Abstract
Patients with neoplasms have a high predisposition to bacterial infections, due to the implemented treatment that impairs immunity and numerous risk factors. Numerous research studies have been published on this problem but epidemiological studies are insufficient, and existing data are difficult to generalize on different populations. The aim of the study was to assess the epidemiology of bacterial and fungal bloodstream infections and contaminations in cancer patients hospitalized between 2011 and 2021, with a focus on identifying predominant pathogens, resistance mechanisms, and evaluating the effectiveness of infection prophylaxis. We collected data of blood contaminations and infections epidemiology with cooperation with the Department of Clinical Microbiology UCH. Between 2011 and 2021, 7,667 blood samples were collected and 32,610 tests were performed on 1,914 patients. The analysed cultures were divided into 3 groups depending on the substrate specific for a given group of microorganisms. The number positive test result was 5.5%. The highest detection was noticed in 2021. Differences in the distribution of patients with positive and negative results in individual years were not statistically significant. The most common pathogen detected was Staphylococcus epidermidis, which was also the leader among Gram-positive microorganisms. There were not dominant species among the isolated Gram-negative microorganisms. Detection of anaerobic organisms was rare (only 4 different anaerobic organisms were isolated in single patients). The same was among the fungal observed. Mechanisms of resistance were included in the analysis of all identified strains- the most common was methicillin-resistant Staphylococcus epidermidis (MRSE). Our results confirmed that bacterial infections are still a problem and may indicate the effectiveness of prophylaxis. Most of our results are consistent with the current literature, however we were able to highlight data unique to our patient population. Our findings can be helpful for clinical practice and be base for further research.
Keywords: Bacterial infections, Pediatric oncology, Pediatric hematology, Epidemiology, Colonization
Subject terms: Bacteriology, Clinical microbiology
Introduction
Infections are one of the most the most important complication of cancer treatment. Patients undergoing chemotherapy or radiotherapy are at an increased risk of developing all types of infectious diseases, that could lead to chronic health disorders and higher mortality compared to healthy population1. Oncological therapy can spill over to a state of impaired immunity, making patients vulnerable to various pathogens. Except for the side effects of applied pharmaceuticals and symptoms of the primary disease, other factors such as malnutrition, neutropenia, disrupted mucosal barriers among others, contribute to the vulnerable state2.
Moreover, cancer patients often develop complicated infections that are difficult to treat. Immunocompromised state makes room for opportunistic pathogens that cause therapeutic problems. In addition, the treatment often requires frequent hospitalizations and necessary prophylactic measures. Despite preventive use of antibiotics being currently unadvised without a solid justification3,4, multi drug resistant pathogens are still a severe problem5. Antibiotic resistance became a global issue and a subject of WHO surveillance, using international institutions to help integrate epidemiological data collected by national authorities6.
Nonetheless, monitoring local hospital epidemiology and bacterial phenotypes is still a necessary element to facilitate early pathogen detection and to improve patient care. It is particularly valid in the treatment of patients with cancer. Existing reports on that topic are available but limited7, often focusing on particular clinical situations8, and of little application to a specific facility.
We aimed at reporting the analysis of local epidemiology of bacterial blood infections in children diagnosed with hematologic and oncologic diseases of the University Children’s Hospital in Krakow (UCH), during the period of 2011–2021.
Materials and methods
Blood cultures were performed at The Department of Clinical Microbiology of UCH. A total of 123,252 samples were tested, of which 32,610 (26%) were collected in the Department of Oncology and Hematology (DOH). An observation period of 11 years was estimated as adequate to estimate changes in the number of performed tests and detected microorganisms. Throughout the analyzed period, our department diagnosed and treated an average of 112 new cases of childhood cancer per year. In Poland, the distribution of childhood cancers is approximately as follows: leukemias—around. 27%, CNS tumors—20%, lymphomas—13%, neuroblastoma—8%, nephroblastoma—7%, osteogenesis imperfecta—7%, soft tissue sarcomas—6%, germinal tumors—4%, retinoblastoma—2%, hepatic neoplasms—2%, histiocytosis—2%, and other rare neoplasms collectively account for 2%.
We did not collect information concerning patients’ personal data, detailed clinical diagnoses, symptoms and course of treatment. Analysed data concerned epidemiological information from a microbiological point of view. All methods were carried out in accordance with relevant guidelines and regulations. The study protocol was approved by institutional ethical committee.
Available data included all children with oncological and hematological diseases treated in UCH who underwent microbiological blood testing through years 2011–2021. A total of 1914 patients were included (1088 male, 786 female). The number of blood cultures in subsequent years are presented in Table 1.
Table 1.
Number of blood cultures in subsequent years.
| Year | 2011 | 2012 | 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | 2019 | 2020 | 2021 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Number of patients | 228 | 235 | 165 | 220 | 151 | 144 | 138 | 160 | 161 | 151 | 161 |
| Female (%) | 87 (38,2%) | 84 (35,7%) | 70 (42,4%) | 98 (44,5%) | 79 (52,3%) | 64 (44,4%) | 56 (40,6%) | 64 (40,0%) | 64 (39,8%) | 63 (41,7%) | 57 (35,4%) |
| Male (%) | 141 (61,8%) | 151 (64,3%) | 95 (57,6%) | 122 (55,5%) | 72 (47,7%) | 80 (55,6%) | 82 (59,4%) | 96 (60,0%) | 97 (60,2%) | 88 (58,3%) | 104 (64,6%) |
| Number of blood cultures | 3435 | 3499 | 3357 | 3080 | 2699 | 2424 | 2243 | 3097 | 3223 | 2794 | 2759 |
Department of Clinical Microbiology run a thorough, multidirectional microbiological analysis of blood samples, including aerobic and anaerobic bacteria and fungi.
Further detailed quantitative-analysis applied the number of tests (not samples). As a test, we classified samples collected from one patient, but in different combinations according to the order of attending physician. Decision making process was based on clinical symptoms, accordingly to the effective standards (guidelines for the management of febrile neutropenia). Blood samples were collected directly from a peripheral vein or central venous catheter or both simultaneously. The following combinations were commissioned depending on clinical criteria:
Combination 1 included blood drawn for aerobic and anaerobic bacterial and fungal cultures
Combination 2 included blood drawn for aerobic and anaerobic bacteria
Combination 3 included blood drawn for aerobic bacterial and fungal cultures
Combination 4 included blood drawn for aerobic bacterial cultures.
Technical details of microbiological analysis were as follows. Blood samples were inoculated in 3 types of media: Peds Plus/F (resin medium for aerobic bacteria), Plus Anaerobic/F (medium for anaerobic bacteria) and Mycosis IC/F (medium for fungi). All described media were produced by Becton Dickinson, USA. Plates were incubated in Bactec FX 400 blood culture system for a maximum of 7 days in case of bacteria, and a maximum of 14 days in case of yeast and mold fungi. Bactec FX 400 system (Becton Dickinson, USA) signalises the presence of a pathogen. Each positive sample was additionally prepared for further analysis with a direct method and with Gram’s staining, and grown for the second time in media (all agars descripted below were produced by OXOID company, United Kingdom):
Agar medium with 5% sheep blood, incubated with 5% CO2 at a temperature of 36° C
chocolate agar medium with yeast extract, incubated with 5% CO2 at a temperature of 36° C
MacConkey agar medium, incubated with 5% CO2 at a temperature of 36° C
Wilkins-Chalgren agar for anaerobic bacteria, incubated in anaerostat with 5% CO2 at a temperature of 36° C
Sabourad agar plate for fungi, incubated at a temperature of 36° C and 30° C.
Cultured microorganisms were identified using commercially available methods, automatic and manual, eg. the Becton Dickinson Phoenix and Remel Rapid ID tests. Additionally, drug sensitivity was tested according to the European and Polish guidelines (EUCAST, eng. European Committee on Antimicrobial Susceptibility Testing and KORLD, eng. National Reference Center for Antimicrobial.
Susceptibility). Resistance mechanisms were detected using a disc-diffusion method (OXOID comp., UK) and E-test gradient strip tests (Liofilchem comp., USA) to establish the minimal inhibitory concentration of an antibiotic (MIC). The Mueller–Hinton agar (MH, produced by OXOID comp.,
UK) was used for resistance testing, with adequate supplementing of medium in according to producer’s recommendations. The MIC was formulated as the minimal antibiotic concentration required to restrict bacterial growth in an inoculum of particular density, expressed with mg/l unit. All tests were controlled in compliance with the EUCAST guidelines, using ATCC sample strains for routine disk and E-test control.
Disc-diffusion method interpretation was based on EUCAST tables for the measurement of growth restriction area (measured with a caliper). The gradient strip test combines the methods of diffusion and the serial dilution method. Each strip is saturated with an antibiotic, with its concentration consecutively marked on a scale. The MIC is the value of antibiotic concentration read from the scale, where it intersects with the border of growth restriction area. Results from the disc-diffusion method and Etest are presented in three categories: sensitive, sensitive depending on the dosage and resistant, with an addition of the precise antibiotic dosage in case of MIC.
Detailed detected resistance mechanisms can be found below:
MRSE/MSSE (methicillin resistant/sensitive Staphylococcus epidermidis), MRSA/MSSA (methicillin resistant/sensitive Staphylococcus aureus), MRCNS/MSCNS (methicillin resistant/sensitive Staphylococcus coagulase negative CNS). Above mechanisms were detected for Staphylococcus spp. using a disc infused with cefoxitin 30 µg in Mueller–Hinton agar (suspension 0,5 McFarland, incubation in 35 °C ± 1 °C, O2, 18 ± 2 h).
MLSB / iMLSB (macrolide-lincosamide-streptogamin B resistance). Mechanism for Staphylococcus spp. was detected using disks infused with clindamycin 2 µg and erythromycin 15 µg, disk edges 12-20 mm apart in Mueller–Hinton agar (suspension 0,5 McFarland, incubation in 35 °C ± 1 °C, O2, 18 ± 2 h). For Streptococcus spp. disks infused with clindamycin 2 µg and erythromycin 15 µg, disk edges 12-16 mm apart in Mueller–Hinton agar + 5% defibrinated horse blood and 20 mg/L β-NAD (MH-F), (suspension 0,5 McFarland, incubation in 35 °C ± 1 °C, CO2, 18 ± 2 h.
HLGR (high level of gentamicin resistance). Examined strains acquired resistance mechanisms of high grade to aminoglycoside antibiotics, except for streptomycin (separate assessment was not performed in this study). Resistance mechanism for Enterococcus spp. was detected using a disk with gentamicin 30 µg in Mueller–Hinton agar (suspension 0,5 McFarland, incubation in 35 °C ± 1 °C, O2, 18 ± 2 h).
ESBL (extended-spectrum beta-lactamases). Mechanism for Enterobacterales (among others K.pneumoniae, E.clocae, E.coli) was detected using disks with ceftazidime 30 µg, cefotaxime 30 µg and cefepime 10 µg, and disks with amoxicillin with clavulanic acid 20/10 µg, disk centers 2 cm apart, in Mueller–Hinton agar (suspension 0,5 McFarland, incubation in 35 °C ± 1 °C, O2, 18 ± 2 h).
MBL (metallo-β-lactamases). A screening test was performed to detect resistance in Pseudomonas aeruginosa, using a disk with imipenem 10 µg and ceftazidime 30 µg and a disk with EDTA, disk centres 2 cm apart, in Mueller–Hinton agar (suspension 0,5 McFarland, incubation in 35 °C ± 1 °C, O2, 18 ± 2 h). Strains grown in 2011 and 2014 were referenced to a KORLD centre in Warsaw to confirm MBL resistance mechanism.
Statistical analysis was performed using STATISTICA 13 program. Number of positive results in respective years was compared using Pearson’s chi-squared test. Statistical significance was established at p value < 0.05. The analysis focused on finding differences in the number of positive test results, with an accent on different aspects explained further in the “Results” and “Discussion” sections. Additionally, examined antibiotic resistance mechanisms were included in data analysis.
Results
32,610 blood culture samples were analysed for the Department of Oncology and Hematology. Samples were cultured in aerobic (13,392 samples), anaerobic (11,346 samples) conditions and for fungi (7 847 samples). Table 2 presents the detailed number of samples collected in respective years, divided into mentioned three groups. During the analysed period, 1803 out of 32,610 (5,52%) blood culture samples were positive. Further analysis referred to the number of tests, defined by authors as samples collected from a single patient. Table 3 presents information on analysed tests according to the source of sample collection, as well as positive results through analysed years.
Table 2.
Number of blood culture samples collected from the DOH for microbiological analysis, 5 divided according to the culture.
| Year | 2011 | 2012 | 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | 2019 | 2020 | 2021 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Aerobic blood culture | 1318 (38%) | 1399 (40%) | 1293 (39%) | 1143 (37%) | 1070 (40%) | 966 (40%) | 955 (43%) | 1232 (40%) | 1395 (43%) | 1265 (45%) | 1356 (49%) |
| Anaerobic blood culture | 1173 (34%) | 1210 (35%) | 1130 (34%) | 969 (31%) | 916 (34%) | 839 (35%) | 785 (35%) | 1093 (35%) | 1111 (34%) | 1045 (37%) | 1075 (39%) |
| Mycological blood culture | 946 (28%) | 890 (25%) | 934 (28%) | 968 (31%) | 713 (26%) | 589 (25%) | 503 (22%) | 775 (25%) | 717 (22%) | 484 (17%) | 328 (12%) |
| Total | 3437 | 3499 | 3357 | 3080 | 2699 | 2394 | 2243 | 3100 | 3223 | 2794 | 2759 |
Table 3.
Number of tests run in respective years, including the source of sample collection and positive 8 results.
| Year | 2011 | 2012 | 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | 2019 | 2020 | 2021 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Number of tests | 797 | 792 | 729 | 638 | 603 | 574 | 546 | 716 | 773 | 719 | 780 |
| Drawn from peripheral vein (%) | 117 (14%) | 143 (18%) | 103 (14%) | 106 (17%) | 70 (12%) | 66 (11%) | 68 (12%) | 89 (12%) | 111 (14%) | 106 (15%) | 119 (15%) |
| Positive results from peripheral vein (%) | 17 (15%) | 21 (15%) | 16 (16%) | 22 (21%) | 2 (3%) | 5 (8%) | 11 16% | 14 16% | 19 17% | 15 14% | 15 13% |
| Drawn from a central venous catheter (%) | 680 86% | 649 82% | 626 86% | 532 83% | 533 88% | 508 89% | 478 88% | 627 88% | 662 86% | 613 85% | 661 85% |
| Positive results from a central venous catheter (%) | 72 11% | 133 21% | 52 (8%) | 85 16% | 53 10% | 54 11% | 51 11% | 71 11% | 66 10% | 62 10% | 99 15% |
Percentage of patients with positive test results in respective analysed years is detailed in Fig. 1 below. Statistically significant increase in the proportion of patients with positive test results was found in 2021, compared to years 2011–2014 (p = 0.011, 0.024, 0.0452, 0.0281, respectively), and in 2020 compared to 2011 (p = 0.0362). Remaining differences in the proportion of positive results were not statistically significant, according to Paerson’s chi-squared test (p > 0.05). Total numbers of cultured isolates each year is summarized in Table 4.
Fig. 1.
Percent of patients with positive test results (total number in brackets).
Table 4.
Total number of isolates through respective years.
| Year | 2011 | 2012 | 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | 2019 | 2020 | 2021 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Number of isolates | 89 | 91 | 68 | 97 | 55 | 59 | 62 | 85 | 85 | 77 | 114 |
Cultured bacterial species and its resistance mechanisms were also analysed. Each year, dominating species of bacteria was Staphylococcus epidermidis. Remaining Gram-positive and Gram-negative species were isolated with various frequency.
Firstly, we present a detailed number of Gram-positive bacterial species isolated each year, as shown in Fig. 2. Isolated coagulase-negative Staphylococci (CNS) included S.haemolyticus, S.hominis, S.warnerii, S.capitis and S.simulans. Enterococcus species included E. faecalis and E. faecium. Streptococcus species constituted for viridans Streptococci.
Fig. 2.
Number of the most frequently isolated Gram-positive bacteria in respective years.
Each cultured Gram-positive bacteria species was examined for antibiotic resistance, except for Bacillus spp. Table 5 presents resistant variants in cultured Staphylococcus epidermidis strains. Table 6 presents resistance mechanisms found for Staphylococcus aureus (SA), coagulase-negative Staphylococci (CNS) and Enterococcus spp. (ESP) Streptococcus spp (STV). Antibiotic resistant phenotypes were most often found for CNS and ESP.
Table 5.
Number of tests positive for Staphylococcus epidermidis and resistance mechanisms 13 through the years.
| Year (total number | 2011 (89) | 2012 (91) | 2013 (68) | 2014 (97) | 2015 (55) | 2016 (59) | 2017 (62) | 2018 (85) | 2019 (85) | 2020 (77) | 2021 (114) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Species | Number of staphylococcus epidermidis isolates (SE) | ||||||||||
| SE total | 61 68,5% | 33 36% | 20 29,4% | 34 35% | 19 34,5% | 20 34%) | 13 21% | 21 25% | 58 68% | 36 47% | 44 38% |
| MSSE (% of SE) | 39 63,9% | 6 18,2% | 5 5,0% | 20 58,8% | 2 10,5% | 6 30,0% | 4 30,8% | 4 19,0% | 29 50,0% | 7 19,4% | 17 38,6% |
| MRSE (% of SE) | 22 36,1% | 27 81,8% | 15 75,0% | 14 41,2% | 17 89,5% | 14 70,0% | 9 69,2% | 17 81,0% | 29 50,0% | 29 80,6% | 37 84,1% |
| MLS (% of SE) | 20 32,8% | 17 51,5% | 15 75,0% | 8 23,5% | 13 68,4% | 13 65,0% | 7 53,8% | 14 66,7% | 21 36,2% | 25 69,4% | 15 34,1% |
Abbreviations: MSSE, Methicillin sensitive Staphylococcus epidermidis; MRSE, 14 Methicillin resistant Staphylococcus epidermidis; MLS, Macrolide-lincosamide-streptogramin B 15 resistance.
Table 6.
Resistance mechanisms found for Staphylococcus aureus (SA), coagulase-negative 18 Staphylococci (CNS), Enterococcus spp. (ESP) and Streptococcus spp. (STV) cultured in examined 19 blood samples.
| Year (total number of isolates) | 2011 (89) | 2012 (91) | 2013 (68) | 2014 (97) | 2015 (55) | 2016 (59) | 2017 (62) | 2018 (85) | 2019 (85) | 2020 (77) | 2021 (114) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Species | Staphylococcus aureus isolates (SA) | ||||||||||
| SA total | 6 | 4 | 3 | 6 | 2 | 2 | 2 | 4 | 3 | 4 | 9 |
| MRSA | 1 (16,67%) | 2 (50%) | 1 (33,33%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (33,33%) | 3 (75%) | 8 (88,89%) |
| MSSA | 5 (83,33%) | 2 (50%) | 2 (66,67%) | 6 (100%) | 2 (100%) | 2 (100%) | 2 (100%) | 4 (100%) | 2 (66,67%) | 1 (25%) | 1 (11,11%) |
| MLS | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Coagulase-negative Staphylococci isolates (Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus warnerii, Staphylococcus capitis, Staphylococcus simulans), (CNS) | |||||||||||
| CNS | 4 | 7 | 4 | 8 | 7 | 4 | 13 | 19 | 22 | 6 | 11 |
| MRCNS | 2 (50%) | 7 (100%) | 2 (50%) | 5 (62,5%) | 6 (85,71%) | 4 (100%) | 12 (92,31%) | 19 (100%) | 13 (59,09%) | 5 (83,33%) | 0 0% |
| MSCNS | 2 (50%) | 0 (0%) | 2 (50%) | 3 (37,5%) | 1 (14,29%) | 0 (0%) | 1 (7,69%) | 0 (0%) | 11 (50%) | 1 (16,67%) | 11 100%) |
| MLS | 0 (0%) | 0 (0%) | 0 (0%) | 4 (50%) | 6 (85,71%) | 3 (75%) | 10 (76,92%) | 19 (100%) | 8 (36,36%) | 5 (83,33%) | 1 (9,09%) |
| Enterococcus spp. isolates (Enteroccus faecalis, Enteroccus faecium), (ESP) | |||||||||||
| ESP | 9 | 8 | 2 | 7 | 0 | 1 | 1 | 7 | 1 | 4 | 5 |
| HLGR | 8 (88,89%) | 2 (25%) | 2 (100%) | 3 (42,86%) | 0 (0%) | 1 (100%) | 1 (100%) | 2 (28,57%) | 1 (100%) | 0 (0%) | 3 (60%) |
| Streptococcus spp. (STV) | |||||||||||
| STV | 3 | 3 | 4 | 6 | 3 | 3 | 4 | 6 | 3 | 1 | 16 |
| MLS | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 4 (100%) | 1 (17%) | 0 (0%) | 0 (0%) | 0 (0%) |
Percent of total number of isolates for specific bacteria in brackets. Abbreviations: 20 MRSA, Methicillin resistant Staphylococcus aureus; MSSA, Methicillin sensitive Staphylococcus 21 aureus; MLS, Macrolide-lincosamide-streptogramin B resistance; MRCNS, Methicillin resistant 22 coagulase-negative Staphylococci; MSCNS, Methicillin sensitive Staphylococcus coagulase negative; 23 HLGR, High level of gentamicin resistance.
Remaining findings include Gram-negative bacterial species, isolated with various frequency each year, with no significant difference between years, as presented in Table 7. Enterobacterales were the most frequent species.
Table 7.
Gram-negative bacteria species isolated through years.
| Year (total number of isolates) | 2011 (89) | 2012 (91) | 2013 (68) | 2014 (97) | 2015 (55) | 2016 (59) | 2017 (62) | 2018 (85) | 2019 (85) | 2020 (77) | 2021 (114) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Species | Acinetobacter spp. isolates (Acinetobacter junii, Acinetobacter lwoffii), (A.spp) | ||||||||||
| A.spp | 1 1% | 4 4,4% | 3 4,4% | 0 0% | 6 10,9% | 8 13,6% | 1 1,6% | 3 3,5% | 0 0% | 3 3,9% | 5 4,4% |
| Enterobacter cloacae isolates (ECL) | |||||||||||
| ECL | 2 2% | 1 1% | 4 5,9% | 2 2% | 0 0% | 0 0% | 6 9,7% | 8 9,4% | 2 2,4% | 5 6,5% | 8 7% |
| ESBL strains | 0 0% | 0 0% | 1 25% | 0 0% | 0 0% | 0 0% | 0 0% | 1 12,5% | 0 0% | 0 0% | 4 50% |
| Klebsiella spp. isolates (Klebsiella pneumoniae, Klebsiella oxytoca), (K.spp) | |||||||||||
| K.spp | 3 3,4% | 13 14% | 3 4,4% | 3 3% | 1 1,8% | 2 3,4% | 8 12,9% | 7 8% | 0 0% | 5 6,5% | 5 4,4% |
| ESBL strains | 2 67% | 5 38,5% | 0 0% | 1 33,3% | 0 0% | 0 0% | 2 25% | 1 14,3% | 0 0% | 5 100% | 3 60% |
| Escherichia coli isolates (EC) | |||||||||||
| EC | 3 3,4% | 3 3,3% | 3 4,4% | 1 1% | 5 9% | 3 5% | 6 9,7% | 5 5,9% | 3 3,5% | 7 9% | 5 4,3% |
| ESBL strains | 0 0% | 0 0% | 0 0% | 0 0% | 0 0% | 0 0% | 3 50% | 2 40% | 0 0% | 2 28,5% | 0 0% |
| Pseudomonas aeruginosa isolates (PA) | |||||||||||
| PA | 8 9% | 0 0% | 2 3% | 5 2% | 2 3,6% | 3 5% | 3 4,8% | 2 2,4% | 1 1% | 3 3,9% | 8 7% |
| MBL strains | 2 25% | 0 0% | 0 0% | 1 20% | 0 0% | 0 0% | 0 0% | 0 0% | 0 0% | 0 0% | 0 0% |
|
Other pseudomonas spp. (Pseudomonas putida, psudomonas oryzihabitans), (P.spp) | |||||||||||
| P.spp | 1 1% | 1 1% | 4 5,9% | 3 3% | 0 0% | 1 1,7% | 3 4,8% | 2 2,3% | 3 3,5% | 0 0% | 1 0,9% |
Abbreviations: ESBL, Extended-26 spectrum beta-lactamases; MBL, Metallo-β-lactamases.
Other Gram-negative bacteria non specified in Table 7. included as follows. One case of Proteus mirabilis was found in 2015, two cases of Serratia marcescens found in 2011 and 2020 each, two cases of Salmonella group D in 2012 and 2017 each and two cases of Stenotrophomonas maltophilia found in 2013 and 2015 each.
Only 4 different types of anaerobic bacteria were detected through the years. A case of Campylobacter jejunii was found in 2019, a case of Fusobacterium spp. in 2020, Bacteroides fragilis in 2021 and Veilonella spp. in 2021. Additionally, 8 species of yeast fungi were isolated through the years. Details are presented in Table 8.
Table 8.
Fungi species isolated from blood samples through the years.
| Year (number of tests) | 2011 [946] | 2012 [890] | 2013 [934] | 2014 [968] | 2015 [713] | 2016 [589] | 2017 [503] | 2018 [775] | 2019 [717] | 2020 [484] | 2021 [328] |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Species | Number of isolates (percent of total) | ||||||||||
| Candida parapsilosis | 2 (0,2%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Candida tropicalis | 0 | 0 | 0 | 2 (0,2%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Candida guiliermondii | 0 | 1 (0,1%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Candida krusei | 0 | 0 | 0 | 0 | 1 (0,1%) | 0 | 0 | 4 (0,5%) | 0 | 0 | 0 |
Discussion
As it was shown, the number of positive tests has been stable for the past years. A significant increase was found in 2021. We believe the COVID-19 pandemic and medical care delays resulting from it, could have contributed to more advanced cases being admitted to the hospital with more predisposition for various complications, including infectious. The analysis of positive blood cultures revealed Staphylococcus species to be the most common bacterial pathogen in children with cancer the years 2011–2021. Overall, Gram-positive (GP) bacteria dominated over Gram-negative (GN) bacteria. Staphylococcus spp. were most often isolated, out of which Staphylococcus epidermidis dominated in cultures collected from both peripheral venous blood and central catheters. It is not surprising, given that this pathogen resides on human skin and mucosa. Despite being mostly harmless, it can cause serious infections in an immunocompromised state9. Long term usage of central venous catheters, often required during chemotherapy and prolonged hospitalization predisposes to transferring bacteria to the blood. Additionally, chemotherapy impairs mucosal barriers, enabling it even further for various pathogens to penetrate. Literature shows that Staphylococcus epidermidis most often causes infections in case of chronic vein catheterization10, which can be prevented by adequate CVC care11. Furthermore, we noticed fluctuations in MRSE and MLS phenotypes through years.
Staphylococci coagulase negative were the second most common type of bacteria, among which S. haemolyticus, S. hominis, S. wernerii, S. capitis and S. simulans were cultured. Most were resistant to methicillin and to macrolides as well as lincosamides. Resistant phenotypes dominated in previous years, with a low frequency in 2021. In the literature, CNS were found to be one of the most common infection causing bacteria in oncologic patients, nonetheless its clinical significance has been questioned12. Regardless, they are often multi drug resistant13, which was also true for our centre.
Similarly, to other centres, Staphylococcus aureus infection rate stayed at a lower level of around 37.9% (as given in Table 6.) each year. This pathogen seems to be less of a threat nowadays for patients with cancer, even despite stable incidence of resistant phenotypes, due to antiseptic measures and cautious care of medical staff7,14. Most of the cultures were methicillin sensitive. Higher rates of methicillin resistance were only found in 2020 (75% of all SA) and 2021 (88,9%). According to ECDC MRSA incidence has been stable15.
Enterococcus species, among which E. faecium and E. faecalis, were isolated with similar incidence. In years 2011 and 2012 were isolated more frequently, at a rate of 10% and 8.8% respectively. This bacterial species, being natural inhabitants of human gastrointestinal tract, are often an important infectious factor in oncologic patients16. Almost all of the cultured Enterococci were HLGR phenotype strains. Resistant strains are also more characteristic for hematologic-oncologic departments and have been reported frequently in the literature17,18. In addition, there has been an increase in HLGR Enterococcus phenotypes in Poland according to ECDC-WHO surveillance report15. This finding stands as a serious matter and a challenge for the treatment of patients in our centre.
An interesting finding was presence of viridans Streptococci, bacterial species that was diagnostically challenging due to difficult identification with traditional biochemical methods. This type of bacteria can be found in oral mucosal microbiome, causing infections mainly in patients with neutropenia and damaged mucosa membranes. This pathogen was observed at a rate of around 3.3–7% each year in our centre, except for 2021, when incidence was at 14% (as given in Table 6. and Fig. 2). It was also noticed in the literature, more often in patients after stem-cell transplantation or haematological neoplasms in general19,20.
Corynebacteria spp. and Bacilli spp. were also observed, with lower incidence. Probably related to improper collection of blood sample for testing. In control tests, no growth of these microorganisms was observed. Additionally, we assume that the increase in Bacillus superinfections of blood samples in the years 2012–2015: 13% (9/68), 8% (8/97), 16% (9/55), 13.6% (8/59) was related to construction and renovation works of the hospital in the close vicinity of the clinic.
Despite GP bacteria being more frequently detected, we did observe an increase in GN. Some previously reported data7,21,22 showed an increase in GN strain incidence in oncologic patients.
Nonetheless, we did not notice a significant shift. Most detected Enterobacterales species were Klebsiella pneumoniae, Enterobacter clocae and Escherichia coli. ESBL fenotype was quite frequent, although variable through years. They were found to have a quite low antibiotic sensitivity, with Klebsiella spp. being particularly resistant (ESBL), which is alarmingly consistent with literature as well as existing reports13,15. On this account, antibiotic choice was limited. KORLD (eng. National Reference Center for Antimicrobial Susceptibility) disadvises using 3rd or 4th generation cefalosporins or aztreonam, as well as penicillins and their combinations with Blactamase inhibitors in invasive ESBL-positive Enterobacterales infections, even despite their in vitro sensitivity to these antibiotics23. A Polish study from 2020 reported this bacteria species to be common in similar population24. Additionally, other non-fermenting Gram-negative bacteria were detected, including Pseudomonas aeruginosa and Acinetobacter species (Acinetobacter junii, Acinetobacter Iwoffii). These types of bacteria are rare, but consisted of natural and acquired antibiotic resistance mechanisms, according to the ECDC report14. Over the course of 10 years, we detected 3 cases of Pseudomonas aeruginosa infections with the MBL phenotype. Overall antibiotic resistance was more frequent in GN species. No statistically significant difference was found for percentage of antibiotic resistant strains through the years.
In addition, we took notice that collected samples rarely showed presence of fungal pathogens. We suspect that the clinical primary evaluation has been targeted correctly for bacterial infections, in cases that symptoms were suggestive.
The increasing resistance of microorganisms to available drugs has become a global problem and poses a serious threat to human health. In recent years, an increase in resistance to almost all groups of antibiotics has been observed worldwide. In 2015, WHO Member States unanimously endorsed the Global Action Plan to Combat Antimicrobial Resistance (GAP-AMR) and on 22 October 2015, WHO launched the Global Surveillance System for Antimicrobial Resistance and its Use (GLASS). The WHO priority pathogens list (BPPL) was created, which is modified every year and currently includes 24 pathogens from 15 families of bacterial pathogens resistant to antibiotics that have critical priority, e.g. Acinetobacter baumannii—resistant to carbapenems; Enterobacterales—resistant to third-generation cephalosporins; Enterobacterales—carbapenem-resistant or high priority e.g. Enterococcus faecium—vancomycin-resistant; Pseudomonas aeruginosa—carbapenem-resistant; Staphylococcus aureus—methicillin-resistant or medium priority e.g. group A streptococci—macrolide-resistant; Streptococcus pneumoniae—macrolide-resistant; Haemophilus influenzae—ampicillin-resistant. The list is updated every year and unfortunately indicates a continuous increase in microbial resistance to new drug groups, which is why work at the level of hospital and out-ofhospital treatment in each country is so important. Unfortunately, in our hospital we also isolate microorganisms from WHO lists, as we presented in the analyses discussed above, mainly Enterobacterales resistant to third-generation cephalosporins, Pseudomonas aeruginosa resistant to carbapenems, Staphylococcus aureus—resistant to methicillin. In the daily work of our hospital, a Team for Hospital Antibiotic Policy was established, which brings together specialist doctors, pharmacists and clinical microbiologists. The aim of the team is to take actions aimed at reducing the growth of resistance. Based on the analysis of the cultured microorganisms and their resistance profile, we take actions to rationalize the therapy. We create guidelines for the treatment of various infections, indicating empirical treatment, and then, based on the microbiological result, targeted treatment. We have introduced a list of antibiotics, separating antibiotics, the prescription of which requires authorization. We conduct audits of the wards to reduce the frequency of inappropriate antibiotic therapy and, where possible, switch from intravenous to oral therapy, and verify antibiotic dosage depending on the type of infection or its etiology25.
Conclusions
We did not observe significant differences in the microbiological analysis between years. However, we noticed a statistically significant increase in the percentage of patients with positive test results, especially in 2020 and 2021. The dominant microorganisms were Gram-positive bacteria, especially the Staphylococcus genus, among which we observed mainly coagulase-negative Staphylococcus, which constituted the natural flora of the skin and mucous membranes. One of the reasons for the isolation of these microorganisms from the blood is the primary serious condition of oncological patients resulting from cancer and the associated disorders of humoral and cellular immunity, as well as the occurring damage to the skin and mucous membranes, which, when damaged as a result of diagnostic and therapeutic procedures, lose their role as a natural anatomical barrier protecting against these microorganisms. Of course, the potential superinfection of the examined material as well as the colonization of central and venous entrances due to improper care should always be taken into account. Statistical data allows for the development of epidemic maps and makes it easier for Hospital Policy Teams to develop therapeutic and early response procedures by including safe antibiotics. In the case of the Department of Oncology and Hematology of the University Children’s Hospital, the number of isolated Staphylococcus spp. in the amount of 50–80% are methicillin-resistant strains, therefore the first-line drug is vancomycin. In case of allergy to this antibiotic or obtaining an MIC ≥ 2.0 mg/mL (considered non-therapeutic), daptomycin or linezolid is started in these infections. Infections caused by Gram-negative bacilli are rare in our center, but the course of the infection is extremely severe, therefore, in the case of their isolation based on statistical information, meropenem is included as the first-line treatment, taking into account that Enterobacter clocae 12.5% to 50%, and Klebsiella pneumoniae 33% to 100% are ESBL positive strains. Always after obtaining a result with drug resistance of the tested strain, the treatment can be modified and, above all, the dosage can be individualized based on the MIC and the measurement of the antibiotic concentration in the blood serum. Epidemiological mapping provides key knowledge of the etiological factors of the department and is invaluable in making the first decisions about the type of antibiotic therapy used.
High percentage of S. epidermidis suggests even more caution should be paid to venous catheter care. We do not collect data on specific clinical symptoms; therefore, it was difficult to show whether these bacteria were in any case pathogenic, or just an accidental finding due to its normal presence in human microflora. High prevalence of antibiotic resistant bacteria is an important outcome of the study. Despite many steps being taken to prevent growing of antibiotic resistance, it is still a huge problem worldwide. It is especially valid for children with cancer, who undergo often aggressive treatment and are at a significant risk of complications due to infectious causes. Furthermore, epidemiological data from various available reports seems inconsistent, which gives more arguments for focusing on local epidemiological situation to improve oncological patient care, as well as relying on national and international data and guidelines, especially regarding possible treatment and prophylactic measures.
Author contributions
J.K., K.K., K.Ż., M.W-G., W.C. collected data, J.K., Z.Z., S.S. analysed the data, J.K., K.Ż. wrote the main manuscript text and S.S. prepared figures. All authors reviewed and edited the manuscript.
Funding
This study did not require funding.
Data availability
The datasets used and analysed during the current study available from the corresponding author on reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Ethics
The study protocol was approved by institutional ethical committee: Bioethics Committee of the Jagiellonian University. The informed consent was waived by institutional ethical committee: Bioethics Committee of the Jagiellonian University.
Consent for publication
All authors declare consent for publication.
Footnotes
Publisher’s note
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Contributor Information
Szymon Skoczeń, Email: szymon.skoczen@uj.edu.pl.
Wojciech Czogała, Email: wojciech.czogala@uj.edu.pl.
Zuzanna Zakrzewska, Email: zuzanna.zakrzewska@uj.edu.pl.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and analysed during the current study available from the corresponding author on reasonable request.