Bone Marrow Transplantation (2001) 27, 537–542  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Dental health Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients

CJ Graber1, KNF de Almeida1, JC Atkinson2, D Javaheri2, CD Fukuda3, VJ Gill3, AJ Barrett4 and JE Bennett1

1Clinical Mycology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, 2National Institute of Dental and Craniofacial Research, 3Microbiology Service, Department of Clinical Pathology, Warren Grant Magnuson Clinical Center, and 4Stem Cell Allotransplant Unit, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

Summary: laxis with fluoroquinolones which have poor Gram positive activity.11 The impact of dental health as a risk factor for Viridans streptococci were the most common cause of viridans is not known. bacteremia in 61 consecutive myeloablative allogeneic hematopoietic stem cell transplant (HSCT) recipients, occurring in 19 of 31 bacteremic patients (61%) during Patients and methods the period of post-transplant neutropenia. Seven of the 19 had more than one viridans streptococcus in the Patient characteristics same blood culture. Twenty isolates from 15 patients were . Most viridans streptococci Medical charts and dental records were reviewed of 61 con- were resistant to norfloxacin, used routinely for prophy- secutive patients with hematological malignancies receiv- laxis. Comparison of the 19 patients with viridans strep- ing myeloablative allogeneic HSCT at the National Heart, tococcal bacteremia with a contemporaneous group of Lung and Blood Institute in the 21-month period from Janu- 23 allogeneic HSCT recipients with fever and neutro- ary 1997 to October 1999 (NIH protocols 93-H-0212, penia but no identified focus of infection found that 94-H-0092, 97-H-0099, 98-H-0122, 99-H-0046). patients with viridans streptococcal bacteremia were The conditioning regimen during the pre-transplant per- more likely to have severe intraoral pathology while iod was usually total body irradiation followed by two neutropenic (26% vs 0%) and slightly shorter interval infusions of high-dose cyclophosphamide (60 mg/kg i.v.). between the last dental procedure and the onset of neu- Two patients received busulfan in place of total body tropenia (11 vs 14 days). Poor underlying dental health irradiation or fludarabine instead of cyclophosphamide. and the use of norfloxacin thus appear to predispose to Cyclosporine was also given to approximately half of the viridans streptococcal bacteremia. Bone Marrow Trans- 61 cases. Norfloxacin 400 mg p.o. twice a day was begun plantation (2001) 27, 537–542. 7–10 days prior to transplantation and continued until the Keywords: viridans streptococcus; bacteremia; neutro- patient’s neutrophil count was sustained above 1000 penia; transplant; dental; resistance cells/␮l. Weekly trimethoprim-sulfamethoxazole prophy- laxis for Pneumocystis carinii pneumonia was started on day 30 post-transplant or upon discharge from hospital. Acyclovir was given until 30 days after transplantation as The past decade has seen a change from Gram negative prophylaxis against herpesvirus . Intravenous to Gram positive organisms as a cause of bacteremia in immunoglobulin 0.5 g/kg was given weekly for the first 100 neutropenic patients.1 Staphylococcus epidermidis has been days post transplant. G-CSF 5.0 ␮g/kg/day was given from the Gram positive bacterium2 most frequently encountered, day 7 post-transplant until the neutrophil count exceeded largely due to increased use of intravascular catheters.3,4 1 × 109/l for 3 consecutive days or until day 21 post-trans- Viridans streptococci, which are oral commensals, have plant. The first two patients received infusions of donor also been reported to cause bacteremia and may cause adult bone marrow cells; the others received stem cells harvested respiratory distress syndrome, shock, or .5–7 from peripheral blood. Factors reported to be associated with viridans strepto- coccal bacteremia have been oral mucositis,5,6,8 high-dose cytosine arabinoside,9 younger age,10 and antibiotic prophy- Blood cultures Most blood cultures were drawn from intravenous cath- Correspondence: Dr JE Bennett, Clinical Center, Room 11C304, National eters. An 8–10 ml blood sample was inoculated into an Iso- Institutes of Health, Bethesda, MD, 20892, USA lator tube (Wampole, Cranbury, NJ, USA) and 3–5 ml into Received 25 April 2000; accepted 10 December 2000 a blood culture bottle (BacTAlert, Organon Teknika, Dur- Dental health and viridans streptococcal bacteremia CJ Graber et al 538 ham, NC, USA). Isolator concentrate was inoculated on to Table 1 Demographic and clinical parameters of viridans streptococ- five plates (two chocolate agar, two blood agar and one cus bacteremic patients and controls brain heart infusion agar) incubated aerobically with 5% CO . Plates and bottles were incubated for 5 days before Cases Controls 2 (n = 19) (n = 23) considered negative. Sex Male 10 13 Female 9 10 Organism identification and antibiotic susceptibility Median age at transplantation (years) 36 39 testing Underlying diagnosis Chronic myelogenous leukemia 7 13 Acute myelogenous leukemia 7 5 Alpha hemolytic or nonhemolytic streptococci were ident- Myelodysplastic syndrome 3 3 ified using a composite of phenotypic characteristics and Chronic lymphocytic leukemia 2 0 biochemical reactions included in the API 20 Strep identi- Acute lymphocytic leukemia 0 1 Multiple myeloma 0 1 fication panel (bioMerieux, Marcy L’Etoile, France) as well Median duration of neutropeniaa (days) 13 12 as additional biochemical testing as needed. The identifi- Median time from neutropenia onset to 4 2 cations were the closest individual species designations that feverb onset (days) Median duration of fever (days) 3 3 could be determined and not the broader group designations c 12 Patients with mucositis 16 18 recently proposed. All isolates were tested for antimicro- Complications from presumed sepsis or bial susceptibility using the Etest method (AB BioDisk, sepsis-related syndrome Solna, Sweden). Multiple strains of the same streptococcal Intensive care unit admission 1 1 species isolated in the same culture were differentiated by Intubation 1 0 colony morphology and subsequent antibiotic resistance Death 1 0 patterns. aThe first day of neutropenia was defined as the first day the patient’s absolute neutrophil count fell below 500 cells/␮l coincident with or fol- lowing the first day of the conditioning regimen. Neutropenia was con- sidered resolved when the absolute neutrophil count was greater than 500 Analysis of dental health cells/␮l for at least 2 consecutive days (the first of these dates was recorded as the date of neutropenia resolution). bFever was generally defined as the patient’s first recorded temperature of Fifty-six of the 61 patients were evaluated in the dental 38.0°C or above while neutropenic that was deemed to require antibiotic clinic before transplantation with a complete dental examin- therapy. Resolution of fever was defined by at least 48 continuous hours ation and panographic radiograph. Caries were diagnosed of recorded temperatures less than 38.0°C. Only the first febrile episode during the neutropenic period was included in this analysis. by clinical examination and appropriate bite wing and per- cMucositis was defined by the presence of oral lesions or erythema on iapical radiographs. Alveolar bone loss (a measure of physical examination or mouth and/or throat pain requiring parenteral cumulative periodontal disease) was calculated from pano- analgesia. Records from three control patients were insufficient to deter- graphic radiographics with the aid of a Schei ruler.13 The mine the presence or lack of mucositis. number of days between any dental treatment and the onset of neutropenia was documented. Nineteen of the 56 patients Results had bacteremia from viridans streptococcus. In order not to confound our results and ensure a relatively homogenous Causes of bacteremia control group, 14 patients with documented infection or All 61 patients in this cohort had fever during neutropenia, bacteremia during neutropenia were excluded, leaving 23 31 accompanied by a positive blood culture. Gram negative of the remaining 37 patients to serve as controls to analyze were isolated in only three episodes (two Escher- for dental risk factors for viridans streptococcal bacteremia. ichia coli and one Capnocytophaga species). In two of While the reviewer of the patients’ dental records was these episodes, Gram positive organisms were also isolated. aware of the patients’ microbiological status, possible den- Of the 30 patients who had Gram positive bacteria, 19 tal risk factors were determined prior to dental chart review. (61%) had viridans streptococci. Of these, eight had one Characteristics of patients with viridans streptococcal bac- strain of Streptococcus mitis, five had two strains of S. mitis teremia and case controls are given in Table 1. There were in the same specimen, one had S. mitis and S. sanguis I in no significant differences between the two groups. the same specimen, and one had S. mitis and S. sanguis II in the same specimen. One had a single strain of S. sanguis I; another had a single strain of S. sanguis II. Two patients had unidentified species of viridans streptococci. The Statistical analysis remaining Gram positive organisms isolated were Staphylo- epidermidis (three episodes), Fisher’s exact test was used to compare nominal inde- (two episodes), Gemella species (two episodes), Entero- pendent variables, Mann–Whitney analysis was used to coccus faecium (two episodes), and one episode each of compare ordinal independent variables, and Student’s t-test Stomatococcus species, , Entero- was used to compare continuous independent variables for coccus faecalis, Lactococcus species, and Streptococcus cases and case controls.14 agalactiae.

Bone Marrow Transplantation Dental health and viridans streptococcal bacteremia CJ Graber et al 539 Severity of viridans streptococcal bacteremia isolates were sensitive to ceftriaxone (MIC range 0.004– 12 ␮g/ml), but three isolates, all S. mitis, were resistant. Eighteen of 19 patients with viridans streptococcal bactere- In two of these three episodes, the patient had received a mia responded promptly to treatment with ceftazidime and cephalosporin in the previous 2 weeks. One patient had a vancomycin. One patient developed septic shock and acute 5-day course of cefazolin discontinued approximately 1 respiratory distress accompanied by a blood culture positive week prior to bacteremia, and one patient had been receiv- for S. mitis. She was admitted to the intensive care unit the ing ceftazidime for 12 days and was still receiving ceftazid- following day and required ventilatory support. Although ime at the time of bacteremia. Overall susceptibility to the septicemia responded promptly to antibiotic therapy, penicillin (MIC range 0.004 to 12 ␮/ml) was comparable she failed to improve clinically, remained on the ventilator, to that of ceftriaxone. The majority of isolates tested were and died 5 weeks later from multiple organ failure. In all resistant (MIC range 2 to Ͼ256 ␮g/ml) to norfloxacin. patients, viridans streptococci were isolated from blood Notably, the two strains that were most resistant to ceftri- only once during the period of post-transplant neutropenia, axone (the same two strains in which the patient had and the median duration of fever in the patients with received a cephalosporin in the 2 weeks prior to viridans streptococcal bacteremia was 3 days. bacteremia) were the most resistant to norfloxacin (MIC Ͼ256 ␮g/ml) as well. Antimicrobial susceptibility of viridans streptococci

The antimicrobial susceptibility of the 26 viridans strepto- Intraoral pathology coccus isolates are shown in Table 2. All isolates were sensitive to vancomycin (MIC range 0.38–1 ␮g/ml), despite Dental characteristics and procedures performed on cases one patient having received 4 days of vancomycin therapy of viridans streptococcal bacteremia and case controls are that was discontinued 12 days prior to bacteremia. Most summarized in Table 3. The necessity for dental extractions

Table 2 Antibiotic susceptibility of Streptococcus viridans isolates recovered during neutropenia (by E-test)

UPN Organism Minimum inhibitory concentration Penicillin Norfloxacin Prior Vancb Prior Cephc (␮g/ml)/Susceptibilitya

Vancomycin Ceftriaxone

62 S. mitis 0.5 S 2 R 6 R 8 I No No 70 S. mitis 0.75 S 0.25 S 0.5 I Ͼ256 R No No 73 S. mitis 0.5 S 0.047 S 0.032 S 96 R No No 82d S. mitis Ͻ1SϽ0.5 S Ͻ0.06 S 24 R No No 96 S. mitis 0.75 S 0.032 S 0.094 S 8 I No Yes 99 S. mitis 1 S 0.125 S 0.064 S 32 R No No 99 S. mitis 1 S 0.125 S 0.064 S 8 I No No 103d S. mitis Ͻ1SϽ0.5 S 0.5 I 6 I No No 104 S. mitis 0.38 S 0.016 S 0.047 S 12 I No No 121 S. mitis 0.5 S 0.064 S 0.094 S 48 R No No 127 S. mitis 0.38 S 0.094 S 0.023 S 96 R No No 127 S. mitis 0.75 S 0.19 S 0.125 S 32 R No No 131 S. mitis 0.75 S 3 R 4 R Ͼ256 R Yes Yes 139 S. mitis 0.75 S 0.016 S 0.016 S 64 R No No 139 S. mitis 0.75 S 0.38 S 1.5 I 8 I No No 157 S. mitis 0.5 S 0.064 S 0.023 S 24 R No No 157 S. mitis 0.5 S 0.064 S 0.032 S 12 I No No 165 S. mitis 0.75 S 0.032 S 0.023 S 4 S No No 165 S. mitis 0.38 S 0.004 S 0.004 S 32 R No No 183 S. mitis 0.5 S 12 R 12 R Ͼ256 R No Yes 72d S. sanguis I Ͻ1SϽ0.5 S 0.5 I 2 S No No 121 S. sanguis I 1 S 0.032 S 0.023 S ND — No No 66 S. sanguis II 0.5 S 0.023 S 0.006 S 16 R No No 70 S. sanguis II 1 S 0.047 S 0.25 I 96 R No No 61 ␣-hemo. strepe 0.75 S 0.064 S 0.047 S 32 R No No 67 ␣-hemo. strepe 0.38 S 0.125 S 0.047 S 12 I No No aNCCLS breakpoints: vancomycin: susceptible: MIC р1 ␮g/ml; ceftriaxone: susceptible: MIC р0.5 ␮g/ml, intermediate: 1 ␮g/ml, resistant: у2 ␮g/ml; penicillin: susceptible: MIC р0.12 ␮g/ml, intermediate: 0.25–2 ␮g/ml, resistant: у4 ␮g/ml; norfloxacin: NCCLS breakpoints are not available for suscep- tibility of viridans streptococci to norfloxacin by E-test. The breakpoints used here are those used for susceptibility of Staphylococcus and sp. to norfloxacin for urinary indications only (susceptible: MIC р4, resistant: MIC у16). bTreatment with vancomycin within the 2 weeks prior to S. viridans bacteremia. cTreatment with a cephalosporin within the 2 weeks prior to S. viridans bacteremia. dLower limit of MIC not determined for vancomycin, ceftriaxone, and penicillin. eAlpha-hemolytic streptococcus, not identified further. ND, not done.

Bone Marrow Transplantation Dental health and viridans streptococcal bacteremia CJ Graber et al 540 Table 3 Dental care characteristics of viridans streptococcus bacter- emic patients and culture-negative controls

Cases Controls P value (n = 19) (n = 23)

Patients with dental caries on initial 16 15 0.29 examination Patients receiving prophylactic dental 14 20 0.43 cleaning prior to transplantation Median time from last dental procedure 11 14 0.12 to onset of neutropenia (days)a Patients having 1 or more teeth 10 10 0.76 extracted prior to transplantation Median time from date of last 14.5 18.5 0.47 extraction to onset of neutropenia (days) Patients having one or more impacted 5 3 0.43 third molars extracted prior to transplantation Mean periodontal bone loss (mm)b 13.1 13.2 0.99 Patients who had severe intraoral 5 0 0.014 pathology while neutropenic

aSixteen Streptococcus viridans bacteremic patients and 21 control patients had dental procedures performed. bPeriodontal bone loss could not be calculated in one of the control patients (a child) because of erupting adult teeth.

in 20 of 42 patients and the fact that 31 of the 42 patients presented with dental caries on initial examination was characteristic of this patient population. In six patients (three cases and three controls), impacted wisdom teeth communicating with the oral cavity were removed because Figure 1 Radiographs of posterior maxillary teeth of UPN 103 exhibit- they were potential sources of infection. In seven cases and ing multiple periapical abscesses and advanced periodontal disease. Arrows indicate periapical abscesses. (a) Maxillary right posterior teeth; eight controls, teeth were extracted because of advanced (b) maxillary left posterior teeth. caries or periodontal disease (one control patient had an impacted third molar removed prophylactically and had another tooth removed because of advanced periodontal penia. The days on which all the dental procedures were disease). performed and the day of positive blood culture for the S. Five of the 19 patients with viridans streptococcal bacter- viridans group are summarized in Table 4. As noted in emia had severe intraoral pathology, defined a priori as a Table 1, most patients in both groups had some degree of loss of integrity of the alveolar mucosa and bone, at the mucositis during the first 7–10 days post-transplant. time of neutropenia versus none of the 23 case controls (P = 0.014). This result was significant even when consider- ing that multiple comparisons were made in this study. Discussion Three of the five patients had an unhealed extraction site as evidenced by continued pain in the extraction site after The incidence of post-transplant neutropenic viridans strep- the onset of neutropenia (two patients) or clinical evidence tococcal bacteremia in our myeloablative allogeneic HSCT of an open site during neutropenia (one). One of these population is high (19 of 61 patients, 31%) and exceeds patients, who had chronic myelogenous leukemia in accel- the incidence reported in other centers.9,15,16 Other centers erated phase, had a granuloma at the site of extraction also report a higher incidence of -negative sta- found to contain leukemic cells on biopsy. Two other phylococci relative to that of viridans streptococci. With patients had multiple carious teeth exhibiting periapical regard to the shock syndrome reported for neutropenic can- abscesses on pre-transplant dental radiographs. These cer patients with viridans streptococcal bacteremia,7,17 it is abscesses, which had eroded significant bone at the apices important to note that only one patient in our series of the teeth, were not treated before myeloablative therapy developed septic shock, which contributed to her death was started because of the urgency of the transplant pro- from multiple organ failure 5 weeks later. cedure. Radiographs exhibiting multiple periapical Several factors may account for the high incidence of abscesses of the posterior maxillary teeth of one of these viridans streptococcal bacteremia at our institution. Firstly, patients (UPN 103) are shown in Figure 1. The patients the preparative regimen of cyclophosphamide and total with viridans streptococcal bacteremia also had a shorter body irradiation leads to significant mucositis. Secondly, (although not statistically significant) time period between the choice of quinolone prophylaxis may have favored viri- the last dental procedure performed and the onset of neutro- dans streptococcal bacteremia. Norfloxacin was initially

Bone Marrow Transplantation Dental health and viridans streptococcal bacteremia CJ Graber et al 541 Table 4 Dental treatment received by patients who developed neutropenic viridans streptococcal bacteremia

UPN Disease Day of dental procedurea Other op.c Day of positive Organisms isolated Dental pathology during Prophyb Extractions blood culturea transplant course

61 CML 0 ␣-hemo. strep Multiple periapical abscess 62 MDS/Fanconi −16 0 S. mitis 66 CML-CP −15 −23 −14 +3 S. sanguis II 67 CML −22 −26 −21 +3 ␣-hemo. strep 70 AML −13 −35 +1 S. mitis, S. sanguis II 72 AML-M5 −13 −14 −9 +3 S. sanguis I 73 CML accel. −9 −90S. mitis 82 CML-CP −37 −37 +6 S. mitis Unhealed extraction site 96 MDS-RAEB −8 −8 +4 S. mitis 99 CLL −11 +6 S. mitis (2 strains) 103 AML +4 S. mitis Multiple periapical abscess 104 AML −9 −13 −13, −9 +2 S. mitis 121 CLL +4 S. mitis, S. sanguis I 127 CML −7 −12 +3 S. mitis (2 strains) Unhealed extraction site 131 AML −27 −29 +6 S. mitis 139 AML −15 −14, −13 +4 S. mitis (2 strains) 157 CML −14 −14 +4 S. mitis (2 strains) 165 MDS −13 +2 S. mitis (2 strains) 183 AML-M1 −8 −8 −8 +4 S. mitis Unhealed extraction site aAs related to the first day of donor marrow/hematopoietic stem cell infusion. bProphylactic dental cleaning. cOther intraoral operations. chosen as prophylaxis for these patients to protect against penia appears to be important. Only two of the 42 patients Gram negative infections and to reduce aerobic Gram nega- in this study started myeloablative treatment with periapical tive bowel flora. However, it is relatively ineffective against abscesses; both acquired viridans bacteremia. Both of these Gram positive organisms, particularly viridans streptococci, patients had progressive leukemia that required emergent as shown here. Even so, the MICs of several of the strains transplantation. It was decided that invasive procedures to tested were higher than those typically reported for nor- correct intraoral pathology would not be performed because floxacin against streptococci,18–20 and the two strains with there was not enough time between dental clinic visit and the highest resistance to norfloxacin were the strains that onset of neutropenia to ensure adequate healing. had the highest resistance to ceftriaxone. These strains were Certainly, infected teeth should be removed before the isolated in the patients who received a cephalosporin within onset of neutropenia if time permits. Other dental treatment the 2 weeks prior to bacteremia in addition to norfloxacin needs, such as cleaning of the teeth, extractions of teeth prophylaxis. Similar resistance to beta-lactams21,22 and qui- with advanced caries or periodontal disease, and restorative nolones23 have been reported in neutropenic cancer patients procedures are carried out as the patient’s condition permits taking these agents. The incidence of penicillin resistance according to published guidelines.24,25 However, the trend (MIC у4 ␮g/ml) in our population (three of 26 isolates, toward a shorter time period between dental procedures and 12%) is lower than that previously reported for viridans neutropenia onset in patients with viridans streptococcal streptococci isolated from neutropenic cancer patients.21 bacteremia suggests that such procedures should be perfor- Finally, many of our patients were referred from coun- med well in advance of the anticipated transplant date. In tries where dental care is usually inadequate. As noted particular, extractions should be done as soon as possible. above, several past studies have suggested an association Though published guidelines state that 10 days is adequate between chemotherapy-induced severe mucositis and virid- for healing after an extraction, two cases in this study (UPN ans streptococcal bacteremia. These findings support the 82 and 127) had very delayed healing of their extraction hypothesis that disruption of the mucosal barrier separating sites. Both patients had chronic myelogenous leukemia that the body from resident oral flora is a risk factor for the recurred after transplantation, suggesting that their under- acquisition of viridans bacteremia. Other oral pathology has lying malignancy delayed normal healing. received less attention as a possible portal for viridans In general, the oral health needs of the patients in this streptococcal bacteremia. The finding in this study of five study were extensive. Thirty-one had dental caries, often cases with a loss of integrity in the alveolar bone around of multiple teeth, on initial examination. Several cases and the teeth (two from abscesses and three from unhealed controls had abscessed teeth that were detectable only on extraction sites) suggests that an intact alveolar barrier is dental radiographs. Though the reasons for the extensive also important in preventing bacteremia with oral flora. dental pathology cannot be determined from this small At our institution, it is policy to carry out a dental exam- group, the fact that patients had persistent illness that ination prior to transplantation and aggressively treat dental necessitated hematopoietic stem cell transplantation was pathology when the pace of disease progression permits. likely a contributing factor. Therefore, the oral health of Control of intraoral pathology prior to the onset of neutro- patients should be assessed well in advance of myeloabl-

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Bone Marrow Transplantation