A survey on hematology-oncology pediatric AIEOP centers: prophylaxis, empirical therapy and nursing prevention procedures of infectious complications.
ABSTRACT A nationwide questionnaire-based survey was designed to evaluate the management and prophylaxis of febrile neutropenia in pediatric patients admitted to hematology-oncology and hematopoietic stem cell transplant units. Of the 34 participating centers, 40 and 63%, respectively, continue to prescribe antibacterial and antimycotic prophylaxis in low-risk subjects and 78 and 94% in transplant patients. Approximately half of the centers prescribe a combination antibiotic regimen as first-line therapy in low-risk patients and up to 81% in high-risk patients. When initial empirical therapy fails after seven days, 63% of the centers add empirical antimycotic therapy in low-and 81% in high-risk patients. Overall management varies significantly across centers. Preventive nursing procedures are in accordance with international guidelines. This survey is the first to focus on prescribing practices in children with cancer and could help to implement practice guidelines.
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ABSTRACT: The pattern of infections among neutropenic cancer patients has shifted in the last decades to a predominance of Gram-positive infections. Some of these Gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment. To assess the effectiveness of empirical anti-Gram-positive (antiGP) antibiotic treatment for febrile neutropenic cancer patients in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment. We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to 2004), EMBASE (January 1980 to 2004), LILACS (1982 to 2004), conference proceedings, and all references of included studies. First authors of all included and potentially relevant trials were contacted. Randomised controlled trials comparing one antibiotic regimen to the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic cancer patients. Two reviewers independently assessed trial eligibility, methodological quality and extracted all data. Relative risks (RR) with 95% confidence intervals (CI) were calculated. A random effects model was used for all comparisons showing substantial heterogeneity (I(2 )> 50%). Outcomes were extracted by intention-to-treat and the analysis was patient-based whenever possible. Thirteen trials and 2392 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in eleven studies and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Seven studies were assessed in the overall mortality comparison and no significant difference between the comparator arms was seen, RR 0.82 (95% CI 0.56 to 1.20, 852 patients). Ten trials assessed failure including modifications as failures, while six assessed overall failure, disregarding treatment modifications. Failure with modifications was significantly reduced, RR 0.76 (95% CI 0.68 to 0.85, 1779 patients) while overall failure was equal, RR 1.00, 95% CI (0.79 to 1.27, 943 patients). Both mortality and failure did not differ significantly among patients with Gram-positive infections, but comparisons were small. Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates, and were associated with a reduction in documented Gram-positive superinfections. Resistant colonisation was not documented in the studies. Current evidence shows that the addition of antiGP treatment, namely glycopeptides, prior to documentation of a Gram-positive infection does not improve outcomes.Cochrane database of systematic reviews (Online) 01/2005; · 5.70 Impact Factor
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ABSTRACT: To evaluate the effectiveness of oral amoxicillin/clavulanate (25 mg/kg every 12 h) for prevention of fever and/or infection in neutropenic children with cancer. Multicenter, prospective, randomized, double blind placebo-controlled trial. In the intention-to-treat analysis, amoxicillin/clavulanate had a 12% benefit increase in terms of reduction in the incidence of febrile or infectious episodes, compared with placebo [44 of 83 (53%) vs.55 of 84 (65%); 95% confidence interval, -28% to +3%; P = 0.101]. This benefit was also associated with a 30% increase in the probability of failure-free survival at Day 15 (P = 0.138). A logistic regression analysis showed the effect of prophylaxis to be relevant, especially in patients with leukemia or lymphoma and in those not receiving hematopoietic growth factors, with 17 and 15% absolute benefit increases (logistic P = 0.014 and 0.034, respectively). Compliance with oral drugs was good, with very few and nonsevere drug-related adverse events. In this study amoxicillin/clavulanate was associated with a detectable clinical effect in the reduction of fever and infection in neutropenic children with cancer, especially those with acute leukemia and not receiving growth factors; the study was not powered to demonstrate a statistically significant effect in the overall patient population.The Pediatric Infectious Disease Journal 05/2003; 22(4):359-65. · 3.57 Impact Factor
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ABSTRACT: The purpose of our study was to evaluate the incidence and clinical characteristics of febrile episodes during neutropenia following chemotherapy in children with cancer. A prospective, 3-year single-center observational study of periods of neutropenia was performed. Epidemiology and clinical diagnoses of febrile episodes occurring during the neutropenic periods were evaluated, taking into consideration different categories of anticancer treatment based on the type of tumor and phase of therapy. A total of 703 febrile episodes were observed during 614 (34%) of 1792 neutropenic periods (34%), for a total of 28,001 days at risk, accounting for a rate of 0.76 episodes per 30 days at risk. The highest proportions of neutropenic periods with primary febrile episodes were observed after autologous hemopoietic stem cell transplantation (58%), aggressive treatment for acute leukemia or non-Hodgkin lymphoma (48%), and allogeneic hemopoietic stem cell transplantation (44%); the lowest proportion (9%) was observed during maintenance chemotherapy for acute leukemia (P<.001). The most frequent clinical diagnosis was fever of unknown origin (in 79% of cases), followed by bacteremia (10%); invasive mycosis was diagnosed in only 2% of cases. The overall incidence of febrile neutropenia and severe infectious complications in children with cancer is low, with differences according to the aggressiveness of chemotherapy. This fact must be considered when designing clinical trials on the management of infectious complications in children with cancer.Clinical Infectious Diseases 11/2007; 45(10):1296-304. · 9.37 Impact Factor
A survey on hematology-oncology pediatric AIEOP centers:
prophylaxis, empirical therapy and nursing prevention procedures
of infectious complications
by Susanna Livadiotti, Giuseppe M. Milano, Annalisa Serra, Laura Folgori,
Alessandro Jenkner, Elio Castagnola, Simone Cesaro, Mario R. Rossi,
Angelica Barone, Giulia Zanazzo, Francesca Nesi, Maria Licciardello,
Raffaella De Santis, Ottavio Ziino, Monica Cellini, Fulvio Porta, Desiree Caselli,
and Giuseppe Pontrelli
Haematologica 2011 [Epub ahead of print]
Citation: Livadiotti S, Milano GM, Serra A, Folgori L, Jenkner A, Castagnola E, Cesaro S,
Rossi MR, Barone A, Zanazzo G, Nesi F, Licciardello M, De Santis R, Ziino O, Cellini M,
Porta F, Caselli D, and Pontrelli G. A survey on hematology-oncology paediatric AIEOP
centers: prophylaxis, empirical therapy and nursing prevention procedures of
infectious complications. Haematologica. 2011; 96:xxx
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Published Ahead of Print on October 11, 2011, as doi:10.3324/haematol.2011.048918.
A survey on hematology-oncology pediatric AIEOP centers: prophylaxis,
empirical therapy and nursing prevention procedures of infectious
Running title: Infections in pediatric hematology-oncology units
Susanna Livadiotti1, Giuseppe Maria Milano2, Annalisa Serra3, Laura Folgori1,
Alessandro Jenkner3, Elio Castagnola4, Simone Cesaro5, Mario R. Rossi6, Angelica Barone7,
Giulio Zanazzo8, Francesca Nesi9, Maria Licciardello10, Raffaella De Santis11, Ottavio Ziino12,
Monica Cellini13, Fulvio Porta14, Desiree Caselli15, and Giuseppe Pontrelli1 for the the Infectious
Diseases Working Group of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)
1Immunoinfectivology Units, IRCCS Children’s Hospital Bambino Gesù, Rome, Italy;
2Pediatric Hematology Oncology, Hospital "S. Maria della Misericordia", Perugia, Italy;
3Hematology Oncology Units, IRCCS Children's Hospital Bambino Gesù, Rome Italy;
4Infectious Diseases Units, Department of Hematology and Oncology, “G. Gaslini” Children’s
Hospital, Genoa, Italy; 5Pediatric Hematology Oncology, Verona, Italy;
6Department of Pediatric Hematology, San Gerardo Hospital, Monza, University of Milan-Bicocca,
Italy; 7Pediatric Hematology Oncology, Universitary Hospital, Parma,Italy;
8Pediatric Hematology Oncology, IRCCS Children’s Hospital Burlo Garofalo, Trieste,Italy;
9Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina
Margherita Children’s Hospital, Turin, Italy;
10Pediatric Hematology Oncology, Universitary Hospital "Gaspare Rodolico", Catania, Italy;
11Pediatric Hematology Oncology, San Giovanni Rotondo, Foggia,Italy;
12Pediatric Hematology Oncology, Children’s Hospital "G. Di Cristina" ARNAS, Palermo,Italy;
13Pediatric Hematology Oncology, Universitary Hospital, Modena,Italy;
14Oncoematologia, Ospedale dei Bambini, Brescia,Italy, and 15Department of Pediatric
Hematology Oncology, Universitary Hospital Meyer, Firenze, Italy
A complete list of the members of participating members of the Infectious Diseases Working Group
of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) is reported in the
Key words: infectious diseases, neutropenia fever, paediatric, empiric therapy, prophylaxis.
A nationwide questionnaire-based survey was designed to evaluate the management and
prophylaxis of febrile neutropenia in paediatric patients admitted to Hematology-Oncology and
Hematopoietic Stem Cell Transplant Units. Of the 34 participating centres, 40 and 63%
respectively, continue to prescribe antibacterial and antimicotic prophylaxis in Low Risk subjects
and 78 and 94% in transplant patients. Approximately half of the centers prescribes a combination
antibiotic regimen as first-line therapy in Low Risk patients and up to 81% in High Risk patients.
When initial empirical therapy fails after 7 days, 63% of the centres add empirical antimicotic
therapy in Low and 81% in High Risk patients. Overall management varies significantly across
centers. Preventive nursing procedures are in accordance with international guidelines. This survey
is the first focused on prescribing practices in children with cancer and could facilitate
implementing practice guidelines.
Febrile neutropenia (FN) is a relatively frequent event in pediatric patients receiving cancer
treatment. It is a potentially life-threatening condition that requires prompt medical intervention.
Despite improvements in long-term survival, infection remains a common complication and causes
the majority of chemotherapy-associated deaths1. Prophylaxis and empirical treatment with
antimicrobial agents before microbiological documentation of infection, is justified in the pediatric
patient with FN. Recent studies have identified factors associated with increased risk of infection
and suggested a more appropriate approach to empiric therapy and prophylaxis2. No well defined
guidelines, such as those long established for adults, have been devised so far for pediatric patients
Design and Methods
A standardized questionnaire was sent out to all 49 Hematogy-Oncology Units belonging to the
Italian Paediatric Hematology-Oncology Association (AIEOP). The survey was designed to assess
the current practice of empirical antimicrobial chemotherapy and chemoprophylaxis for FN. The
questionnaire comprises four parts according to the patient’s risk of infection:
1. Low Risk (LR) patients: less than 10 days of expected neutropenia after chemotherapy;
2. High Risk (HR) patients: more than 10 days of expected neutropenia, and
3. Autologous (AUTO) transplantation patients; 4. Allogeneic (ALLO) transplantation patients.
Furthermore, another questionnaire was designed to assess the current precautions used by nurses,
focusing on hand hygiene procedures, barrier precautions, safe work and isolation practices for
patients in ordinary and isolation wards.
The answers were required to represent the local policies, therefore faithfully reflecting current
practice and not personal opinion. The results were entered and analyzed with EpiInfo (Centers for
Diseases Control, Atlanta , GA, USA) statistical software.
Results and Discussion
A total of 34 centers (response rate: 70%) filled in the survey questionnaire; 58% of the
participating units performed allogeneic and autologous bone marrow transplantations.
For the prophylaxis we analyzed antibacterial, antimycotic, antiviral and anti Pneumocysis jiroveci
The percentage of centers adopting antibacterial prophylaxis varied across the risk categories: 40%
in LR, 63% in HR patients, and 78% in both allogeneic and autologous recipients (Table 1).
The most commonly prescribed antibiotic regimen for antibacterial prophylaxis, both in LR and HR
groups, was amoxicillin/clavulanate (60 and 75% respectively) and fluoroquinolones (10 and 20%).
In transplanted patients heterogeneity of treatment was higher, with more frequent use of
The use of antimycotic prophylaxis varied from 47% in LR to 94% in allogeneic transplant patients,
with 81% in HR and 91% in autologous subjects.
Fluconazole was the most widely used agent in all risk groups, often substituted with other
antifungal agents like Itraconazole, Liposomal Amphotericin and Echinocandin in HR patients.
Twenty percent of centers employed antiviral prophylaxis for LR patients (16% of centers
exclusively in AbHSV+ patients), and 28% for HR (20% exclusively in AbHSV+ patients).
Antiviral prophylaxis was used by 62% of the centers (19% in AbHSV+ patients) in autologous
transplant patients, and by 95% (6% in AbHSV+ patients) in allogeneic transplant patients.
Acyclovir was the drug of choice.
Pneumocystis Jiroveci prophylaxis was administered to all patients undergoing allogeneic and
autologous transplants; LR and HR patients received prophylaxis in 85% (10% only in selected
patients) and in 91% (3% only in selected patients) of cases respectively. The most commonly
prescribed drug in all groups was Trimethoprim Sulfamethoxazole (TMP-SMZ), while Pentamidine
was prescribed less frequently.
Furthermore, the survey assessed the use of combination therapy versus monotherapy as empirical
antibiotic treatment (Table 2). Combination therapy was most frequently employed in all patients; a
high frequency of combination therapy was observed in the treatment of HR patients (81 vs 19% of
monotherapy), as compared with LR patients (57 vs 43% respectively), where combination and
single agent therapies were almost equally employed. In auto-transplant patients, combined therapy
and monotherapy were chosen in similar proportions (55 vs 45%, respectively). Allogeneic
transplant patients received combination therapy two times more frequently than monotherapy (67
vs 33%, respectively).
Piperacillin/tazobactam, third (ceftazidime and ceftriaxone) and fourth generation (cefepime)
cephalosporins were the most frequently used molecules in monotherapy.
The preferred combination regimen consisted of amikacine plus piperacillin/tazobactam or a third
generation cephalosporin. The most common approach was to add a glycopeptide (immediately at
onset or within 48 hrs) to the ongoing regimen (ranging from 64% of units on LR patients to 76% in
the allogeneic transplant ones) (Table 2), with teicoplanin chosen approximately three-fold as often
Empirical antifungal therapy was administered by 81% of centers in HR and by 78% in HSCT
subjects, while in LR patients it was given less frequently but still at high rate (approximately 63%).
The choice of antifungal agent for empirical treatment varied according to the risk of infection;
however, liposomal Amphotericin was the molecule of choice in most cases.
Regarding the nursing prevention strategies, specific protocols were applied in 80% of centers, both
in ordinary and isolation wards (Table 3).
Hand washing was reported either before or after patient contact in nearly 90% of centers, with no
difference observed among the two types of wards as far as the use of antiseptic soaps (80%) and
common detergents was concerned.
Donning of caps, disposable overalls and masks differed among the two wards, reaching almost
90% in the isolation wards as compared to 50% in the ordinary wards.
Overshoes were mainly employed in isolation wards (60%). Gloves use did not substantially differ
regardless the type of wards. In the isolation wards, nurses took care of the patient’s hygiene
exclusively in 40% of cases; sterile water was used in 20% and antiseptic soap and sterile sheets in
50% of cases.
In need of patient transfer, masks were used in 80% of cases, independently of ward type and
FFP2/FFP3 type were employed in 30% of isolation ward patients only.
Disposable material and chlorine-containing agents were used for room cleaning in more than half
of the centers, independently of the ward type.
The preparation of chemotherapeutical agents and parenteral nutrition bags was centralized in 50
and 80% of centers, respectively.
In 80% of centers food was prepared as pre-packed individual meals and was distributed employing
standard precautions (donning cap, mask and washing hands) in the same percentage, while gloves
were used in less than half of the centers.
Patients suffering from neutropenia may undergo severe infections and the risk increases according
to the duration and degree of the neutropenia. Surveys on the management of FN have been carried
out only in adult populations3-5, and no surveys in the pediatric hematology-oncology population
have been published.
Furthermore, scant data have been reported and no guidelines on antimicrobial prophylaxis have
been outlined for this patient group.
Moreover, empirical therapies have been assessed in few pediatric trials, and not all molecules have
been approved for pediatric use.
The data collected in our survey add an interesting contribution to the field. The use of antibacterial
prophylaxis, despite the absence of recognized guidelines, is frequently employed, even in LR
The use of antibacterial prophylaxis in HR subjects is now widely accepted in adult populations,
and this is reflected in our pediatric survey. In pediatric transplant patients an ad hoc prophylaxis is
almost always used, according to adult guidelines6-7. The lack of proper recommendations could
explain the very heterogeneous use of antimicrobials in the transplant setting, whereas in LR and
HR patients data show a prevalent use of amoxicillin/clavulanate, and a relevant use of
fluoroquinolones, consistently with relevant pediatric studies8-9. Furthermore we observed that 80%
of HR patients undergo an antifungal prophylaxis, and 47% of LR patients also receive such
prophylaxis. Differently from adult patients10-11, no well designed clinical trials evaluating
antimycotic prophylaxis in children have been performed, and limited evidence of benefit has been
provided by few prospective and retrospective studies.
The Second European Conference on Infections in Leukemia guidelines underline that antiviral
prophylaxis is indicated in HSV-seropositive patients undergoing ALLO-SCT (AI) and in HSV-
seropositive patients treated with chemotherapy for acute leukemia (BIII)12. Notwithstanding, our
data show that, in addition to HSV-positive patients, also the majority of HSV-negative subjects
received antiviral prophylaxis.
Anti-PCP prophylaxis resulted widely used in all patient categories.
This survey has shown that the most commonly used antibiotic for first-line empiric treatment in
pediatric neutropenic patients is represented by third generation cephalosporins or by piperacillin-
tazobactam in combination with an aminoglycoside, thus showing that combination therapy is
widely employed in all patient groups, even in LR subjects (about one half of the patients).
The rationale for the use of combination therapy is the rapidly bactericidal action of amikacine, its
synergy with β-lactams and a less common onset of resistance.
Antibiotic monotherapy is still less frequently used, despite the positive results of meta-analyses on
the empiric treatment of febrile neutropenia in adults13-14. These studies suggest that monotherapy is
preferable, and treatment with a single drug belonging to the beta-lactam class is associated with
better outcome and survival, while side effects are more frequent with combination therapy
(particularly as far as nephrotoxicity is concerned), as confirmed by recent publications15-16.
In the HSCT patient group (both autologous and allogeneic), combination therapy is less frequently
used (55% for autologus and 67% for allogeneic tranplants), as compared to LR and HR groups
(57% on LR and 81% on HR), probably due to a better management of HSCT patients on the basis
of more recent evidences. Addition of a glycopeptide, such as teicoplanin or vancomycin, to the
empiric therapy has generated a heated debate on the risk of development of resistance, especially
Our survey showed that 64 to 76% of our different patient categories receive a glycopeptide at the
beginning of the empirical therapy or within 48 hours; however, this practice is not supported by the
indications reported in the current literature. Present evidence shows that the addition of anti Gram-
positive treatment with glycopeptides, in the absence of proven Gram-positive infection, does not
improve outcome, and is associated with increase of adverse events17. Their empirical use is
currently recommended only in case of clinical suspicion of a catheter-related infection, skin and
soft tissue infections, bone and joint infection, and severe mucositis18-19.
The empirical antifungal therapy is adopted in 63% of centers for LR patients and in more than 70%
for patients belonging to other categories. Only two randomized studies have been carried out in
pediatric patients, but none of them were controlled with nil or placebo20-21. A recent Italian
randomized study indicated empirical antifungal therapy clearly not to be necessary in LR patients
(D. Caselli in press). This results confirm the need of a different approach, made possible by recent
improvement of diagnosis, with the use of pre-emptive antifungal therapy, aimed at treating a
fungal disease when suggestive but not definitive diagnosis is present.
Many drugs have been tested for this indications, and this heterogeneity was reflected in our survey;
only a recent pediatric study was published on liposomal Amphotericin B vs Caspofungin20.
The nursing survey confirmed that Standard Precautions are applied in the majority of centers
(protocols are used in 80% of them), where they represent a mainstay for preventing infection
transmission during routine patient care.
In conclusion, our survey was focused only on antimicrobial agents and nursing prevention
procedures, but at the same time contributes an original snapshot of the actual prescribing practices
in children with cancer. A high number of AIEOP units are still using combination therapy in the
empirical treatment of FN, despite indications available in literature. Antifungal prophylaxis was
also widely used in all categories, which is not in line with what reported in literature so far. As far
as empirical antifungal therapy is concerned, its use in LR category is still high, despite adult
guidelines and pediatric studies do not recommend it in this setting.
This survey confirms the absolute need of accurate guidelines and/or recommendations for the
treatment of neutropenia in children affected by cancer. To this end, well designed clinical trials are
Cagliari, Ospedale Regionale per le Microcitemie, Adele Sanna; Padova, Dipartimento di
Pediatria Università di Padova, Simone Cesaro; Verona, Policlinico “G.B: Rossi”, Pierluigi
Marradi Bolzano, Ospedale Regionale, Laura Battisti; Tricase, Ospedale Card. G. Panico, Adele
Civino Milano, Policlinico San Raffaele, Sarah Marktel; Milano, Ospedale Niguarda, Fedeli
Catanzaro, Ospedale Pugliese-Ciaccio, Caterina Consarino; Pescara, Ospedale Civile, Giuseppe
Fioritoni; Udine, Policlinico Universitario, Agostino Nocerino; Pisa, Azienda Ospedaliero
Universitaria Pisana, Claudio Favre; Bologna, Policlinico Sant’Orsola Malpighi, Arcangelo Prete
Varese, Ospedale Filippo Del Ponte, Silvana Binda Napoli, Ospedale Cardarelli, Fiorina Casale
Napoli, Ospedale Santobono, Nicoletta Marra Rimini, Ospedale Infermi, Roberta Pericoli Ancona,
Ospedale Salesi, Pierani Cosenza, Ospedale Annunziata, Carpino Novara, Azienda Ospedaliera
Maggiore della carità, only nursing Pesaro, Ospedale San Salvatore, Guiducci Lecce, Ospedale
Authorship and Disclosures
SL originated the study and designed the questionnaire, SL, GP, LF, GMM and AS provided input
into design of questionnaire, built the electronic database, contributed to the interpretation of data;
SL, GP, LF wrote the paper; GMM, EC, SC, MRR, AB,GZ, FN, ML, RDS, OZ, MC, DC answered
to the surveys, gave comments, and approved the manuscript.
The authors reported no potential conflicts of interest.
This work was supported by the Italian Association of Pediatric Haemathology and Oncology
(AIEOP). We thank all the centers for their participation in this survey with a prompt response.
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Patients. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious
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Table 1. Prophylaxis (antibacterial, antimycotic, antiviral, anti PCP).
antibacterial (%) antimycotic (%) antiviral (%) anti-PCP (%)
LR (neutrophil count < 10 days) 40 47 20 85
HR (neutrophil count > 10 days) 63 81 28 91
autologous transplant 78 91 62 100
allogenic transplant 78 94 95 100
Table 2. Empirical antimicrobial therapy,
LR (neutrophil count < 10 days) 57 43 64 63
HR (neutrophil count > 10 days) 81 19 71 81
autologous transplant 55 45 71 73
allogenic transplant 67 33 76 78
1. at start of treatment or after 48h
2. after 5-7 days of antibiotic treatment
Table 3. Nursing prevention/precautionary rules.
Use of protocols
Hand washing before/after the contact with the patient
Use of antiseptic soap
Use of cap, disposable overall, mask
Use of overshoes in isolation ward
Patient’s hygiene procedures in isolation ward
Antiseptic soap and sterile sheets
Use of mask during patient’s transport
Room cleaning with disposable material and chlorine by-products
Prepacked individual meal