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Keywords:

  • Staphylococcus aureus;
  • Streptococcus;
  • bacteremia;
  • treatment failure;
  • vancomycin tolerance

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The clinical significance of infections caused by vancomycin-tolerant (Vt) Gram-positive organisms in patients with cancer remains unclear.

METHODS

Twenty-five patients with nonenterococcal Gram-positive bloodstream infection, which was refractory to vancomycin therapy, were identified by reviewing the Infectious Diseases consultation database at the tertiary care cancer center. Among these, 8 patients in whom vancomycin-tolerance was documented are described. Antibiotic tolerance was defined as a >32 times increase in minimum bactericidal concentration compared with minimum inhibitory concentration.

RESULTS

Eight patients with persistent fever and bacteremia of >72 hours' duration after the initiation of vancomycin therapy were treated. The median age of these patients, which included 3 men and 5 women, was 44 years ± 11 years. Solid tumors were more common (6 patients) and 2 patients had acute leukemia. Six patients (75%) were neutropenic (absolute neutrophil count <500/mm3), including 2 breast cancer patients who had undergone autologous stem cell transplantation. The causative organisms were Staphylococcus aureus (n = 3 patients), group G streptococci (n = 2 patients), and Staphylococcus epidermidis, Streptococcus mitis, and Streptococcus sanguis (1 patient each). All isolates demonstrated a minimum bactericidal concentration for vancomycin that was at least 32 times greater than the minimum inhibitory concentration. Rapid defervescence (≤24 h) and resolution of bacteremia occurred with the addition of gentamicin (4 patients) or gentamicin plus rifampin (4 patients). None of these infections recurred after discontinuation of therapy.

CONCLUSIONS

Lack of clinical and/or microbiologic response to vancomycin should raise the suspicion of possible infection due to Vt Gram-positive bacteria, and alternative bactericidal therapy should be instituted early, especially in patients with underlying immune suppression. Cancer 2006. © 2006 American Cancer Society.

Gram-positive bacteria (GPB) are the predominant cause of bloodstream infection in cancer patients.1–3 The widespread use of indwelling vascular devices, antimicrobial prophylaxis directed primarily against Gram-negative bacilli, and severe orointestinal mucosal excoriation caused by intensive antineoplastic regimens are the primary predisposing factors.3–6 Many Gram-positive organisms such as coagulase-negative staphylococci, Staphylococcus aureus, and viridans group streptococci have shown increasing resistance to agents commonly used for prophylaxis or empiric therapy in neutropenic patients, including the fluoroquinolones, various beta-lactams, and the aminoglycosides.6–9 Vancomycin is considered the cornerstone of therapy in this setting, although many clinicians consider it to have slow bactericidal activity, which might be an important consideration in patients with impaired host defenses.10–12 One recent study suggested that the bactericidal activity of vancomycin decreases and the chances of clinical failure increase as vancomycin minimum inhibitory concentrations (MICs) rise, even though the organisms remain in the susceptible range (ie, 1-2 μg/mL).13 Another potential mechanism for slowness of response or failure of vancomycin therapy could be vancomycin tolerance (Vt).14 Vt (minimum bactericidal concentration [MBC] ≥32 times the MIC) has been reported among clinical isolates of Streptococcus pneumoniae,11, 15 viridans group streptococci,16 group C and G Streptococcus,17, 18 and Staphylococus aureus.19 However, to our knowledge, the clinical significance of infection with tolerant organisms, particularly in cancer patients with or without neutropenia, is unclear. In the current study, we report on 8 patients treated at our comprehensive cancer center between 1993 and 2003 who had refractory bactermeia due to Vt organisms.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Twenty-five patients with nonenterococcal Gram-positive bloodstream infection, which was refractory to vancomycin therapy, were identified by reviewing the Infectious Diseases consultation database at our tertiary care cancer center. Among these, 8 patients in whom Vt was documented are described in this article. Patient information was obtained from patients' chart and computerized hospital data systems. The microorganism identification and antimicrobial susceptibilities were performed at the Microbiology Laboratory, M. D. Anderson Cancer Center.

The organism identification was performed by standard methods described previously.3, 17 In vitro MIC and MBC analysis were performed by guidelines issued by the National Committee on Clinical Laboratory Standards (NCCLS).20–22

Bacteremia was the presence of pathogenic bacteria in blood culture isolates with clinical signs and symptoms of bloodstream infection. Sustained bacteremia was considered if blood cultures remained positive for >72 hours after treatment with vancomycin was commenced. Antibiotic tolerance was defined as >32 times an increase in MBC compared with MIC.23 Central venous catheter infection was considered in the following situations: 1) clinical signs and symptoms of catheter insertion site or subcutaneous tunnel infection; 2) catheter tip cultures demonstrated organisms that were isolated from catheter and blood culture samples; or 3) 4-fold greater bacterial counts in blood obtained from central venous catheter (CVC) compared with peripherally obtained blood culture samples (note that quantitative blood cultures were not available for all patients described in this study). Duration of systemic antimicrobial therapy for uncomplicated bloodstream infection was 10-14 days along with clinical (fever resolution) and microbiologic (sterile blood culture) evidence of effective therapy. The daily gentamicin dose ranged from 3-5 mg/kg body weight given in 2-3 divided doses and oral rifampin was given at 600 mg as a single dose or in 2 divided doses; vancomycin was given as 1 g administered every 12 hours. The peak and trough were measured 1 hour after infusion had ended after the third dose and 1 hour before the fourth vancomycin dose, respectively. Vancomycin dose was adjusted in patients with azotemia, or evidence of chronic renal insufficiency.

Refractory infection was defined as sustained bacteremia for >72 hours after therapy with vancomycin commenced despite removal of infected indwelling CVC in patients in whom infected CVC was considered the source of bloodstream infection.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In Table 1 the characteristics of 8 patients with refractory Gram-positive bacteremia who failed vancomycin therapy are presented.

Table 1. Characteristics of Vancomycin Refractory Gram-Positive Bacteremia in Patients with Cancer
Patients*Age, ySexCancerANCMicroorganismsMICMBCMucosal ExcoriationInitial TherapyAdditional TherapyResponse
  • ANC: absolute neutrophil counts in cells/mm3; MIC: minimum inhibitory concentration in μg/mL; MBC: minimum bactericidal concentration in μg/mL; mucosal excoriation: mild (Grade 1-2), moderate (Grade 2-3), and severe (Grade 3-4); response: hours after the subsequent antimicrobial therapy was given; Van: vancomycin; Imp: imipenem; Gen: gentamicin; Rif: rifampin; Cef: ceftazidime; Auto-SCT: autologous stem cell transplantation; Azt: aztreonam.

  • *

    All 8 patients had an indwelling central venous catheter, and none demonstrated clinical signs of catheter entry site or tunnel infection. Similarly, secondary infection foci such as suppurative complications including endocarditis, deep vein thrombophlebitis, and osteomyelitis were not observed in any of the presenting patients. There were no evidence of infection-associated death or infection recurrence at the 12-week follow-up.

  • The patient with Kaposi sarcoma had human immunodeficiency virus associated immunodeficiency syndrome and was neutropenic due to ganciclovir therapy for human cytomegalovirus retinitis.

Sex
155femaleOvarian, metastatic300Staphylococcus aureus0.2532NoVan, ImpGen, Rif< 24 h
260maleAML100Staphylococcus aureus164Grade 2-3Van, CefGen, Rif< 24 h
342femaleBreast, auto-SCT450Staphylococcus epidemidis2128NoVan, AztGen, Rif< 24 h
444maleKaposi sarcoma300Streptococcus, group G0.2516NoVan, ImpGen, Rif< 24 h
538femaleBreast, auto-SCT< 100Streptococcus mitis0.532Grade 3-4Van, CefGen< 24 h
637femaleAML< 100Streptococcus sanguis0.1232Grade 3-4Van, CefGen< 24 h
744maleSarcoma, metastatic5000Staphylococcus aureus1128NoVan, ImpGen24 h
868femaleMalignant melanoma2000Streptococcus group G0.1232NoVan, ImpGen24 h

Case 1

A 55-year-old woman with metastatic ovarian cancer presented with chemotherapy-induced febrile neutropenia. On physical examination, no focus of infection was identified. Empiric therapy included vancomycin (1 g every 12 h) and imipenem (500 mg every 8 h). Serum vancomycin levels were therapeutic (peak of 44 μg/mL and trough of 10 μg/mL). Twenty-four hours after hospitalization, peripheral and CVC blood culture samples grew methicillin-susceptible Staphylococcus aureus. Despite catheter removal, she remained febrile (39°C) and phenotypically identical S. aureus persisted in blood cultures for ≥ 5 days after hospitalization (vancomycin MIC of 0.25 μg/mL and MBC of 32 μg/mL). After the addition of gentamicin, blood cultures became sterile and fevers abated. There was no recurrence after 12 months of follow-up.

Case 2

A 60-year-old man with acute myelogenous leukemia (AML) presented with neutropenic fever (40.1°C) after receiving antineoplastic therapy. Moderate oral mucosal excoriation was present on examination. The empiric antimicrobial regimen consisted of vancomycin (1 g every 12 h) and ceftazidime (2 g every 8 h). Methicillin-susceptible S. aureus was isolated from peripheral and CVC samples. Due to persistent bacteremia and fever, the CVC was removed 72 hours after hospitalization. Gentamicin plus rifampin were added when the vancomycin MIC and MBC (1 μg/mL and 64 μg/mL, respectively) became available and the patient was still febrile and blood cultures continued to grow S. aureus. There was a rapid response to this regimen, despite neutropenia, which persisted for another 11 days. No recurrence was reported.

Case 3

A 42-year-old woman, presented with febrile (39.3°C) neutropenia (absolute neutrophil count [ANC] 450 cells/mm3) 5 days after receiving autologous stem cell transplant for breast cancer,. Mild erythema was noted at the CVC entry site, and the catheter was promptly removed. Initial therapy included vancomycin (1 g every 12 h) and aztreonam (2 g every 8 h). Methicillin-resistant Staphylococcus epidemidis was isolated from blood cultures. Seventy-two hours after catheter removal and systemic antibiotic therapy, her fever persisted (39.5°C). Venous flow study did not demonstrate intravascular thrombosis. The S. epidemidis vancomycin MIC was 2 μg/mL and the MBC was 128 μg/mL. A prompt response occurred after gentamicin plus rifampin were added to the existing regimen. There was no evidence of infection recurrence after antimicrobial treatment was discontinued.

Case 4

A 44-year-old man with acquired immunodeficiency syndrome presented with febrile neutropenia (ANC < 300 cells/mm3) while receiving ganciclovir for cytomegalovirus retinitis. On examination, multiple cutaneous Kaposi sarcoma lesions were evident. Empiric therapy included vancomycin (1 g every 12 h) and imipenem (500 mg every 6 h). Blood cultures (peripheral and CVC) grew Streptococcus group G. The indwelling intravascular catheter was removed 48 hours after hospitalization and, due to persistent fever, positive blood culture 5 days after initial antimicrobial therapy (vancomycin MIC of 0.25 μg/mL and MBC of 16 μg/mL), gentamicin plus rifampin were added. A prompt (< 24 h) clinical response (fever resolution) was accompanied by sterile blood cultures. No infection recurred during a 6-month follow-up.

Case 5

A 38-year-old woman with breast cancer underwent autologous stem cell transplantation (SCT). On post-SCT Day 4, she developed fever (38.6°C) with rigors while receiving norfloxacin antimicrobial prophylaxis, and on examination had evidence of severe (Stage 3-4) oral mucosal excoriation. Her ANC was < 100 cells/mm3. Treatment with vancomycin (1 g every 12 h) plus ceftazidime (2 g every 8 h) was given empirically. Streptococcus mitis was isolated from blood cultures and the CVC was removed (catheter tip cultures were sterile). Due to persistent bacteremia 48 hours after catheter removal, and vancomycin tolerance (MIC of 0.5 μg/mL and MBC of 32 μg/mL), gentamicin was added. The patients fever resolved within 24 hours and all follow-up blood cultures remained sterile. No infection recurrence occurred.

Case 6

A 37-year-old woman with AML receiving ciprofloxacin prophylaxis presented with fever (40°C) during an episode of chemotherapy-induced neutropenia (ANC < 100 cells/mm3). On examination, severe (Grade 3-4) oral mucosal excoriation was noticed. Empiric antimicrobial therapy included vancomycin (1 g every 12 h) and ceftazidime (2 g every 8 h). Streptococcus sanguis (MIC 0.12 μg/mL and MBC 32 μg /mL) was isolated from peripheral and catheter blood cultures. Due to persistent febrile bacteremia, gentamicin was added. Within 24 hours the patient defervesed and blood cultures became sterile.

Case 7

A 44-year-old man with metastatic sarcoma was hospitalized with fever (39°C) that accompanied chills. He had no detectable focus of infection, the CVC site appeared normal, and the ANC was 5000 cells/mm3. Empiric therapy included vancomycin (1 g every 12 h) and imipenem (500 mg every 6 h). Blood cultures on admission showed methicillin-susceptible Staphylococcus aureus; 72 hours after systemic antimicrobial therapy, fever persisted and blood cultures remained positive for phenotypically similar strain of S. aureus (MIC of 1 μg/mL and MBC of 128 μg/mL). The CVC was exchanged over the guide wire due to limited options for central venous access. After gentamicin was added a rapid clinical response (afebrile) was accompanied by sterile blood cultures. He received systemic antimicrobials for 14 days and no recurrence was noted.

Case 8

A 68-year-old woman with malignant melanoma was hospitalized due to a febrile episode (38.5°C), which accompanied chills and rigors. She had no localizing signs of infection and her ANC was 2000 cells/mm3. Vancomycin (1 g every 12 h) and imipenem (500 mg every 6 h) were given empirically. Streptococcus group G (vancomycin MIC of 0.12 μg/mL and MBC of 32 μg/mL) was isolated from blood cultures obtained upon admission. Due to persistent fever and sustained streptococcal bacteremia 72 hours after admission, gentamicin was added on hospital Day 5. She underwent a rapid defervescence (<24 h); follow-up blood culture became sterile. Treatment was continued for 14 days and the CVC was not removed.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Infections caused by Gram-positive bacteria that are tolerant to vancomycin present a treatment challenge because bactericidal testing is not routinely preformed. MIC values alone do not reflect suboptimum treatment response due to possible “drug tolerance.”24 In the 8 patients presented in the current study, clinical and microbiologic vancomycin failure created suspicion of possible drug tolerance because all isolates had vancomycin MIC values within the susceptible range. In a recent study, a vancomycin MIC of >0.5 μg/mL in clinical isolates of methicillin-resistant S. aureus indicated reduced in vitro bactericidal activity, and a high risk of clinical vancomycin failure.25 Similarly, 2 of the 3 Staphylococcus strains presented herein were found to have vancomycin MICs between 1 μg/mL and 2 μg/mL. However, this pattern did not occur in Vt Streptococcus isolates; the MICs in these 5 patient bloodstream isolates were several-fold lower (0.12- 0.5 μg/mL) (Table 1). The discrepancy in high MIC values and possible tolerance to vancomycin noted among Staphylococcus species and the lack of correlation among streptococci is of clinical interest and needs further investigation.

Antimicrobial agents such as the β-lactams and glycopeptides disrupt bacterial cell wall synthesis and result in arrested bacterial growth. This by itself does not result in cell death. To achieve bacterial cell death, antibiotic-induced arrested cell growth serves as a triggering event, which in turn enhances expression of certain bacterial genes leading to self-disintegration. The synthesis of autolysins is essential in the final destruction of antibiotic-damaged bacterial (cell wall) exoskeleton.11, 15, 26, 27 The mechanisms that control bacterial autolysis are complex and to our knowledge are not fully understood. However, it is evident that strictly regulated stress-response pathways are pivotal in implementing the bactericidal effect of the cell wall lytic antibiotics.11, 15, 24 A down-regulated or suppressed autolysin-gene expression will result in antibiotic-induced arrested bacterial growth, albeit these bacteria will remain viable and infection may persist, a phenomenon known as “drug tolerance.” Upon discontinuation of antibiotics, bacterial growth may resume, leading to a possible recurrence of infection, albeit the clinical significance of this mechanism of drug failure remains disputed.

Potential consequences of antimicrobial tolerance include: 1) nonresolving bacteremia in neutropenic patients who are at increased risk of secondary complications and septic shock, and 2) tolerance may in fact indicate the initial phase in evolution of definite drug resistance.14, 15 The latter poses a grave concern because vancomycin is still considered the treatment of choice for infections due to nonenterococcal, multidrug-resistant Gram-positive bacteria. New agents such as the lipopeptide daptomycin, which has demonstrated rapid bactericidal activity against most pathogenic Gram-positive cocci, and investigational agents such as dalbavancin and oritavancin may provide viable treatment options in the event Vt and vancomycin resistance gains a foothold.

Interestingly, in a murine endocarditis study with Vt S. aureus, bacterial density in heart valve vegetation was not found to be different after therapy with vancomycin, teicoplanin, or daptomycin.28 These strains were not tolerant to either teicoplanin or daptomycin. Low-dose daptomycin was found to be just as effective against both Vt and non-Vt strains, whereas low-dose vancomycin led to markedly suboptimum bacterial clearing.28 In contrast, our patients with persistent Vt S. aureus bacteremia had failed therapeutic dose vancomycin therapy. In clinical studies of S. aureus endocarditis, bactericidal therapy not only led to rapid clinical and microbiologic resolution of infection,29 but in 1 study involving 20 patients, a 40% mortality rate was noted in patients who received nonbactericidal therapy.30 Similarly, after the addition of gentamicin29 with or without rifampin, a complete resolution of bacteremia occurred in all 8 presenting patients. Other potential antimicrobials that may be explored in patients with Vt S. pneumonia infections include linezolid with or without rifampin, or moxifloxacin.31

In cancer patients receiving antineoplastic therapy, the selection of an bactericidal antibiotic is important due to underlying immune suppression.32 Tolerance to vancomycin may be an underdiagnosed phenomenon. Currently, a prospective study is under way at our institution to determine the scope of this problem in nosocomial bloodstream isolates and the clinical significance in patients with an underlying malignancy. Our experience to date indicates that a slow response or therapeutic failure of vancomycin should raise suspicion of infection possibly associated with Vt organisms. We also have demonstrated a prompt clinical and microbiologic response with the administration of bactericidal combinations.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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