The development of resistance to antibiotics is due to the widespread use of a wide variety of antimicrobials, coupled with the ability of bacteria to acquire and spread resistance and the ability of humans to disseminate them. The possible consequences of antimicrobial resistance leads to greater chances of hospitalization, prolongation of hospital stay and increased mortality. Furthermore, treatment of drug resistant bacteria requires the use of more toxic drugs and more expense for the patient and hospitals. The main objective of the present study was to determine the frequency and nature of antimicrobial resistance of microorganisms in oncologic and hematologic patients at a Mexican Pediatric Hospital. A retrospective, observational, and analytical study was realized, where we reviewed the clinical records of 20 cases. Blood cultures were obtained from the Laboratory of our institution from 2010 to 2011. The data obtained were organized and analyzed. We observed that the E. coli and S. aureus were the bacteria most resistant, showing the same percentage between gram-positive and gram-negative bacteria. The cancer diagnosis most common in our study was acute lymphoblastic leukemia. It may be concluded that multidrug-resistant bacteria in these patients are of a nosocomial origin, without a specific group of germ (gram positive vs. gram negative).
Keywords: Antimicrobial Resistance; Oncologic Patients; Children; Neutropenia.
The oncological disease and chemotherapeutic treatment in children are able to produce a state of neutropenia.1 This state of low immunity in children increases the incidence of infection. The severity of these infections is related to the degree of reduction of neutrophils in the blood. Both solid tumors and hematologic malignancies predispose to this type of complication.1 Septic processes in immune-compromised patients and malignant diseases are associated with high morbidity and mortality.2 The empirical use of antimicrobial agents has led to changes in the etiology of bacterial infections and, therefore, this practice is now strongly associated with bacterial resistance mechanisms. The inappropriate use of broad-spectrum antibiotics for prophylactic or therapeutic purposes induce the selection of resistant strains associated with bacteremia and super-infections by hongos.3, 4 Infectious episodes remain the leading cause of morbidity and mortality in these patients. So today, the subject being treated for cancer does not die as often by the cancer itself, but for serious infectious complications due to the combination of chemotherapy (pillar of cancer treatment). In this sense, many agents are capable of producing myelo-suppression, which promotes neutropenia, which is the leading factor in producing infections.5 There are other contributing factors that alter the immunity, such as loss of integrity of the physical barrier of the skin and mucous membranes, which can be altered by the tumor itself, or the chemotherapy and radioterapia.6 It is known that with a shorter duration of neutropenia (less than 7 to 10 days), there is less risk of infection and better response to antimicrobial therapy, compared with the emergence of infections by a more intense and prolonged neutropenia (greater than 15 days).7-9
Drug resistance refers to a situation in which the drugs that usually destroy the bacteria no longer do so. Some of the main causes of antibiotic drug resistance are antibiotic overuse, abuse, and in some cases, misuse, due to incorrect diagnosis. There are five major mechanisms of antibiotic drug resistance, which are due to chromosomal mutations: 1. Reduced permeability or uptake; 2. Enhanced efflux; 3. Enzymatic inactivation; 4. Alteration or over-expression of the drug target; 5. Loss of enzymes involved in drug activation.10 The etiologic agents of episodes of fever in neutropenic patients differ by hospital, in some cases gram-positive cocci have become the most frequent causative agents of febrile episodes (70 %). However, gram-negative bacilli still have a significant role in serious infections. From the first, the most commonly isolated in blood cultures are: Staphylococcus aureus and alpha-hemolytic streptococci and beta. Frequent infections by Gram-negative bacteria are caused by Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Furthermore, the need for prolonged antibiotic treatment in states of prolonged neutropenia is associated to opportunistic fungal infections, particularly Candida and Aspergillus.2
Infections related to vascular lines in oncological patients are a common cause of morbidity, occurring between 8 and 55 % of these patients. Also, it has been reported that in patients with vascular access, Staphylococcus aureus and coagulase-negative Staphylococcus are the etiological agents most frequently isolated, often associated with infection at the insertion site. However, other agents such as P. aeruginosa, S. maltophilia, C. jeikeium sp and Candida can also cause vascular colonization of the device.2
The problem of antibiotic resistance has increased significantly over the past 10 years. Currently, the presence of multi-resistant microorganisms is a real problem we face. Its incidence is increasing in the community setting and in the hospital, especially in intensive therapy units.11
Due to a lack of well-designed studies, infection with multi-resistant microorganisms is associated with treatment failure, prolonged hospital stay, increased hospital costs and increased mortality, especially in critically ill patients. Mortality rates and hospital stay are at least twice as many in patients infected with multi-resistant microorganisms.12 Therefore, the main objective of the present study was to determine the frequency and nature of antimicrobial resistance of microorganisms in oncologic and hematologic patients at a Mexican Pediatric Hospital.
A retrospective, analytical, cross-sectional descriptive study was conducted over a period of two years (2011-2012), in the hemato-oncologic service at a Mexican Pediatric Hospital. Patients with microbiological cultures showing antimicrobial resistance, admitted to the hemato-oncologic service, any gender and any age were included. Laboratory studies were obtained, which demonstrated the microorganism involved, sensitivity and resistance to different antimicrobials. Seventy-five patients were hospitalized in the hemato-oncologic service at the stipulated time of the study. Of this total, 20 patients were resistant to antimicrobials. The Ethics and Investigation Committees approved the study protocol and the study was performed according to the guidelines delineated by the Declaration of Helsinki.
Data were entered into a computerized database. The SPSS version 17 for Windows (SPSS Inc., Chicago, IL, USA) was used for descriptive statistical analyses. Data were analyzed and measures of central tendency, dispersion, frequencies and proportions were determined.
The incidence and antimicrobial resistance in the population of the hemato-oncologic service was 28% (20 of 75 cases). Twelve patients (60 %) were boys and eight patients (40 %) were girls. The age ranges were from 6 months to 17 years, with a median of eight years and mode of one year. Of the cases found, nine (45 %) were from patients with acute lymphoblastic leukemia L1, followed by three osteosarcoma (15 %) and the remaining conditions are shown in Table 1.
Table 1. Diagnoses Presented by the 20 Patients Included
Microbiological cultures showed that gram negative bacilli was present in 10 patients (50%) and large cocci in the other 10 patients (50%) (Table 2).
Table 2. Microorganisms Found in the 20 Patients
Although empirical antimicrobial therapy was started immediately, 100% (20 cases) of patients developed resistance to different antibiotics; S. aureus and E. coli germs developed greater resistance to this type of treatment (Table 3).
Table 3. Empiric Treatment of Different Germs Found
The number in each cell is the number of cases
A. Ceftazidime; B. Clindamycin; C. Amikacin; D. Cefotaxime; E. Dicloxacillin; F. Vancomycin; G. Ciprofloxacin; H. Trimethoprim/sulfamethoxazole; I. Metronidazole; J. Meropenem; K. Cefuroxime; L. Cephalothin; M. Fluconazole; N. Ampicillin; O. Imipenem
In Table 4 we can observe the types of chemotherapeutic agents used for different pathologies found in our study.
Table 4. Chemotherapy Used for Each Patient
Patients who developed fever during the study showed resistant pathogens in up to 85% of the sample (17 cases). The most frequent site for the isolation of germs was the central catheter in 55% (11 cases), followed by peripheral blood cultures in 25% (5 cases), 10% by port catheter (two cases) and infusion with the same 10%, corresponding to two cases. Of the patients with multi-resistant microorganism isolated, 90% of the population had venous access (18 cases). The sensibility of the microorganisms to different antimicrobials is shown in Table 5. After that, Table 6 shows the intermediate sensitivity to antimicrobials of some microorganisms. Table 7 shows the antimicrobial resistance of the microorganisms. Table 8 shows the type of cancer and the microorganisms found in the patients.
Table 5. Sensibility of the Microorganisms to Different Antimicrobials
The number in each cell is the number of cases
A. Vancomycin; B. Dicloxacillin; C. Rifampicin, D. Linezolid, E. Cefepime; F. Cefotaxima; G. Imipenem; H. Amikacin; I. Meropenem; J. Ciprofloxacin; K. Ceftazidime; L. Gentamicin; M. Teicoplanin; N. Trimethoprim/sulfamethoxazole.
Table 6. Intermediate Sensitivity to Drugs Used of Some Microorganisms
Table 7. Resistances Found with Drugs Used
The number in each cell is the number of cases
A. Dicloxacillin, B. Ceftriaxone, C. Ceftazidime, D. Clindamycin, E. Meropenem, F. Gentamicin, G. Ciprofloxacin, H. Cefepime; I. Trimethoprim / sulfamethoxazole, J. Amoxicillin / Clavulanate, K. Cefuroxime; L. Cefotaxime, M. Amikacin, N. Ticarcillin; Ñ. Imipenem.
Table 8. Type of Diagnoses and Microorganisms Found
The number of "x" is the number of repetitions of the same organism.
A. S. aureus; B. E. coli; C. E. cloacae; D. P. aeruginosa; E. S. hominis;
B. F. S. epidermidis; G. S. maltophilia.
During the last two decades, the approach to patients with cancer, fever and neutropenia has involved hospitalization for parenteral administration of broad-spectrum antimicrobials until defervescence is achieved. This behavior has significantly decreased mortality associated with episodes of neutropenia and fever. The antimicrobial resistance in patients with cancer never had been evaluated in the Hospital del Niño DIF Hidalgo. Through the specific selection of patients, we decided to determine the frequency of antimicrobial resistance and to determine which bacteria are showing greater resistance to specific antibiotics in our patients. Likewise, to know the characteristics of antimicrobial resistance, and finally to determine the most common type of drug resistance sources. One of the drawbacks of our study population was the sample size. However, this sample size is not far from other prevalent studies that have been done in other parts of the world. The kind of cancer most common in our hospital was acute lymphocytic leukemia L1, followed by osteosarcoma and myelocytic leukemia, lymphoma and neuroblastoma, which in some way is in agreement with the frequency of neoplastic disease in the pediatric population. Several publications2, 13, 14 have agreed that the Gram-positive bacteria account for 60 to 70 % of microbiologically documented infections. This information is very interesting if you look at our patients, where the isolation rate is to the inverse to that published in the literature. In this sense, in our study, the number of Gram-negative bacilli was 55 %, which is similar to that reported in the study of Cheguirian et al., where it was found a higher prevalence for gram- negative bacilli (45.8 %), followed by Gram-positive cocci (35.7 %) and yeast (18.5 %).15 In Latin America, the prevalence of beta-lactamase bacteria varies from 5 to 32% for E. coli and from 26 to 73 % for K. pneumoniae.16 Data released by the antibacterial resistance committee of the Pan-American Association of Infectious Diseases (PAID) mentioned that the frequency range was from 2 to 18 % for E. coli and from 20 to 57 % for K. pneumoniae.16
One of the important aspects that must be considered in the management of febrile neutropenic patients is the type of treatment that you should administer. That is why you need to assess the epidemiological situation of the health clinic where the child is hospitalized. In our study, the frequency of isolation of gram -positive cocci accounted for 47.6 % of our sample (10 cases), where Staphylococcus aureus was the most prevalent with 23.8% (five cases), followed by S. hominis in three cases (14.2 %) and S. epidermidis in two patients (9.5 %).
In the case of patients with neutropenia, the resistance rate is higher than in non-neutropenic patients and the mortality therefore rises from 80 to 100 %.17 Empirical antimicrobial therapy in these patients should be periodically evaluated to try to find an antimicrobial scheme that offers the most coverage for the most frequently isolated microorganisms, in order to obtain greater efficiency clínica.17 In the case of our study, patients that had fever during the study showed resistant pathogens in up to 85 % (17 cases) of the sample, being the most frequent site for the isolation of germs the central catheter in 55 % (11 cases ), followed by peripheral blood cultures in 25 % (five cases): This last aspect of our research allows us to propose a more intensive training in medical and nursing care in order to avoid infections related to these vascular lines in febrile neutropenic patients and to decrease the morbidity. Moreover, we must to be alert to the presence of severe neutropenia, so it is considered by itself as a risk factor.5
One of the greatest problems that doctor will face in the coming years is antimicrobial resistance, which already represents a problem of worldwide clinical and epidemiological importance. There are several articles on nosocomial infections in our country, but the importance of the present study is to assess the frequency of antimicrobial resistance that occurs in these patients, since it is common requiring broad-spectrum antibiotics. Chemotherapy had an important role in the study, because, as discussed earlier in this paper, according to the type of chemotherapy, it may produce a different degree of neutropenia, thus demonstrating the relationship between aggressive chemotherapy and a greater degree of neutropenia, infection and development of antimicrobial resistance.
It may be concluded that multidrug-resistant bacteria in this group of patients are of nosocomial origin, without a specific group of seed, so it is important to insist on identifying risk factors and preventive measures to avoid infection.
1. Dufort Alvarez G. Guía para el Tratamiento del Paciente con Neutropenia Febril. Arch Pediatr Urg 2009;80: 37-42.
2. Gaytan MJ, Mateos GE, Sánchez CE, González LJ, Casanova CL, Fuentes-Allen JL. Microbiological findings in febrile neutropenia. Arch Med Res 2000; 31: 388-92.
3. Santoya de P. ME, Rabagliati B. Consenso manejo racional del paciente con cáncer, neutropenia y fiebre. Rev Chil Infect2005; 22 (Supl 2): S79.
4. Gaytán-Martinez J, Ávila-Moran M, Mata-Marin JA. Patrones de suceptibilidad bacteriana en infecciones en pacientes adultos con neoplasias, hematológicas, fiebre y neutropenia. Gac Méd Méx 2011; 147: 325-32.
5. Freifeld AG, Walsh TJ, Pizzo PA. Infectious complications in the pediatric cancer patient. En: Pizzo PA, Poplack DG (eds.). Principles and practices in pediatric oncology. Philapdelphia: Lippincott-Raben Publisehrs, 1997:1069.
6. Rubin RH, Ferraro MJ. Understanding an diagnosing infectious complications in the immunocompromised host. Hematol Oncol Clin North Am 1988; 74:795-81013
7. Bodey GP. Patients with neutropénica: Old a new treatament modalities. Empirical antibiotic therapy for fever in neutropenic patients. Clin infect Dis 1993; 17( Suppl 2 ): S 378-384.
8. Rubin M, Hathorn JW, Pizzo PA. Controversies in the management of febrile neutropenic cancer patient. Cancer Investet 1998; 6: 167-184.
9. Pizzo PA, Commers JR, Cotton DJ. Approaching the controversies in the antibacterial management of cancer patient. Am J Med 1984; 76: 436-445.
10. Peterson LR. Apretando el globo de los antibióticos: efectos del uso de diversas clases de antimicrobianos sobre la aparición de resistencias Clin Microbiol infect (ed. cast). 2005; 11 Suppl 5: S4-16.
11. Kollef MH, Fraser VJ. Antibiotic resistance in the intensive care unit. Ann Intern Med 2001; 134: 298-314.
12. Rello J, Gallego M, Mariscal D. The Value of routine microbial investigation in ventilator associated pneumonia AM J Respir Crit Care Med 1997; 156:196-200.
13. Fernández Alonso R, González Garcia ME, Fernández García J. Profilaxis antimicrobiana en el paciente neutropénico. Rev Clin Esp 2004; 204(12): 645-8.
14. Bruckner L, Gigliotti S. Viridians Group Streptococcal Infections Among Children With Cancer and the importance of Emerging Antibiotic Resistance. Semin Pediatr Infect Disae 2006; 17(3):153-60.
15. Cheguirián ML, Carvajal LR, Ledesma EM, Enrico MC, Reale AL, Culasso C, et al; Prevalencia de microorganismos causantes de bacteriemias y fungemias en pacientes oncológicos pediátricos. Patrones de sensibilidad a los antimicrobianos. Rev. Argent. Microbiol. 2008; 40:111-115.
16. Casellas J. M. Informe del Comité de resistencias a Antibacterianos de la API, periodo 2003-2004. Rev Panamer Infect 2004, 6:4.
17. Torres Harrys A. Neutropenia Febril: una revisión del tema. En http://vitae.ucv.ve/pdfs/ VITAE_3187.pdf . Acceso 12 enero 2012.
 Hospital General de Pachuca, de la Secretaría de Salud de Hidalgo, Pachuca, Hidalgo. Mexico.
 Hospital del Niño DIF Hidalgo, Pachuca, Hidalgo. Mexico.
 Escuela Americana de Pachuca, Pachuca, Hidalgo, Mexico
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