Pneumococcal and Meningococcal Vaccination

To provide a guide for the use of antimicrobial agents for chemotherapy-induced fever and neutropenia in patients with cancer. The patient population targeted included adult and pediatric patients with neutropenia.

For this guideline document, the IDSA Standards and Practice Guidelines Committee reconvened many members of their original guideline panel, together with additional experts, in the management of patients with fever and neutropenia. The committee included experts in infectious diseases, oncology, and hematopoietic stem cell transplantation (HSCT) in both adult and pediatric patients. The literature was reviewed and graded according to a systematic weighting of the level and grade of the evidence for making a recommendation.

Patients were undergoing the active treatment phase of care.

Antibiotic Prophylaxis 

Fluoroquinolone prophylaxis should be considered for high-risk neutropenic patients (patients expected to have absolute neutrophil counts (ANCs) of 100 cells/mm³ or lower for more than seven days. Levofloxacin and ciprofloxacin are the agents that have been evaluated the most and are generally equivalent, although levofloxacin is preferred for patients at risk for oral mucositis-related invasive viridans group streptococcal infection (B-1). The addition of a gram-positive active agent to fluoroquinolone prophylaxis is not recommended (A-1). Antibacterial prophylaxis is not indicated for low-risk patients anticipated to be neutropenic for less than seven days (A-III). 

Antifungal Prophylaxis

Patients at high risk for candida infection, such as recipients of allogeneic HSCT and patients with acute leukemia undergoing intensive chemotherapy, should be treated with antifungal prophylaxis with fluconazole, itraconazole, voriconazole, posaconazole, micafungin, or caspofungin (A-I). Patients aged 13 years or older who are undergoing intensive chemotherapy for acute leukemia or myelodysplastic syndrome who are at high risk for aspergillus infection may be treated with posaconazole for antifungal prophylaxis (B-I). Prophylaxis against aspergillus infection is not effective in recipients of pre-engraftment HSCTs, but it is recommended for patients with a prior history of invasive aspergillosis (A-III), anticipated neutropenia of at least two weeks (C-III), or a prolonged period of neutropenia prior to transplantation (C-III). Antifungal prophylaxis is not recommended for patients with an anticipated duration of neutropenia of less than seven days (A-III). 

Antiviral Prophylaxis

Herpes simplex virus–positive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis (A-I). Annual influenza vaccination is recommended for all patients being treated for cancer (A-II). The optimal timing has not been established, but serologic responses may be best between chemotherapy cycles (more than seven days after the last treatment) or more than two weeks prior to the start of therapy (B-III). 

Colony-Stimulating Factors

Colony-stimulating factors are recommended for prophylaxis against neutropenia when the anticipated risk of fever and neutropenia is 20% or greater.

Prevention of Catheter-Related Bloodstream Infections

Hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine are recommended for all central venous catheter insertions (A-I). 

Hand Hygiene

Hand hygiene is the most effective means of preventing infection in the hospital (A-II).

Environment

HSCT recipients should be in private rooms (B-III). Patients with neutropenia do not need to be placed in single-patient rooms. Allogeneic HSCT recipients should be in rooms with more than 12 air exchanges, high-efficiency particulate absorption filtration, and positive pressure (A-III). Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients (B-III). 

Isolation and Barrier Precautions

No specific protective gear (gowns, gloves, or masks) are necessary during the routine care of neutropenic patients. Standard barrier precautions should be used for all patients when contact with body fluids is anticipated.

Food

In general, food should be well cooked. Well-cleaned uncooked fruits and vegetables are acceptable.

Skin and Oral Care

Daily showers are recommended to maintain skin integrity (expert opinion). Patients should brush their teeth two times per day or more with a regular toothbrush, and flossing can be performed if it can be performed without trauma (expert opinion). Patients with mucositis should rinse their mouths with sterile water, saline, or sodium bicarbonate rinses four to six times per day (expert opinion). Menstruating immunocompromised women should avoid tampons (expert opinion). Rectal thermometers, enemas, suppositories, and rectal examinations are contraindicated for patients with neutropenia (expert opinion).

This was a comprehensive guideline developed by the Infectious Diseases Society of America (IDSA) to guide clinicians in the care of patients with chemotherapy-induced neutropenia and in the management of febrile neutropenia. The full guide can be located at http://cid.oxfordjournals.org/content/52/4/e56.full.

To provide a guideline for the use of antimicrobial prophylaxis for patients in an allogeneic bone marrow transplantation setting.

This was classified as a guideline of evidence-based medicine criteria.  The author used a table to rate available evidence-based articles about antimicrobial prophylaxis in allogeneic bone marrow transplant recipients.

• The phase of care was active treatment surrounding hematopoietic stem cell transplantation (HSCT).
  • Pre-engraftment occurred until day 30.
  • Post-engraftment occurred from days 30 to 100.
  • Late post-engraftment occurred after more than 100 days.

Evidence was rated using this table.   

Category, Grade                        Definition

Strength of Recommendation
A             Good evidence to support a recommendation for use (strongly recommended)
B             Moderate evidence to support a recommendation for use (generally recommended)   
C             Poor evidence to support a recommendation (optional)
D             Moderate evidence to support a recommendation against use (generally not recommended)
E             Good evidence to support a recommendation against use (never recommended)

Quality of Evidence
I                Evidence from at least one well-executed randomized, controlled trial
II               Evidence from at least one well-designed clinical trial without randomization; cohort or
                     case-controlled analytic studies (preferable from more than one center); multiple time-series    
                     studies; or dramatic results from uncontrolled experiments
III              Evidence from opinions of respected authorities based on clinical experience, descriptive
                      studies, or reports of expert committees.

Bacterial

Al:  Fluoroquinolones should be used for antibacterial prophylaxis.
BII:  Pneumococcus prophylaxis should be used for any patient with active chronic graft-versus-host disease and for the remainder of the patient's life following splenectomy.
BIII:  Patients already receiving Pneumocystis carinii pneumonia (PCP)-prophylaxis with trimethoprim/sulfamethoxazole (TMP-SMZ) should have additional prophylaxis based on the epidemiology for the area and patterns of resistance.
DI:  Anti-infectious prophylaxis with intravenous immunoglobulins should be used.

Cytomegalovirus

Preventing Exposure

AIII:  All patients being considered for allogeneic stem cell transplant should have anti-cytomegalovirus (CMV) IgG-antibody testing.  This is recommended to establish the risk for reactivation (de novo infection).
BIII:  CMV-negative transplant candidates and patients should not share drinking cups or eating utensils that have been used by others.  If a patient who is CMV-negative is in a monogamous relationship, his/her partner is advised to be CMV-serotested. If his/her partner is positive or the patient is not in a monogamous relationship, condom use during sexual contact is recommended.
Al:  Transplant recipients who are CMV-seronegative should receive blood products from donors who have also tested negative. When blood banks lack CMV-negative donors, only leukocyte-depleted red cells and thrombocytes should be issued to this group.
DI:  CMV prophylaxis should use preparations of human immunoglobulin for CMV-negative matched related donors.

Preventing Disease and Reactivation

BIII:  For a CMV-positive recipient, most transplant physicians recommend a CMV-positive donor.
Al:  Any patient at risk for CMV disease should be screened for pp65 antigenemia or nucleic acid using real-time polymerase chain reaction (PCR) at least weekly after transplant from days 10 to 100.
Al:  Patients should begin pre-emptive therapy following one positive pp65 or two consecutive PCR results.  Pre-emptive therapy is advised for two weeks, followed by another two weeks of maintenance therapy.
AI:  In a pre-emptive setting, if the patient has resistance to ganciclovir, switching to foscarnet is recommended.
AI:  The recommendation for herpes simplex virus (HSV) reactivation in IgG-positive patients is acyclovir.  Acyclovir therapy should begin between the start of conditioning therapy and day 1 after the transplant and should continue until day 30 after stem cell transplantation.
Al:  The recommendation of drugs for prophylaxis or therapy of CMV are ganciclovir and foscarnet.  (Cidofovir has a BII recommendation.)
EI:  High-dose acyclovir and valacyclovir should be used to prevent CMV.
El:  Human immunoglobulins should be used for prophylaxis or therapy of CMV.

Herpes Simplex Virus

Preventing Exposure

AIII:  Serum tests for anti-HSV serostatus are mandatory.

Preventing Reactivation

AI:  Acyclovir should be used for standard reactivation prophylaxis, beginning between the start of conditioning therapy and day 1 posttransplant and continuing to day 30 following stem cell transplant.
CI:  Evidence is lacking for the use of acyclovir prophylaxis increased to 100 days or more.
BIII:  If repeated reactivation is present after 30 days of prophylaxis, continued therapy is recommended.
EIII:  Acyclovir is not recommended for continued HSV prophylaxis at times when gancyclovir or foscarnet is used for CMV therapy or prophylaxis because gancyclovir and foscarnet are effective against HSV in vitro.
CIII:  The effectiveness of valacyclovir and famciclovir in preventing HSV reactivation lacks the support of trials, but they are presumed effective.

Varicella-Zoster Virus

AIII:  All patients being considered for stem cell transplant should avoid contact with those suspected of active varicella-zoster virus (VZV) infection or reactivation.
BIII:  Those living with or in close contact with a transplant patient should be vaccinated before transplant.
AIII:  To prevent nosocomial spread, transplant patients with overt VZV disease are to be isolated until all lesions are crusted.
CIII:  Long-term acyclovir prophylaxis is not effective for prevention.

Epstein-Barr Virus

AIII:  Seronegative transplant candidates and patients with Epstein-Barr virus (EBV) should not share drinking cups or eating utensils that have been used by others.  If a patient negative for EBV is in a monogamous relationship, his/her partner is advised to be EBV-serotested.  If his/her partner is positive or the patient is not in a monogamous relationship, condom use during sexual contact is recommended.

Community Respiratory Virus

AIII:  Exposure prophylaxis is critical in avoiding respiratory syncytial virus, influenza, parainfluenza, and adenovirus.
BII:  Those living with or working on units with transplant patients should be vaccinated for influenza.
BIII:  Patients should receive a two-week course of amantadine or rimantadine for chemoprophylaxis if vaccination occurred during an influenza outbreak.

Yeasts

CIII:  Foods at risk for allowing fungi to colonize in the gastrointestinal (GI) tract should be restricted.
AIII:  Hand washing and disinfecting by personnel should be performed to prevent GI-colonizing fungi from reaching patients at risk.
Al:  It is recommended to take fluconazole 400 mg/day IV or orally  to prevent yeast infections in allogeneic stem cell recipients while they are neutropenic.  
BI:  One study found itraconazole superior to fluconazole but noted that GI side effects can limit oral use.
EII:  Itraconazole is not recommended for yeast prophylaxis because of interactions with metabolism of busulfan.   
EI:  Itraconazole is not recommended for yeast prophylaxis because of interactions with metabolism of cyclophosphamide.

Molds

AII:  Stem cell transplant candidates and patients must avoid construction, renovation, or other areas with dust exposure.
AII:  Use of air conditioning with high-efficiency particulate absorption filtration or laminar air flow in transplant units reduces mold spore presence in the air and mortality related to fungal invasion.
BIII:  Transplant patients should wear appropriate fitting masks when traveling through or to areas off the transplant unit.
BII:  No drug demonstrates effectiveness for the primary prophylaxis of aspergillosis following bone marrow transplant.      
DII:  Itraconazole capsules are limited based on low bioavailability.
AI:  For patients with acute leukemia, itraconazole solution reduced the incidence of invasive aspergillosis if plasma levels were greater than 500 ng/mL.
AIII:  Secondary prophylaxis with a drug having systemic effectiveness was recommended despite a lack of trial evidence.

Pneumocystis jiroveci (formerly Pneumocystis carinii)

BIII:  Stem cell recipients are not to have contact with patients with known PCP.
AII:  TMP-SMZ prophylaxis should be used for all allogeneic transplant patients beginning at engraftment until the completion of immunosuppressive therapy or when chronic graft-versus-host disease is resolved.  
AII:  Dapsone or aerosolized pentacarinate should be used when TMP-SMZ is contraindicated or when the patient does not tolerate it.  Higher breakthrough rates are noted with these alternate drugs.

Toxoplasmosis

AIII:  Allograft recipient candidates should be tested for Toxoplasma gondii antibodies to identify risk for reactivation.  Education should include ways to avoid exposure.
CIII:  Toxoplasma prophylaxis at the time of acute graft-versus-host disease or secondary prophylaxis following history of toxoplasmosis should be performed.

Food

BIII:  Foods with a risk of fungi, bacteria, or other contamination should be eliminated during and following stem cell transplant, and safer alternatives should be used (e.g., pasteurized cheese instead of unpasteurized cheese).

Vaccination After Stem Cell Transplant

AIII:  Immunity against specific pathogens should be analyzed one year after allogeneic transplant with reimmunization with inactivated vaccine or toxoids.

The article also states that stem cell transplant recipients are not to receive live-attenuated virus vaccination during the two years after transplant.  No rating was provided for this “strictly contraindicated” recommendation.

• Some clinical trials during the 1990s did not specify allograft recipients for inclusion, so patients undergoing allograft and autologous stem cell transplants may have been included.
• Placebo studies are rare for this area of study, so most trials compared an old medication with a new one.
• Advances in allogeneic stem cell transplantation over the past 15 years make comparisons of patients who received growth factor stimulation after transplant and those who did not, which is problematic.
   

Specific recommendations with strong evidence, AI and EI, should be included in nursing practice guidelines with recommendations for and against practice, respectively.  Other recommendations should not be included until higher evidence from trials can be demonstrated or included in the “Evidence Not Established” category. 

To update previous recommendations (released in 1995 and last updated in 1999) for vaccinations in pediatric and adult hematopoietic stem cell transplantation (HSCT) recipients.

This resource was classified as a guideline.  

Recommendations for 18 vaccinations were drawn from published data, most of which were specific to stem cell transplantation recipients. The strength of each recommendation and the quality of evidence supporting it are noted in a summary table, using grading standards endorsed by the Centers for Disease Control and Prevention (CDC).

• Patients were undergoing long-term follow-up care.
• The study has clinical applicability for late effects and survivorship, as well as pediatrics.

Patients undergoing HSCT are advised to be vaccinated against bacterial and viral infections beginning six to 12 months after transplantation, with the exception of meningococcal vaccine. Because polysaccharide pneumococcal vaccines are ineffective in patients with chronic graft-versus-host disease (GVHD), antibiotic prophylaxis should be given to patients with GVHD in addition to the pneumococcal vaccine. Three doses of Haemophilus influenzae type B (Hib) conjugate vaccine, tetanus toxoid vaccine, and diphtheria toxoid vaccine should be given beginning six months posttransplantation and spaced one to three months apart. Routine vaccination against pertussis was not recommended. Bacillus Calmette-Guerin vaccine was specifically contraindicated in this population.

Inactivated influenza vaccine was recommended for all patients undergoing HSCT, beginning no earlier than four to six months posttransplantation.  For patients undergoing allogeneic HSCT, influenza vaccination should be given annually (prior to influenza season) and continue at least as long as the patient remains immunocompromised. For patients undergoing autologous HSCT, the duration of yearly influenza vaccination should be assessed individually. Patients undergoing HSCT and those in close contact with them (e.g., family members and hospital staff who care for these patients) should be vaccinated against polio using the inactivated poliovirus vaccine only.

Patients undergoing HSCT should receive three doses of the inactivated vaccine, beginning six to 12 months following transplantation, with subsequent doses one to three months apart. Hepatitis B vaccination (HBV) is recommended for patients undergoing HSCT living in countries where HBV is recommended for the general public and should be given six to 12 months following HSCT. Vaccination with two doses of hepatitis A may be considered for patients who live or plan to travel to areas where the disease is endemic. The measles, mumps, and rubella (MMR) vaccine is generally recommended to begin no sooner that 24 months after HSCT but may be considered earlier if there is a high risk of measles. MMR is contraindicated in patients with chronic GVHD or ongoing immunosuppression. To prevent varicella, seronegative family members should be immunized with the varicella-zoster virus (VZV) vaccine. Seronegative patients undergoing HSCT may be considered for the VZV vaccine two years following transplantation, provided they are free of GVHD or ongoing immunosuppression. Vaccination of seropositive patients undergoing HSCT is not recommended.

Vaccination against yellow fever should only be considered in patients undergoing HSCT who must travel to areas of the world where yellow fever is endemic. Guidelines for serological testing of immune status are also included, again following the CDC grading standards. Immunity testing before vaccination is not necessary for tetanus toxoid, diphtheria toxoid, polio, influenza, pneumococcal, and Hib but is recommended for HBV, measles, mumps, and rubella (MMR), and varicella-zoster virus (VZV). Postvaccination testing to assess immune response is not recommended for tetanus toxoid, diphtheria toxoid, polio, Hib, or influenza. It is recommended for hepatitis B, MMR, and VZV and also may be considered for pneumococcal vaccine for patients at increased risk of poor response.

This article provided a concise summary for providers to use when considering the vaccination needs of HSCT recipients. It rated the strength of each recommendation using CDC guidelines. The article was extensively referenced to aid readers who wish to delve more deeply into the studies supporting each recommendation.

To provide guidance for clinical practices for the prevention and treatment of infection in patients with cancer.

This resource is a consensus-based guideline.

Patients were undergoing the active antitumor treatment phase of care.

The guideline

• Recommends the consideration of general antibacterial prophylaxis in patients at intermediate and high risk for infection, consideration of antifungal prophylaxis during neutropenia and for anticipated mucosits, and antiviral prophylaxis for intermediate- and high-risk patients.
• Provides suggestions for specific agents for prophylaxis and treatment in various clinical scenarios.
• Outlines treatment and diagnostic/assessment approaches for neutropenic fever and specific clinical presentations.
• Notes that chlorhexidine and sliver sulfadiazine-coated short-term central catheters have been shown to decrease the incidence of catheter colonization and bloodstream infections, but not in patients with hematologic malignancies requiring indwelling catheters for approximately 20 days.
• Notes that vaccination recommendations for transplantation recipients and their household members should be performed.
• Recommends the pneumococcal vaccine in asplenic patients.

The National Comprehensive Cancer Network (NCCN) does not currently endorse the use of a vancomycin lock solution for long-term vascular access devices due to concerns about the emergence of bacterial resistance if widely used. Influenza vaccination with a vaccine that does not use live attenuated organisms can be safely given, and the guideline recommends administration at least two weeks before receiving cytotoxic therapy.

This study lacked high-quality evidence, with most recommendations being based on consensus.

This guideline provided comprehensive references to assess patient risk of infection and expert recommendations regarding interventions aimed at the prevention and treatment of infection in patients with cancer. The guideline does not discuss long-term survivorship issues in this area.

To summarize recommendations for care providers regarding screening and prevention practices for adult autologous and allogeneic hematopoietic cell transplantation survivors.

This was classified as an expert opinion.

Recommended practices were developed by a consensus panel from three major blood and marrow transplantation organizations. Most recommendations were developed from studies (not cited) identifying specific complications and associated risk factors in long-term survivors.

• Patients were undergoing long-term follow-up care.
• The study has clinical applicability for late effects and survivorship. 

Guidelines for the prevention of infection for all transplantation patients include Pneumocystis carinii pneumonia prophylaxis for six months and immunization with inactivated vaccines beginning at one year posttransplantation and annually thereafter.  Other infection prevention recommendations include antibiotic prophylaxis for encapsulated microorganisms during immunosuppressive therapy for chronic graft-versus-host disease (cGVHD), possible antifungal prophylaxis for patients on chronic steroids, adhering to the American Heart Association (AHA) guidelines of antibiotic prophylaxis for oral procedures, cytomegalovirus antigen or polymerase chain reaction testing for allogeneic hematopoietic cell transplantation recipients with chronic immunosuppression or cGVHD, and possible prophylaxis for the herpes simplex virus for those on chronic immunosuppressants for cGVHD. This article also includes recommendations for many other aspects of posttransplantation care. Recommendations are summarized in two tables, one organized by body system and the other organized by time after transplantation.

The authors did not include the sources used to arrive at the consensus recommendations, with the following exceptions:

• Recommendations for prophylactic antibiotics for oral procedures follow the AHA guidelines for endocarditis prophylaxis.
• Recommendations for annual vaccinations follow either the Center for Disease Control guidelines or the European Group for Blood and Marrow Transplantation guidelines.

To update previously published guidelines from 2000 for the prevention of infection in patients receiving any type of hematopoietic stem cell transplantation (HSCT). Patients analyzed were adults and pediatric populations receiving allogeneic or autologous HSCT.

The resource was presented as an evidence-based guideline. An international group of experts from identified professional organizations reviewed and graded evidence and developed recommendations.

• Patients were undergoing multiple phases of care.
• The study has clinical applicability for pediatric populations.

The volume and highly specific process were not discussed.

Recommendations were made, and possible opportunistic infections at pre-engraftment, post-engraftment, and late phases of HSCT were identified. Recommendations included

• Antibiotic and antifungal prophylaxis.
• Consideration of hepatitis B vaccination for those who are hepatitis B-naïve and for donors and recipients of allogeneic transplantation prior to cell collection.
• Varicella-zoster virus (VZV) vaccination for people in close contact and healthcare providers who are seronegative at least six weeks prior to HSCT contact.
• Measles, mumps, rubella (MMR) vaccination of those in close contact and healthcare workers.
• MMR patient vaccination for select groups of patients.
• Policies that prohibit visits or close contact for people with respiratory or flu-like symptoms.
• Education to reduce exposure to potential opportunistic infections.
• Pneumococcal vaccination, annual influenza vaccination, hepatitis B vaccination, consideration of hepatitis A vaccination for people in areas where hepatitis A is endemic, diphtheria vaccination for appropriate age children according to general immunization guidelines, and pertussis reimmunization of appropriate patients.

Timing and appropriate individuals for various immunizations are important considerations, and it is recommended that users of this information refer to the full report. Overall, use of live vaccines is contraindicated for these patients; vaccination is contraindicated in those with chronic graft-versus-host disease or when patients are still immunosuppressed.

Some recommendations were based on expert opinion due to lack of research evidence in the area.

Specific interventions for prevention of infection among HSCT recipients is a complex field, and healthcare providers who work with these patients need to be aware of current knowledge. Evidence in this area continues to evolve as HSCT techniques change and further evidence is gained regarding the immediate and long-term effects of HSCT.