Original Studies

Clinical and Microbiologic Outcomes of Quinolone Prophylaxis in Children With Acute Myeloid Leukemia Susanna Felsenstein, MD, MSc,* Etan Orgel, MD, MS,† Teresa Rushing, PharmD, BCPS,‡ Cecilia Fu, MD,† and Jill A. Hoffman, MD* Background: Intensifying treatment for pediatric acute myeloid leukemia (AML) has improved survival, with infections now being a leading cause of morbidity. Because quinolone prophylaxis is effective in adults with AML and in transplant populations, ciprofloxacin prophylaxis (CPx) was introduced as the standard for pediatric AML. We report here the impact of CPx in this population. Methods: Prevalence of fever and neutropenia, frequency and pathogen spectrum of infections, antibiotic use, supportive care and mortality before and after implementation of CPx were retrospectively compared in children with AML. Results: The cohort included 35 patients with de novo and 10 with relapsed AML, who together underwent 153 chemotherapy courses. Fever and neutropenia resulting in the use of empiric antibiotics occurred in 90% of chemotherapy courses (137/153); this was associated with proven bacteremia in 26%. The use of CPx did not change the incidence of febrile or infectious episodes, number of days of fever or antibiotic treatment or mortality. CPx was associated with a significant decrease in infections caused by Gram-negative rods (13.4% vs 4.7%) but a concomitant significant increase in bacteremia caused by viridans streptococci (12% vs 28%), resulting in no significant overall difference in the incidence of bacteremia between the 2 groups (35.9% vs 31.5%). Conclusions: CPx neither alter the incidence of overall bacteremia nor change the pattern of fever or use of supportive care. Our experience supports further investigation into the use of extended-spectrum quinolone prophylaxis during therapy for pediatric AML. Key Words: acute myeloid leukemia, infections, immunocompromised host (Pediatr Infect Dis J 2015;34:e78–e84)

I

n spite of improved cure and survival rates in childhood acute myeloid leukemia (AML),1 infections are a leading cause of morbidity and infection-related mortality.2,3 In adult oncology and hematopoietic progenitor cell transplant (HPCT) populations, quinolone prophylaxis decreases infection-related and all-cause mortality and morbidity.4–6 Prophylactic antibiotics increase survival and lower morbidity in children with hematologic malignancies,7–9 but no unifying recommendations for their use in specific subsets of patients have been agreed upon.2,10 The Infectious Diseases Society of America recommends quinolone prophylaxis in high-risk children including Accepted for publication October 1, 2014. From the *Division of Infectious Diseases, Children’s Hospital Los Angeles, University of Southern California; †Children’s Center for Cancer and Blood Diseases, University of Southern California; and ‡Department of Pharmacy, Children’s Hospital Los Angeles, Los Angeles, CA. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Jill A. Hoffman, MD, Division of Infectious Diseases, Children’s Hospital Los Angeles, 4650 Sunset Blvd, Mailstop #51, Los Angeles, CA 90027. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3404-0e78 DOI: 10.1097/INF.0000000000000591

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HPCT recipients and those undergoing induction chemotherapy for acute leukemia.2,11 Factors such as intensive chemotherapy regimens, prolonged neutropenia, mucosal barrier injury and use of central venous catheters increase the risk of infectious complications and are thought to have contributed to a shift from Gram-negative to Gram-positive pathogens as the leading cause of bacteremia in pediatric patients with AML.10,12 On the basis of the evidence from studies involving adult HPCT recipient and cancer populations,4,5 ciprofloxacin prophylaxis (CPx) was introduced at our institution, a large tertiary pediatric oncology center, for children with AML. We studied retrospectively the prevalence of fever and neutropenia (FN) and the pathogens identified in blood stream infections (BSIs) and other serious infections in children with AML who received CPx and those who did not.

METHODS Patients Children diagnosed with AML between January 2008 and September 2012 at Children’s Hospital Los Angeles were included. Patients with trisomy 21–associated AML, acute promyelocytic leukemia, juvenile myelomonocytic leukemia and secondary AML were excluded to increase the homogeneity of patients included and chemotherapy regimens used.

Intervention CPx was introduced in October 2010, and 15 mg/kg of ciprofloxacin was given intravenously (iv) twice daily (maximum 750 mg twice daily) during each chemotherapy course (CC) once the absolute neutrophil count (ANC) decrease to ≤0.5 × 109/L. Prophylaxis was discontinued when myeloid recovery was evident, and this was typically once an ANC of ≥0.1 × 109/L was reached.

Data Collection A retrospective chart review of clinical data was undertaken for all patients from the time of AML diagnosis to the endpoint of the observation period. Variables reported for each CC included duration of neutropenia, number and duration of febrile episodes and infections, microbiologic pathogen profile, need for imaging investigations and intensive care, duration and type of treatment antibiotics and infection-related and all-cause mortality. Observational endpoints were completion of chemotherapy with count recovery to an ANC ≥0.5 × 109/L, initiation of conditioning therapy in preparation of HPCT, initiation of palliative care, transfer to another facility and death. The study protocol was reviewed and approved by the Institutional Review Board and Ethics Committee at Children’s Hospital Los Angeles.

Definitions Fever was defined as a single measurement of a body temperature of ≥38.3°C or 2 measurements of ≥38.0°C 1 hour apart. FN was defined as fever with an ANC of ≤0.5 × 109/L. Febrile episodes were classified as culture negative with or without localizing

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signs and symptoms or as microbiologically proven bacterial or fungal infection and considered distinct if at least 5 fever-free days apart. Infections were categorized as either1 BSI defined as at least one positive blood culture yielding a bacterial or fungal microorganism or2 localized infection defined as clinical, radiological or microbiological evidence of an infectious process in the absence of a positive blood culture. Culture-negative FN was managed as a suspected infectious episode (SIE) with empiric antibiotic treatment, and daily blood cultures were drawn for the duration of fever. Localized infections were culture positive if microbiological evidence was retrieved from the site or culture negative with clinical or radiological signs of a presumed infection. Fever coinciding with cytarabine infusions and considered a drug reaction not requiring antibiotic therapy by the treating physician were excluded from analysis. Cytarabine dosage was defined as high dose at ≥1 g/m2 per dose per CC or standard dose at 0.5 × 109/L and micafungin (1 mg/kg; maximum 50 mg, iv once daily) while neutropenic. In 13 CCs, micafungin alone was used. Agents for selective gut decontamination or prophylactic granulocyte colony-stimulating factor were not given. Empiric treatment for FN consisted of a combination of either meropenem (20 mg/kg iv every 8 hours) or cefepime (50 mg/kg, maximum 2 g iv every 8 hours) with vancomycin (15 mg/kg iv every 6 hours). In patients deemed critically ill by physician assessment, an aminoglycoside was added. If culture results failed to reveal a need for continuation, vancomycin and aminoglycoside were discontinued after 48–72 hours. Meropenem or cefepime was continued until myelorecovery with modifications according to culture results and clinical response. For continued fevers of 5 days despite broad-spectrum © 2014 Wolters Kluwer Health, Inc. All rights reserved.

Quinolone Prophylaxis in Leukemia

antibiotic treatment, a work-up for IFI and empiric antifungal treatment with liposomal amphotericin or voriconazole was initiated. Patients were hospitalized when receiving chemotherapy and remained inpatient until reaching an ANC of at least ≥0.1 × 109/L. Systematic surveillance for methicillin-resistant Staphylococcus aureus (MRSA) by nasal swab is performed on every admission of MRSA-negative patients; after a positive result, the patient is considered an MRSA carrier. Rectal swab surveillance for vancomycin-resistant enterococci is not routinely performed unless during an outbreak investigation. Clostridium difficile toxin screen is only performed in symptomatic patients.

Statistical Analysis CCs were analyzed in the CPx group on an intentionto-treat basis. Factors that varied by CC within single-patient data, such as administration of CPx, number and duration of infections and febrile episodes, and cytarabine dose were analyzed per CC. Quantitative variables were reported as absolute numbers and percentages and expressed by mean and standard deviation (SD) if normally distributed and by median and interquartile range (IQR) if not. Comparisons between groups were made using the t test or Mann-Whitney test for continuous variables and the χ2 and Fisher exact tests for categorical variables. Odds ratios (ORs) and 95% confidence intervals of infections in CCs with or without CPx, potential predictors for bacteremia caused by viridans Group Streptococci (VGS), Gram-negative rods (GNR) and all-cause bacteremia were estimated using univariate regression modeling. In addition, data were stratified by patient. The Breslow-Day test for homogeneity of ORs across patients was used to identify whether differences between groups existed after stratification by individual patient. All P values were 2 sided and considered statistically significant if 1 SIE per CC. In the 137 CCs where infections were suspected, 198 SIEs occurred overall, and 51/198 (25.8%) were associated with BSIs. Number of febrile days (no CPx: median: 2.1, IQR: 0.2–10.4 vs CPx: 3.8, IQR: 9.7–1.2; P = 0.15), incidence of BSIs [no CPx: 31.5% (28/89) vs CPx: 35.9% (23/64), P = 0.60] and number of any culture-positive infectious episodes [no CPx: 34.8% (31/89) vs CPx: 39.1% (25/64), P = 0.61] did not differ between CCs where CPx had been given and those where it had not. Stratification by patients did not alter the results. A combination of clofarabine (40  mg/m2), etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2) given daily for 4 or 5 days (n = 7) was highly associated with bacteremia, occurring in 6/7 of CCs (Table, Supplemental Digital Content 2, http://links. lww.com/INF/C39).

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Localized infections among all patients mainly included neutropenic enterocolitis and lower respiratory tract infections (Table 2).

Microbiological Spectrum All microbiological isolates of culture-positive infections including bacteremia and urinary tract infections were documented (Table 3). Eight patients grew coagulase-negative Staphylococcus from a single blood culture in 10 CCs. None fulfilled Infectious Diseases Society of America criteria of a central line–associated BSI and were excluded from further analysis. CPx was associated with a significant decrease of infections caused by GNR (P = 0.01) and lower incidence of Gram-negative bacteremia although the latter did not reach statistical significance. Bacteremia caused by VGS was significantly more frequent in CCs where CPx had been given (P = 0.02). In addition, the data were stratified by patient, again showing an increased risk of VGS infection in CCs where CPx was given (OR: 7.28; 95% confidence interval: 1.01–52.4; P = 0.04). The Breslow-Day test for homogeneity of ORs across patients resulted in a P value of 0.86, indicating that there was no significant difference among patients in the association between CPx and VGS infection.

Viridans Group Streptococcal Infections VGS bacteremia occurred in 19% of CCs (29/153) in 38% of patients (17/45). VGS was the most commonly isolated pathogen. © 2014 Wolters Kluwer Health, Inc. All rights reserved.

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TABLE 2.  Localized Infections Number of Episodes Symptom/Localization of Symptoms Abdominal pain/neutropenic enterocolitis Perianal pain Bartholin’s abscess Pneumonia  Radiologically confirmed  Radiologically confirmed  Computed tomography confirmed, suspected fungal Thrombophlebitis/line site complications Paronychia Myositis/fasciitis Otitis media/sinusitis Joint effusion Multifocal osteomyelitis

No CPx 6 3 2 1 12 1 1 1 2 1

CPx 5

Microbiological Results

1

Culture negative Culture negative VRE on swab

1 9

Culture negative Viral No bacterial pathogen found

3 1 1

Culture negative Culture negative Culture negative Culture negative Culture negative MRSA from blood stream

VRE indicates vancomycin-resistant enterococcus.

TABLE 3.  Microbiological Spectrum of Bacteremia and Culture-positive Episodes BSI, n (%) Isolate Viridans group streptococci Enterococcus spp. Aerococcus MRSA GPC infectious episodes excluding CONS CONS Escherichia coli Pseudomonas aeruginosa Pseudomonas orizohabitans Klebsiella pneumoniae Klebsiella oxytoca Serratia liquefaciens GNR infectious episodes (including polymicrobial infections) Bacteremia (GPC and GNR) including polymicrobial infections Candida krusei Candida lipolytica Candida parapsilosis Candida tropicalis Aspergillus versicolor Histoplasma Proven IFI Probable IFI Possible IFI

All Isolates/Infections, n (%)

CPx (n = 64)

No CPx (n = 89)

18 (28.1) 1 (1.5) 0 0 18 (28.1) 4 (6.3) 1 (1.5) 0 0 2 (3.1) 0 0 3 (4.7)

11 (12.3) 5 (5.6) 1 (1.1) 1 (1.1) 16 (17.9) 6 (6.7) 5 (5.6) 3 (3.4) 1 (1.1) 3 (3.4) 1 (1.1) 1 (1.1) 12 (13.4)

0.09

21 (32.8)

28 (31.5)

0.86

2 (3.1) 1 (1.5) 1 (1.5) 0 1 (1.5) 0 5 n/a

0 0 0 0 0 0 0 n/a

P* 0.02* 0.40 0.11 0.40

0.01* n/a

CPx (n = 64)

No CPx (n = 89)

18 (28.1) 1 (1.6) 0 0 18 (28.1) 4 (6.3) 1 (1.6) 0 0 2 (3.1) 0 0 3 (4.7)

11 (12.3) 12 (13.4) 2 (2.2) 1 (1.1) 21 (23.5) 6 (6.7) 7 (7.9) 4 (4.5) 1 (1.1) 6 (6.7) 1 (1.1) 1 (1.1) 16 (17.9)

2 (3.1) 1 (1.5) 1 (1.5) 0 1 (1.5) 1 (1.5) 6 2 8

1 (1.1) 2 (2.2) 0 0 3 4 6

P* 0.02* 0.01* 0.57

0.01*

0.14

*Fisher exact test. CONS indicates coagulase-negative staphylococci; IFI, invasive fungal disease; n/a, not applicable.

Nine of 17 children (53%) with VGS bacteremia experienced at least one recurrence of this infection in subsequent CCs. Although none of the patients who died isolated VGS from blood within 1 month of their death, 9/29 (31%) developed an intermittent oxygen requirement and/or need for fluid resuscitation. Admission to the intensive care unit and inotropic support were required in 1 case. Longer duration of neutropenia was significantly associated with the development of GNR bacteremia. CCs containing high-dose cytarabine or a combination of clofarabine, etoposide and cyclophosphamide were associated with a significantly higher risk for VGS—and all-cause bacteremia (Table 4). In a multivariate regression model, only CPx retained statistical significance as a predictor for VGS bacteremia (OR: 2.8; 95% confidence interval: 1.3–6.8; P = 0.02) and as negative predictor for © 2014 Wolters Kluwer Health, Inc. All rights reserved.

GNR bacteremia (OR: 0.27; P = 0.05) whereas high-dose cytarabine did not (VGS: OR: 2.2; P = 0.09; GNR: OR: 2.4; P = 0.25). Stratification of the dataset by individual patients instead of CC did not alter results or risk factors.

Antibiotic Usage and Resistance Administration of CPx did not impact duration of meropenem use per CC (CPx: median: 10; IQR: 4.2–19 days; no CPx: median: 11; IQR: 3.5–22.5 days; P = 0.62) or duration of vancomycin use per CC (CPx: median: 2; IQR: 2–9 days; no CPx: median: 4, IQR: 4–8 days; P = 0.43). However, it significantly decreased duration of aminoglycoside use per CC (CPx: median: 0; IQR: 0–0 days; no CPx: median: 2; IQR: 0–4 days; P < 0.01), primarily because fewer GNR infections occurred in the CPx group. www.pidj.com | e81

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TABLE 4.  Univariate Analysis Performed by Chemotherapy Cycles or Analysis by Patient for GNR, VGS and All-cause BSI VGS

CPx (CC) Age (P) HDAC vs SDAC (CC) HDAC/CEC vs SDAC (CC) Favorable vs unfavorable cytogenetics (P) Neutropenia in days (CC) Relapse (CC)

Culture-positive Bacteremia

GNR

Culture-positive Infections (All)

OR (95% CI)

P

OR (95% CI)

P

OR (95% CI)

P

OR (95% CI)

P

2.8 (1.2–6.4) 0.9 (0.9–1.0) 1.7 (0.7–4.3) 2.5 (0.9–5.9) 0.8 (0.5–1.2)

0.02* 0.33 0.24 0.05* 0.22

0.3 (0.1–1.1) 1.0 (0.9–1.0) 1.6 (0.5–4.9) 3.1 (0.9–11.2) 1.8 (0.9–3.2)

0.06 0.28 0.40 0.08 0.06

1.2 (0.6–2.4) 0.9 (0.9–1.0) 1.4 (0.8–2.5) 2.6 (1.3–5.7) 1.0 (0.9–1.1)

0.56 0.04 0.28 0.01* 0.87

1.1 (0.6–2.1) 0.99 (0.99–1.0) 1.8 (0.9–3.6) 1.8 (0.9–3.6) 1.0 (0.7–1.4)

0.80 0.13 0.09 0.86 0.95

0.9 (0.9–1.0) 0.7 (0.3–1.9)

0.79 0.48

0.9 (0.9–1.0) 1.8 (0.4–8.2)

0.05* 0.47

1.0 (0.9–1.0) 0.6 (0.2–1.4)

0.67 0.22

0.98 (0.9–1.0) 0.74 (0.31–1.7)

0.11 0.49

CEC indicates Clofarabine + Etoposide + Cyclophosphamide; CI, confidence interval; HDAC, high-dose cytarabine; SDAC, standard-dose cytarabine. *P value ≤0.05.

Conversely, this resulted in longer exposure to treatment antibiotics overall in the group that did not receive CPx (CPx: median: 15; IQR: 5–21 days; no CPx: median: 19; IQR: 12–30.5 days; P < 0.01). Quinolone resistance was observed in 4/23 of GNR isolates, in 2 of which, the patients had received CPx previously. Care-related outcomes did not differ between CCs where CPx was given and those where it was not (Table 5). Comparing frequency of MRSA carriage and C. difficile infection rates between the 2 groups showed no differences.

Fungemia and IFI Of the 45 patients, 25 (56%) developed IFI, 14 patients had possible IFI and 6 patients had probable IFI. The 5 patients with proven IFI presenting as fungemia included an isolate of Aspergillus versicolor on lung biopsy and in blood culture (1) and Candida krusei, (2), Candida lipolytica (1) and Candida parapsilosis (1) in blood culture. Fungemia occurred significantly more frequent in the CPx group. When all proven, probable and possible IFIs were considered combined, including skin biopsies positive for Candida tropicalis (2) and Histoplasma capsulatum (1), a central access device tunnel infection due to C. parapsilosis (1), as well as probable and possible IFIs diagnosed based on serologic and radiographic findings, there was a trend toward fungal infections occurring more frequently during CCs where CPx had been given (Table 3).

Mortality Of the 6 patients who died, 2 had not received CPx at all. The remaining 4 had received CPx during some of their CCs; all 4 patients received CPx at the beginning of the CC preceding their death. In none of the patients who died, a bacterial pathogen was isolated from a sterile body site within the last month of life. The number of CCs treated with CPx [died: mean: 1.3 (SD: 0.82); did not die: mean: 1.4 (SD: 1.3) days; P = 0.81] or total days of CPx exposure [died: mean: 15.2 (SD: 10.3); did not die: mean: 14.8 (SD: 19.3) days; P = 0.95] was not associated with all-cause mortality. Clinical characteristics of patients who passed away are

summarized separately (Table, Supplemental Digital Content 3, http://links.lww.com/INF/C40). In a univariate regression model, days on CPx (OR: 0.99; P = 0.96) and number of CCs treated with CPx (OR: 1.1; P = 0.85) did not impact mortality. Mortality was associated with probable and proven IFI (P = 0.03). None of the 20 patients without but 6/25 (24%) of patients with possible, probable or proven IFI died. Two patients had a proven IFI and 3 patients a probable IFI at the time of death. Another patient with probable IFI passed away in hospice care due to progression of their underlying AML.

DISCUSSION The use of antibiotic prophylaxis in pediatric patients with AML is an area of great interest as the risk of invasive bacterial infection is high, with reported rates of 20–50% per CC,3,14,15 contributing up to 60% to treatment-related mortality in childhood AML.16 Data from studies in adult populations suggest that antibiotic—often quinolone based—prophylaxis results in a significant reduction of all-cause and infection-related mortality, microbiologically proven infections and fever.4,5,17 As host factors differ for children, allowing for greater treatment intensity in hematological malignancies, this is associated with a greater risk of FN and treatment-related complications.18 Therefore, an extrapolation of adult data does not appear sufficient to inform pediatric practice. However, only 2 RCTs and a pilot study have reported on the effect of antibiotic prophylaxis in children studying amoxicillin/clavulanate,19 cefepime or vancomycin plus ciprofloxacin9 and ciprofloxacin alone.20 FN was common in our cohort, occurring in 88% of CCs. Although we excluded febrile episodes that coincided with cytarabine infusion and were thought to not be infectious, its contribution to the overall prevalence of fever in this cohort cannot be fully excluded. The high prevalence of fever impacted on CPx exposure of the patients, as it was discontinued upon initiation of empiric

TABLE 5.  Care-related Outcomes Care-related Outcome (per CC) Chest radiographs All radiographs Chest CTs PICU admission Days on PICU (of those admitted) Inpatient stay (d)

CPx

No CPx

P*

1 (0–2) 2 (0–4) 0 (0–1) 2/64 4.5 (4.5) 31 (25–38)

1 (0–2) 1 (0–3) 0 (0–1) 5/89 3 (1–14) 29 (24–35)

0.68 0.46 0.14 0.69 0.14 0.19

*Fisher exact test. CT indicates computed tomography; PICU, pediatric intensive care unit.

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treatment antibiotics. CPx did not impact on the number of fever episodes or febrile days per CC. Febrile episodes yielded a positive bacterial culture result in 24%, in keeping with other studies reporting culture positivity in 20–37%.14,15,21 All our patients received trimethoprim-sulfamethoxazole throughout as recommended.22 Trimethoprim-sulfamethoxazole had a comparable effect on fever and infection-related morbidity when compared with quinolone prophylaxis in adults4 and will have exerted an added antibacterial effect. We found a significant difference between microbiological spectra in children receiving CPx and those who did not, with a higher proportion of infections caused by Gram-positive bacteria in the ciprofloxacin group. A meta-analysis of studies using prophylactic ofloxacin, norfloxacin or ciprofloxacin in adult patients with malignancies showed no effect on the risk of Gram-positive infections,23 whereas a randomized controlled trial comparing levofloxacin to placebo in adult patients with cancer demonstrated a decrease in both Gram-positive and Gram-negative bacteremia.5 A combination of cefepime and ciprofloxacin or vancomycin decreased Gram-positive infections in children.9,24 Use of prophylactic agents that extend the antibiotic spectrum to include Gram-positive pathogens is likely the cause and offers an explanation for the lack of reduction in Gram-positive infections in this study, as ciprofloxacin was the only agent used. Gram-positive cocci (GPC) accounted for over two-thirds of bacterial blood isolates, 78% of which were VGS. Gram-negative pathogens were isolated in 31%. GPC have repeatedly been shown to be a major cause of bacteremia in children and adults treated for AML, with reported rates ranging from 16% to 65%9,14,21,23,25,26 The increased rate of VGS bacteremia that we identified offset the decrease in Gram-negative infections in CCs where CPx was used, resulting in no net-difference of the incidence of culture-positive bacteremia between the 2 groups. VGS are a common cause of infections in patients treated for AML.25,27 Mucosal barrier injury as a result of antineoplastic chemotherapy has been implicated in this25,26,28 with oropharyngeal,29 gastrointestinal and genital mucosa presenting the likely ports of entry.30 Changes in the composition of colonizing gut and oral flora due to chemotherapy31,32 combined with intensive chemotherapeutic regimens, prolonged neutropenia and mucosal injury appear to be associated with increased colonization density and invasive potential of Gram-positive pathogens such as VGS. This may also be the result of species-specific susceptibilities of bacteria to chemotherapy agents and alterations of the oral and gastrointestinal bacterial colonizing flora more resistant to the chemotherapy and prophylactic antibiotic agents used.22,31 In this context, it is of interest that in this study fungal infections occurred more frequently during CCs where the patient had received CPx. There was an equal distribution of possible and probable mold infections between both groups. Prolonged antibiotic exposure is a wellestablished risk factor for IFI.33 Whether prophylactic antimicrobial and chemotherapeutic agents contribute in combination to an altered composition of intestinal and mucosal microbiome communities predispose the patient to invasive fungal infections would be valuable information best gained from prospective trials in the future focusing on the impact of these interventions on the mycobiome in this patient population. In contrast to our findings, a recent retrospective study did not find a significant difference in the frequency of IFIs comparing patients receiving antimicrobial prophylaxis and those who did not.34 VGS carries a significant morbidity and mortality risk7,25,35,36 though this was not a prominent feature in our cohort. We found a high recurrence risk for VGS bacteremia. Data stratification by patient did not affect this result. Previously © 2014 Wolters Kluwer Health, Inc. All rights reserved.

Quinolone Prophylaxis in Leukemia

identified risk factors for VGS bacteremia in children are young age, treatment with high-dose cytarabine or intensively timed chemotherapy with mucotoxic agents and prior VGS bacteremia.14,25,26,37 Possible explanations for this finding are that children received a higher dose intensity of cytarabine than that received by adults, resulting in a higher prevalence of mucositis in pediatric cohorts.38,39 Implementation of supportive care strategies such as decontamination of gums and gastrointestinal tract has reportedly decreased the incidence of VGS bacteremia.40 Although an increase of GPC bacteremia on quinolone prophylaxis has not been found by all,5,17 prophylaxis directed against Gram-negative infections (ie, with quinolones) has been identified as a risk factor for infections with VGS.22,28,41–44 We found that CPx was effective in decreasing aminoglycoside use, most likely because the incidence of GNR infections was lower. This study was not powered to demonstrate an effect on mortality, and the number needed to treat found in a meta-analysis was 34 for the prevention of 1 death.4 The antibiogram of our institution has consistently shown high levels of susceptibility to ciprofloxacin among GNR isolates from blood during the time of data collection. Susceptibility results for quinolones were available in 20/23 GNR isolates, 4 of which were resistant. Two of these infections occurred in patients who had not received CPx at any point during their treatment. Knowledge of local resistance data and continuous antimicrobial stewardship when deciding on institutional protocols for antibiotic prophylaxis is crucial.45 An increase in the rate of multidrug–resistant GNR has been associated with the introduction of quinolone prophylaxis in adult patients with cancer46–49 although a benefit in morbidity and mortality was retained.50,51 A recent study from Japan however did not replicate these findings.27 Quinolone resistance in VGS isolates is an increasing concern.15 As quinolone susceptibility was not performed for GPC isolates, we have no information on the quinolone susceptibility of the VGS isolates in this study. In addition, gathering data on the carriage of multi-drug–resistant organisms in addition to invasive infections would be informative. A recent study investigating the use of antimicrobials active against Gram-positive organisms demonstrated a higher prevalence of vancomycin-resistant enterococci– positive surveillance cultures in those receiving either iv cefepime or vancomycin as prophylactic agents.24 These questions should be revisited in a larger, ideally prospective trial.

ACKNOWLEDGMENTS The authors thank Colleen Azen and Richard Sposto for their support in the statistical analysis and Michael Montana for his assistance in information technology and data management. REFERENCES 1. Rubnitz JE, Inaba H. Childhood acute myeloid leukaemia. Br J Haematol. 2012;159:259–276. 2. Lehrnbecher T, Ethier MC, Creutzig U, et al. International variations in infection supportive care practices for paediatric patients with acute myeloid leukemia. Br J Haematol. 2009;147:125–128 3. Sung L, Lange BJ, Gerbing RB, et al. Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia. Blood. 2007;110:3532–3539. 4. Gafter-Gvili A, Fraser A, Paul M, et al. Cochrane Database Syst Rev. 2012;1:CD004386 5. Bucaneve G, Micozzi A, Menichetti F, et al. Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) infection program. N Engl J Med. 2005;353:977–987 6. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:794–810.

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