Month: August 2013

The Antifungal Therapy in Cancer Patients with Neutropenia Fever

August 22, 2013 Infectious Diseases, Pharmacotherapy, Respirology, Therapeutics No comments , , ,

Generally, IDSA guideline divided antifungal therapy in cancer patients with FN into two stragetries: empirical antifungal therapy and preemptive antifungal therapy. The former refers to initiation of an antifungal agent at the first possible clinical evidence of fungal infection, which is usually persistent or recrudescent fever or after day 4 of empirical antibiotic therapy. While preemptive antifungal therapy refers to more-targeted, less broad treatment of only those patients with additional findings suggestive of invasive fungal infection, such as serologic test results or chest CT findings.

Due to that clinical manifestations are nonspecific in the early stages of incubating infection, the diagnosis of invasive fungal infection is especially difficult.

Empirical Therapy

High-risk patients who have received intensive cytotoxic chemotherapy are at risk for invasive fungal infection. These fungal pathogens include different kinds of Candida species, molds such as aspergillosis, zygomycosis, and fusariosis. The profound and prolonged neutropenia is a risk factor for invasive fungal infections (IFIs). Patients treated for acute myeloid leukemia are at greatest risk for IFIs with molds, which is 20 times greater than patients with lymphoma and multiple myeloma.

Since that clinical manifestations are nonspecific in the early stages of incubating infection, the diagnosis of invasive fungal infection is especially difficult, and a delay to initiation of therapy might be dangerous, empirical antifungal therapy for persistent or recrudescent neutropenic fever syndrome has been the standard approach for many decades.

Generally, empirical antifungal therapy is instituted for the treatment of “occult” fungal infection presenting as persistent neutropenic fever despite 4-7 days of empirical antibiotic therapy. By this criteria approximately 22%-34% of neutropenic patients with cancer will receive an antifungal drug, but only ~4% have a demonstrated invasive fungal infection. Given that fever is an especially nonspecific surrogate for invasive fungal infection, the true utility of requiring empirical antifungal therapy for every neutropenic patient on the basis of persistent fever alone must be questioned.

The choice of empirical antifungal therapy is basd on likely fungal pathogens, toxicities, and cost. If antifungal prophylaxis has not been given, then candidemia is initially the greatest concern, while of note if fluconazole prophylaxis had been given before, fluconazole-resistant Candida infections, such as Candida krusei or Candida glabrata, or an invasive mold infection would be more likely. If patients have receiving mold-active prophylaxis, there has been insufficient data upon which to base a specific empirical antifungal choice, but a switch to an IV anti-mold agent within a different antifungal class seems prudent.

Amphotericin B desoxycholate has been the standard empirical choice for over 3 decades; clinical trials have identified roles for other antifungal agents, such as liposomal amphotericin B, itraconazole, voriconazole, caspofungin, and so on. But none of these alternatives have proven to have an efficacy advantage, while they have generally been less toxic than amphotericin B desoxycholate.

Preemptive Therapy

Several new technologies facilitate the early detection of fungal infections, which have prompted a critical re-assessment of whether empirical antifungal therapy is mandatory for all persistently febrile neutropenic patients. These new technologies include serum tests for fungal antigens such as β-(1-3)-D glucan test and the galactomannan test, DNA tests such as polymerase chain reaction (PCR) assays for fungal detection, and high-resolution chest CT.

The β-(1-3)-D glucan test detects most of the relevant fungal pathogens, including Candida species, Aspergillus species, Pneumocystis species, and Fusarium species (but not the zygomycetes agents or Cryptococcus species). A positive test result preceded clinical symptoms of IFI in many patients. However, hemodialysis, hemolysis, serum turbidity, hyperlipidemia, visible bilirubin, use of blood products including immunoglobulin and albumin, bacteremia, and the specimen’s exposure to gauze may confound interpretation of the test.

The galactomannan assay detects only Aspergillus species and Penicillium species. But the performance of the galactomannan assay may be confounded by concomitant use of β-lactam/β-lactamase combinations, such as piperacillin-tazobactam (false positives) or anti-mold antifungal agents (false negatives).

PCR assays for fungal detection in blood and BAL (bronchoalveolar lavage) fluid are also being developed and tested, but none are yet commercially available.

CT may reveal abnormalities in either the lungs or the sinuses. Macronodules with or without a halo sign are the most typical findings associated with invasive aspergillosis on chest CT at the initial diagnosis and are evident during neutropenia. The halo sign represents edema or blood surrounding the nodule. Other later manifestations include nodular,wedge-shaped, peripheral, multiple, or cavitary lesions. An aircrescent sign is insensitive and generally appears late, if at all.

Preemptivemanagement, using a combination of clinical, serologic, and CT evidence to initiate antifungal therapy, has been evaluated in several trials. Remember that approximately 22%-34% of neutropenic patients with cancer will receive an antifungal drug, but only ~4% have a demonstrated invasive fungal infection. In a 2005 pilot study serial serum galactomannan tests and early CT were applied prospectively in a preemptive treatment algorithm that lead to nearly 78% reduction (from 35% to 8%) in the use of antifungals among 41 neutropenic patients who would otherwise have qualified for empirical antifungal treatment on the basis of persistent or recurrent fever, without compromising outcomes.

While preemptive antifungal therapy refers to more-targeted, less broad treatment of only those patients with additional findings suggestive of invasive fungal infection, if those tests described above (serologic, DNA, CT) suggested a IFI, then antifungal therapy that covers a broader range of fungal pathogens, including molds should be quickly applied using one of the broad-spectrum antifungals that has documented efficacy in the empirical setting.

At last, a number of important issues about preemptive therapy require further study, which limit the expanding application of this approach.

The Mangement of Relapsed AML

August 12, 2013 Chemotherapy, Hematology, Pharmacotherapy, Therapeutics, Transplantation No comments ,

The only cure of an adult with relapsed AML is a transplantation. However, three important questions shoul be solved when managing relapsed AML.

  1. Whether the patients with relapsed AML should receive a transplantation in untreated relapse rather than undergo reinduction therapy.
  2. Which regimen should be offered to patients with relapsed AML for the purpose of reinduction.
  3. Once the patient with relapsed AML achieve CR2, should conslidation be administered before transplantation.

Question One

In early relapse a transplantation can be performed safely with an outcome that is probably not significantly inferior to performing this in CR2. However, for relapsed AML patients who have a long duration of CR1, there is a greater than 50% chance of achieving CR2 and since it is always preferable to undergo a transplantation while in CR2. If, on the other hand, the duration of CR1 whould be less than 6 months, where the likelihood of achieving CR2 is no greater than 20%, patients with relapsed AML should be proceeded to an allogeneic transplantation in an untreated first relapse.

But there is a expection, it is older individuals with relapsed AML, more than or equal to 60 to 65 years. In these patients a RIC often is the preferred conditioning regimen before transplantation, but the likelihood of a cure when transplantation a patient with elevated blasts with RIC is low, where our own preference in this case would be to administer one cycle of induction therapy in an attempt to obtain a better control of the disease before transplantaion.

Question Two

There is no evidence that any given regimen is superior and much of standard practice is guided by unsubstantiated opinion. Although in theory the use of a non-cross-resistant agent has intuitive appeal, there is no evidence that the efficacy of high-dose cytarabine as a salvage regimen is lessened by the prior use of this agent in consolidation, particularly after a long CR1. Furthermore, although commonly used with or without anthracyclines, etoposide, mitoxantrone, fludarabine, amsacrine, or asparaginase, there is no information collected prospectively to indicate that this is more efficacious than high-dose cytarabine alone. But of note that regimens that do not include cytarabine are equally effective for relapsed patients.

Question Three

For a patient in CR2, some investigators would add consolidation before an allogeneic transplantation if the patient is medically fit, even if this is not the practice in CR1. But some experts would elect to proceed directly to transplantation, with the primary consideration being to reduce transplantation-related toxicity.

Antimicrobial Therapy in Neutropenic and Fever Patients with Cancer (Modification and Duration of Antibiotic Therapy)

August 10, 2013 Hematology, Infectious Diseases, Pharmacotherapy, Therapeutics No comments ,

Once we have initiated empirical antibiotics for fever, all neutropenic patients must be monitored closely for response, adverse effects, emergence of secondary infections, and the development of drug-resistant organisms.

With empirical antibiotics, the median time to defervescence in patients with hematologic malignancies, including HSCT, is ~ 5 days, whereas for patients at lower risk with solid tumor, defervescence occurs at a median of 2 days.

After initial empirical antiboitic therapy for 2-4 days, patients can be categorized into two groups, unexplained fever (response, persistent/recurrent fever) or documented infections. Note that this classification method is not inconsistent with the method used in the risk evaluation (high-risk and low-risk).

Patients with unexplained fever and respond to initial therapy

Patients with unexplained fever who are responding to initial empirical therapy may be maintained on that initial regimen until the recovery of ANC to >500 cells/mm3. If initial regimen  has been IV antibiotics, patients who meet criteria for being at low risk (please refer to post “Antimicrobial Therapy in Neutropenic and Fever Patients with Cancer [Risk Evaluation and Initial Therapy]” for more informaiton) and can tolerate oral medications may be candidates for transitioning to combination oral antibiotics. Some low risk patients might be managed as outpatients with careful selection, however, inpatient treatment is the standard approach for managing an FNE.

Patients with persistent fever in an otherwise asymptomatic and hemodynamically stable status

Persistent fever in an otherwise asymptomatic and hemodynamically stable patient is not a reason for undirected antibiotic additions or changes. Specifically, there is no proven advantage to adding vancomycin empirically in the setting of persistent or recrudescent fever and neutropenia. If treatment with vancomycin was added empirically at the outset of therapy, as part of the initial regimen, it should be stopped if blood cultures have incubated for 48 hours and demonstrated no pathogenic gram-positive prganisms.

A swtich from one empirical monotherapy to another or the additon of an aminoglycoside to the treatment regimen is also not generally useful, unless there is a need for an expanded spectrum of coverage as dictated by clinical or microbiologic data.

An importan exception is for low-risk outpatients who are being treated with empirical oral or IV therapy. If they have not responded with improvements in fever and clinical symptoms with 48 hours, they should be re-admitted to the hospital and re-evaluated, and an IV broad-spectrum antibacterial regimen should be initiated.

Hemodynamically unstable neutropenic patients with persistent fever without a clear source

This type of patients should have their antimicrobial regimen broadened to ensure adequate coverage for drug-resistant gram-negative and gram-positive organisms, as well as for anerobes. This may be achieved by a change from an initial cephalosporin to an anti-pseudomonal carbapenem, such as imipenem or meropenem, as well as by the prompt addition of an aminoglycoside, ciprofloxacin, or aztreonam together with vancomycin. The addition of anti-Candida coverage with fluconazole or a newer antifungal agent (if fluconazole is already being given prophylactically) is also prudent in for patients who experience systmic inflammatory response syndrome during neutropenia.

High-risk patients who have persistent or recurrent fever after 4-7 days of treatment with broad-spectrum antibacterials and who are anticipated to have prolonged neutropenia lasting >10 days are candidates for the additon of empirical anti-mold therapy. We will discuss the antifungal therapy in another post.

Unexplained fever patients with neutropenia who have recurrent or persistent fever > 3 days in duration despite empirical antibiotic therapy should prompt a thorough search for a source of infection, including a new set of blood cultures and symptom-direction collection of other diagnostic tests.

Break-through infections, such as C. difficile-associated diarrhea or a catheter-related skin or bloodstream infection, are not uncommon. Empirical treatment of C. difficile with vancomycin or metronidazole may be employed for patients with symptoms of abdominal cramping and diarrhea until diagnostic results are available or if C. difficile infection is strongly suspected clinically.

Documented Infections

When clinically or microbiologically documented infection have been identified, we called the infection documented infection. Identification of a clinically or microbiologically documented infection should guide any changes to the initial empirical antibiotic regimen. Antimicrobial modifications should be based on identified or suspected pathogens (if none can be cultured) and on available antimicrobial susceptibility data, including local susceptibility and resistance trends. Generally document infections include gram-negative bloodstream infections, gram-positive bloodstream infection, pneumonia, oral ulcerations or esophagitis, and so on.

Gram-negative bloodstream infections in patients with neutropenia may initially be treated with combinations of β-lactam or carbapenem agents plus aminoglycosides or fluoroquinolones to provide broad initial coverage of possible multidrug-resistant pathogens at the outset of treatment. Once the patient is stable and in vitro susceptibilities are known, antibiotic treatment can be reduced to monotherapy with β-lactam agent, which is adequate for most simple bacteremias during neutropenia.

For patients with gram-positive bloodstream isolates, or with skin and soft-tissue infections, the early addition of vancomycin (or linezolid or daptomycin) to the treatment regimen is recommended until susceptibility results are available for the organism(s) that have been isolated.

Pneumonia in FN patients should generally be treated as a heallthcare-acquired infection. Immunosuppressed patients and those who have been hospitalized or received antibiotics within the preceding 90 days are considered to be among those at high risk for developing pneumonia with multidrug-resistant pathogens. An initial broad-spectrum treatment with combinations of a β-lactam or carbapenem plus an aminoglycoside or antipseudomonal fluoroquinolone is recommended for these patients. In severe cases of pneumonia, as documented by hypoxia or extensive infiltrates, or if MRSA is suspected, the addition of vancomycin or linezolid to the treatment regimen is in order.

Oral ulcerations or espphagitis may represent HSV or Candida infections in hight-risk patients, so empirical additions of acyclovir and/or fluconazole or another antifungal are appropriate.

The onset of severe abdominal pain, typically in the right lower quadrant, suggests neutropenic enterocolitis (“typhlitis”). Patients with neutropenic enterocolitis should be treated with an expanded broad-spectrum regimen, although the most effeicacious regimen is unknown. Because anaerobes and gram-negative organisms predominate in causing neutropenic enterocolitis, monotherapy with piperacillin-tazobactam or a carbapenem or a combination of an anti-pseudomonal cephalosporin plus metronidazole are appropriate antibiotic regimens. There is less evidence to support routine additons of vancomycin or an antifungal agent to antimicrobial regimens.

Duration of Antimicrobial Therapy

Unexplained fever in low-risk patients should continue antibiotic therapy until resolution of both fever and neutropenia. This is the standard approach. Certain predictive hematologica criteria may be substituted as an endpoint for resolution of neutropenia, including a daily increase in the absolute phagocyte count (bands and mature neutrophils combined), the absolute monocyte count, or the reticulocyte fraction.

Unexplained fever in high-risk patients should continue antibiotic therapy until there is evidence of marrow recovery too.

For documented infections, the duration of antibiotic therapy should be appropriate for effective eradication of the identified infection. Most bacterial bloodstream infections, soft-tissue infections, and pneumonias require 10-14 days of appropriate antibiotic therapy. Antibiotic treatment may therefore extend beyond resolution of fever and neutropenia. The antibiotic spectrum can be appropriately narrowed to specifically treat the defined infection once fever has resolved. In the absence of significant impairment of gastrointestinal function (e.g., nausea, vomiting, diarrhea, malabsorption, and poor oral intake), an oral antibiotic regimen may be undertaken to complete the full course of therapy.