pediatr Infect Dis J 22(9): 805-808.
50. Mohseny AB, van Velze V, Steggerda SJ, Smits-Wintjens VEHJ, Bekker V, et al. (2018) Late-onset sepsis due to urinary tract infection in very preterm neonates is not uncommon. Eur J Pediatr 177(1): 33-38.
51. Arredondo GJL, Ortíz IFJ, Solórzano SF, Segura CE; Beltrán ZM (1994) Etiología de la septicemia neonatal en una unidad de Perinatología. Análisis de siete años. Bol Med Hosp Infant Mex 51(56): 317-322.
52. Simental SP, Valenzuela FA, Avendaño BE, Plascencia IS, Martínez ND (2007) Agentes causales de sepsis neonatal temprana y tardía: una revisión de diez años en el “Hospital Infantil Privado. REVISTA DE ENFERMEDADES INFECCIOSAS EN PEDIATRÍA 20(80): 99-105.
53. Pérez R, Lona JC, Quiles M, Verdugo MA, Ascencio EA, et al. (2015) Sepsis neonatal temprana, incidencia y factores de riesgo asociados en un hospital público del occidente de México. Rev Chilena Infectol 32(4): 387-392.
54. Ulloa-Ricárdez A, Salazar-Espino B (2019) Epidemiología de infección neonatal temprana y tardía en una Unidad de Cuidados Intensivos Neonatales. Rev Hosp Jua Mex 86(3): 110-115.
55. Reyna-Figueroa J, Ortiz-Ibarra FJ, Esteves Jaramillo A, Reyna-Figueroa J (2009) Costo económico marginal del fracaso terapéutico con ampicilina más amikacina en el tratamiento de la sepsis neonatal temprana. An Pediatr (Barc) 71(1): 54-59.
56. Procianoy RS, Silveira RC (2020) The challenges of neonatal sepsis management. J Pediatr J Pediatr (Rio J) 96(Suppl 1): 80-86.
57. Dong Y, Speer CP (2015) Late-Onset Neonatal Sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed100(3): 257-263.
58. Mohsen L, Ramy N, Saied D, Akmal D, Salama N, et al. (2017) Emerging antimicrobial resistance in early and late-onset neonatal sepsis. Antimicrob Resist Infect Control 6: 63.
59. Giannoni E, Agyeman PKA, Stocker M, Posfay-Barbe KM, Heininger U, et al. (2018) Neonatal Sepsis of Early Onset, and Hospital-Acquired and Community-Acquired Late Onset: A Prospective Population-Based Cohort Study. J Pediatr 201: 106-114.e4.
60. Berlak N, Shany E, Ben-Shimol S, Chertok IA, Goldinger G, et al. (2018) Late onset sepsis: comparison between coagulase-negative staphylococci and other bacteria in the neonatal intensive care unit. Infect Dis (Lond) 50(10): 764-770.
61. Reddy A, Sathenahalli V, Shivanna N, Benakappa N, Bandiya P (2021) Ten Versus 14 Days of Antibiotic Therapy in Culture-Proven Neonatal Sepsis: A Randomized, Controlled Trial. Indian J Pediatr 89(4): 339-342.
62. Gathwala G, Sindwani A, Singh J, Choudhry O, Chaudhary U (2010) Ten Days vs. 14 days Antibiotic Therapy in Culture-Proven Neonatal Sepsis. J Trop Pediatr 56(6): 433-435.
63. Chowdhary G, Dutta S, Narang A (2006) Randomized controlled trial of 7-Day vs. 14-Day antibiotics for neonatal sepsis. J Trop Pediatr 52(6): 427-432.
64. Fursule A, Thakur A, Garg P, Kler N (2022) Duration of Antibiotic Therapy in Neonatal Gram-negative Bacterial Sepsis-10 Days Versus 14 Days. Pediatri Infect Dis J 41(2): 156-160.
65. KwangSik Kim. (2015) Neonatal Bacterial Meningitis. NeoReviews 16: e535.
66. Zainel A, Mitchell H, Sadarangani M (2021) Bacterial Meningitis in Children: Neurological Complications, Associated Risk Factors, and Prevention. Microorganisms 9: 535.
67. Ku LC, Boggess KA, Cohen-Wolkowiez M (2015) Bacterial meningitis in infants. Clin Perinatol 42(1): 29-45.
68. El-Naggar W, Afifi J, McMillan D, Toye J, Ting J, et al. (2019) Epidemiology of Meningitis in Canadian Neonatal Intensive Care Units. Pediatr Infect Dis J 38(5): 476-480.
69. Reyna FJ, Ortíz IFJ, Plazola CNG, Limón RAE (2004) Meningitis bacteriana en recién nacidos. Experiencia en el Instituto Nacional de Perinatología de 1990 a 1999. Bol Med Hosp Infant Mex 61(5): 402-411.
70. Solórzano SF, Arredondo GJL, Udaeta ME, Ortíz IFJ, Echaniz AG, et al. (1989) Infección sistémica neonatal por Listeria monocytogenes. Bol Med Hosp Infant Mex 46: 709-714.
71. Arredondo Garcia JL, Ortiz Ibarra FJ, Sabais Herrera GA, Miguel S (2000) Recién nacido con flacidez generalizada, lesiones dérmicas diseminadas, hemorragia conjuntival bilateral, hepatomegalia e insuficiencia respiratoria. Gac Med Mex 136(6): 595-600.
72. Guillén-Pinto D, Málaga-Espinoza B, Ye-Tay J, Rospigliosi-López ML, Montenegro Rivera A, et al. (2020) Meningitis neonatal: estudio multicéntrico en Lima, Perú. Rev Peru Med Exp Salud Publica 37(2): 210-219.
73. Vélez Leal JL, Dávila Ramírez F (2015) Listeriosis neonatal en Colombia... ¿Igual que hace veinte años? Rev. Cienc. Salud13: 301-308.
74. Victor Nizet Jerome O. Klein (2015) Bacterial sepsis and meningitis. en: Remington and Klein’s Infectious Diseases of the Fetus and Newborn Infant. (8 Edn) Elsevier Health Pp. 222-275.
75. Garcia-Rodriguez E, Calderon-Lopez G, Navarro Marchena L, Pavon-Delgado A (2014) Lesiones secundarias a meningitis neonatal por Salmonella. An pediatr 81(3): 194-195.
76. Chamalla SK, Karri SS, Koripadu S, Mohan N (2018) Elizabeth kingiameningoseptica: An emerging pathogen causing neonatal meningitis. J NTR Univ Health Sci 7: 213-215.
77. Zaidi M, Sifuentes J, Bobadilla M, Moncada D, de León SP (1989) Epidemic of Serratia marcescens Bacteremia and Meningitis in a Neonatal Unit in Mexico City. Infect Control Hosp Epidemiol 10(1): 14-20.
78. Biset S, Benti A, Molla L, Yimer S, Cherkos T, et al. (2021) Etiology of Neonatal Bacterial Meningitis and Their Antibiotic Susceptibility Pattern at the University of Gondar Comprehensive Specialized Hospital, Ethiopia: A Seven-Year Retrospective Study. Infect Drug Resist 14: 1703-1711.
79. Duke T (2005) Neonatal pneumonia in developing countries. Arch Dis Child fetal Neonatal Ed 90(3): 211-219.
80. Balboa de Paz F, Rueda E, Paredes MC, Gomes EB (2008) Neumonías neonatales. Acta Pediatr Esp 66(10): 481-486.
81. Barnett ED, Klein JO (2015) Bacterial Infections of the respiratory tract. en: Remington and Klein’s Infectious Diseases of the Fetus and Newborn Infant. (8 Edn) Elsevier Health, Pp 276-296.
82. Ortíz-Ibarra FJ, Riega CR, Posadas LA, Arredondo GJL (1992) Infección sistémica neonatal por Streptococcus pneumoniae (reporte de un caso). Bol Med Hosp Infant Mex 46: 856-860.
83. Palacios-Saucedo G, Hernández-Hernández TI, Rivera-Morales LG, Briones-Lara E, Caballero-Trejo A, et al. (2017) Infección perinatal por estreptococo del grupo B: panorama global, en América Latina y en México 153(3): 361-370.
84. Rodrigo SN, Mauricio PC (2000) Chlamydia trachomatis en recién nacidos de un servicio de neonatología: Cuatro casos. Rev chil Pediatr 71(5): 423-426.
85. Nissen MD (2007) Congenital and neonatal pneumonia. Paediatr Respir Rev 8(3): 195-203.
86. Mussi-Pinhata MM, Nobre RA, Martinez FE, Jorge SM, Ferlin MLS, et al. (2004) Early-onset bacterial infection in Brazilian neonates with respiratory distress: a hospital-based study. J Trop Pediatr 50(1): 6-11.
87. Mathur S, Fuchs A, Bielicki J, Anker J van den, Sharland M (2018) Antibiotic use for community-acquired pneumonia in neonates and children: WHO evidence review. Paediatr Int Child Health 38(Sup 1): S66-S75.
88. Mathur NB, Murugesan A (2018) Comparison of Four Days Versus Seven Days Duration of Antibiotic Therapy for Neonatal Pneumonia: A Randomized Controlled Trial. Indian J Pediatr 85(11): 963-967.
89. Ozdemir R, Erdeve O, Dizdar EA, Oguz SS, Uras N, et al. (2011) Clarithromycin in preventing bronchopulmonary dysplasia in Ureaplasma urealyticum-positive preterm infants. Pediatrics 128(6): e1496-e1501.
90. Neu J (2020) Necrotizing Enterocolitis: The Future. Neonatology 117(2): 240-250.
91. Patel RM, Knezevic A, Shenvi N, Hinkes M, Keene S, et al. (2016) Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA 315(9): 889-897.
92. Bell MJ, Ternberg JL, Feigin RD, J P Keating, R Marshall, et al. (1978) Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 187(1): 1-7.
93. Walsh MC, Kliegman RM (1986) Necrotizing enterocolitis treatment based on staging criteria. Pediatr Clin North Am 33(1): 179-201.
94. Garcia M (2020) Enterocolitis necrotizante: actualización 2020. RELAPED.
95. Denning N-L, Prince JM (2018) Neonatal intestinal dysbiosis in necrotizing enterocolitis. Mol Med 24: 4 (2018).
96. Dona D, Gastaldi A, Barbieri E, Bonadies L, Aluvaala J, et al. (2021) Empirical Antimicrobial Therapy of Neonates with Necrotizing Enterocolitis: A Systematic Review. Am J Perinatol DOI: 10.1055/s-0041-1730364.
97. Gasque-Góngora JJ (2015) Revisión y actualización de enterocolitis necrosante. Rev Mex Pediatr 82(5): 175-185.
98. Weimer KED, Smith PB, Puia-Dumitrescu M, Aleem S (2022) Invasive fungal infections in neonates: a review. Pediatr Res 91(2): 404-412.
99. De Rose DU, Santisi A, Ronchetti MP, Martini L, Serafini L, et al. (2021) Invasive Candida Infections in Neonates after MajorSurgery: Current Evidence and New Directions. Pathogens 10(3): 319.
100. Calley JL, Warris A (2017) Recognition and diagnosis of invasive fungal infections in neonates. J Infect 74
     (Suppl 1): S108-S113.
101. Lausch KR, Schultz DKH, Callesen MT, Schrøder H, Rosthøj S, et al. (2019) Pediatric Candidemia Epidemiology and Morbidities: A Nationwide Cohort. Pediatr Infect Dis J 38(5): 464-469.
102. Chakrabarti A, Sood P, Rudramurthy SM, Chen S, Jillwin TJ, et al. (2020) Characteristics, outcome and Risk factors for mortality of pediatric patients with ICU‐acquired candidemia in India: a multicenter prospective study. Mycoses doi: 10.1111/myc.13145.
103. Stoll B, Shane A. (2013) Recent Developments and Current Issues in the Epidemiology, Diagnosis, and Management of Bacterial and Fungal Neonatal Sepsis. American Journal of Perinatology,30:131–142.
104. King J, Pana ZD, Lehrnbecher T, Steinbach WJ, Warris A (2017) Recognition and Clinical Presentation of Invasive Fungal Disease in Neonates and Children. J Pediatric Infect Dis Soc 6(suppl_1): S12-S21.
105. Santolaya ME, Alvarado MT, de Queiroz Telles F, Colombo AL, Zurita J, et al. (2013) Recommendations for the management of candidemia in neonates in Latin America. Latin America Invasive Mycosis Network. Rev Iberoam Micol 30(3): 158–170.
106. Pappas PG, Kauffman CA, Andes DR,Clancy CJ, Marr KA, et al. (2016) Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 62(4): e1-e50.
107. Bennett JE (2017) Invasive Candidiasis in Very Premature Neonates: Tiny Totswith Big Problems. Clin Infect Dis 64(7): 928–929.
108. Kaufman DA (2010) Neonatal Candidiasis: Clinical Manifestations, Management, and Prevention Strategies. J Ped. (2010) 156(Suppl 2): A1–S86.
109. Figueras C, Heredia CD, de García JJ, Navarro M, Ruiz-Contreras J, et al. (2011) Recomendaciones de la Sociedad Española de Infectología Pediátrica sobre diagnóstico y tratamiento de la candidiasis invasiva. Ann de Pediatr 74(5): 337.e1–337.e17.
110. Arias FD, Jiménez S (2015) Manejo de la infección por candida en el recién nacido. Revista Repertorio De Medicina y Cirugía 24:123–130.
111. Walsh T, Katragkou A, Chen T, Salvatore C, Roilides E (2019) Invasive Candidiasis in Infants and Children: Recent Advances in Epidemiology, Diagnosis, and Treatment. J Fungi 5(1): 11.
112. Hope WW, Castagnola E, Groll AH, Roilides E, Akova M, et al. (2012) ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp. Clin Microbiol Infect 18(Supply 7): 38–52.
113. Arıkan K, Kalkanlı OH, Calkavur S, Akarslan K, Nuri B, et al. (2021) Safety and Effectiveness of Micafungin in Neonates: A Retrospective Analytical Study from a Tertiary Pediatric Center. Annals of Neonatology Journal 3(2): 50-69.
114. Ruhnke M, Rickerts V, Cornely OA, Buchheidt D, Glöckner A, et al. (2011) Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy. Mycoses 54(4): 279-310.
115. Rheuter T (2020) Neofax 2020.
116. Juárez H, Buendía E, Lares I (2015) Pharmacology for the fetus and the newborn. Gac Med Mex 151(3): 387-395.
117. Rotten CM (2016) Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr 28(2): 141-149.
118. Vallejos A (2007) Reacciones adversas por antibióticos en una unidad de cuidado intensivo pediátrico y neonatal de Bogotá. Revista Biomédica 27(1): 66-75.
119. WHO (2021) The importance of pharmacovigilance.
120. Meyboom RHB, Hekster YA, Egberts ACG, Gribnau FWJ, Edwards IR (1997) Casual or Causal? The role of causality assessment in pharmacovigilance. Drug Saf 17(6): 374-389.
121. Diario oficial de la federación (2021) NORMA Oficial Mexicana NOM-220-SSA1-2016, Instalación y operación de la farmacovigilancia.
122. Aviso de sospecha de reacciones adversas a medicamentos, (2021) Comision Federal para la Protección contra Riesgos Sanitarios.
123. Manual de procedimientos del departamento de farmacia hospitalaria (2011) SECRETARÍA DE SALUD INSTITUTO NACIONAL DE ENFERMEDADES RESPIRATORIAS. Available in: http://www.iner.salud.gob.mx/descargas/normatecainterna/MPdirmedica/MP_DepartamentoFarmaciaHospitalaria_15112018.pdf