ročník 11,2003 č.4
Satelites

Infections caused by Candida spp. in surgical intensive care

F. Vyhnánek, J. Vranková

Department of Surgery, Department of Microbiology
3rd Faculty of Medicine, Charles University, Prague, Czech Republic

Summary

Mycotic infections are lastly a significant morbidity and mortality cause of critically ill patients in surgical intensive care units. The most frequent causative agents of mycotic infections in surgical patients are Candida species. In order to assess the significance of mycotic infections for the critically ill in surgical intensive care and resuscitation units a retrospective evaluation of mycotic infection incidence and of their sensitivity to antimycotics has been performed, and some risk factors occurring in patients with fungal colonization have been determined. It was shown that colonization with yeasts, and candidaemia are most frequently caused by the fungus Candida albicans (88.2 - 93 %). Colonization with yeasts occurs most frequently in the air passages and the efferent urinary tract. The lowest resistance rate of Candida spp. was noted to Amphotericin B. Among the most frequent risk factors occurring in surgical patients with yeast colonization are risks from antibiotic treatment, and from certain interventional therapeutic procedures. In case of simultaneous occurrence of risk factors and proven yeast colonization, the route of choice is prophylactic, or pre-emptive therapy with an antimycotic (fluconazole, or Amphotericin B if resistance to the former has been proven).
Keywords: Candida - yeast infection- yeast colonization - intensive care

Introduction

In the surgical intensive care unit, fungal infection represents a significant cause of morbidity and mortality in neutropenic as well as in non-neutropenic patients, and its usual source is endogenous colonization (2, 7). Among the fungal infections, Candida spp. incidence is increasing: currently, Candida species are third in the row of most frequent pathogens isolated from blood cultures (7, 8) (Table1).

Isolated agent Rate (%)
Gram-positive bacteria 65
Gram-negative bacteria 31
Fungi 4
Tab. No.1 - Incidence of nosocomial bakteriaemia/fungaemia (haematological malignancies, solid malignant tumours, intra-abdominal inflammations in surgical patients)
Lyytikainen, O., 2000

The most invasive fungal infections affecting surgical patients (Table 2, 3, 4) are caused by Candida spp., Aspergillus spp., and Cryptococcus spp.

Candida spp
Aspergillus spp.
Cryptococcus spp.
Tab. No.2 - Most frequent agents of mycotic infections in surgical patients
Holzheimer RG., 2002

Species Rate (%)
Aikawa Tapai
Candida albicans 57 53
Candida tropicalis 14 5
Candida parapsilosis 7 14
Candida glabrata 7 9
Other (Candida neoformans) 14 19
Tab. No.3 - Causative agents of disseminated candidosis in surgical patients admitted to the Intensive Care Unit.
Aikawa N., 2002, Tapia, C., 2002

1. Local / organic affection
2. Disseminated form
Fungaemia (bloodstream infection)
Tab. No.4 - Classification of invasive mycotic infections in the surgical patient

They are classified as local (i.e. in relation to an affected organ), disseminated, or fungaemias (1, 7, 10). In clinical practice a highly specific and sensitive test for the diagnosis of Candida spp. or Aspergillus spp. infection is missing; the clinical features are rather non-specific. The significance of fungi colonization has not been determined so far. Therefore, risk factors for the development of fungal infection have been set (Table 5, 6) indicating patients at higher risk of fungal infection development (3).

  1. Severe underlying disease - tumours, chronic inflammatory diseases, advanced stages of inflammatory acute abdomen,
  2. Immunosuppression (chemotherapy of malignancies, or anti-rejection therapy),
  3. Serious injury (polytrauma, burns),
  4. Long-term broad-spectrum antibiotics administration,
  5. Interventional procedures (intravascular cannulation, artificial ventilation, tracheostomy, parenteral nutrition),
  6. Transplant surgery,
  7. High score APACHE II.
Tab. No.5 - Risk factors related to systemic Candida spp. infection in surgical intensive care

Factors increasing risk Relative risk
Operation 7.3
Parenteral nutrition 3.6
Acute renal failure 4.2
Insertion of a triluminal catheter 5.4
Antimycotic prophylaxis 0.3
Tab. No.6 - Risk factors regarding candidaemia in the surgical ICU
(Blumberg, H.M., 2001)

In this group, particularly in the post-transplant period, or in the patient with burns, antimycotic prophylaxis goes hand in hand with significant reduction of mortality caused by Candida spp. infections. In surgical patients, Candida spp. infections may manifest themselves by inflammatory complications affecting the air passages, the gastrointestinal and urinary tract (4, 6) (Table 7).

  1. Candida spp. peritonitis
  2. Candida spp. infection in intra-abdominal abscesses
  3. Candida spp. infection in septic complications of acute pancreatitis
  4. Candida spp. infection of the GIT (oesophagitis, enterocolitis)
  5. Candida spp. bronchopneumonia, bronchitis, aspiration pneumonia
  6. Candida spp. bloodstream infection (Candida spp. septicaemia)
  7. Candida spp. urinary tract infection (Candida spp. nephritis and cystitis)
Tab. No.7 - Clinical forms of Candida spp. infections in the surgical patient

The most serious condition is candidaemia which may appear as a complication of localized fungal infections or yeast colonization. Diagnosing invasive fungal infection is of paramount importance for the initiation of a targeted treatment. The recommended proceeding schedules (6) which provide for sooner commencement of empiric antimycotic treatment should be used in surgical ICUs on a larger scale. The recommendation, on the basis of general agreement (2), to start antimycotic treatment early in the surgical patient, with regard to the incidence of single disease forms, is of practical significance (Table 9).

  1. Clinical signs of infection after surgery,
  2. Absence of bacterial pathogens and/or failure to respond to systemic antibiotics,
  3. Cultivation of Candida spp. from normally sterile sites, or abundant growth in tracheal aspirate,
  4. Response to antimycotic therapy,
  5. Diagnostic serological test (Candida antibody HA test).
Tab. No.8 - Definition of invasive candidosis
(Geldner G., 2000)

  1. Reccurrent peritonitis secondary to perforation of the digestive tract, with mixed flora including fungi,
  2. Persistent febrile syndrome in a patient with multiple mucosal fungal colonization treated with broad-spectrum antibiotics,
  3. Candiduria and pyuria in a febrile patient,
  4. Candidaemia.
Tab. No.9 - When should early antimycotic therapy be indicated in surgical intensive care patients?
(Alvarez-Lerma, F., 2003)

As far as the single procedures for mycotic infections are concerned (Table 10) (2, 5), in addition to prophylaxis - limited first of all by still missing unequivocal criteria which would allow selection of patients (primarily in the case of already proven fungal colonization) - pre-emptive therapy is recommended meaning prophylactic administration of an antimycotic in selected patients at risk of developing mycotic disease.

  • Prophylaxis / prevention of invasive Candida spp. infection,
  • Pre-emptive therapy / prevention of invasive Candida spp. infection in selected patients at risk using therapeutic dosage of an antimycotic,
  • Empiric therapy / therapy of Candida spp. infection in patients at risk with clinical signs of mycotic infection.
  • Tab. No.10 - Prophylactic and therapeutical procedures in Candida spp. infections

    If invasive infection with Candida spp. is diagnosed be it prevalently on the basis of clinical signs, empirical administration of antimycotics is indicated (9).
    Targeted therapy is only possible with regard to the results of laboratory examinations, and there fore ensues with some delay in time. In compliance with the sensitivity tests, specific therapy of infections caused by Candida spp. are still most often treated with fluconazole, or Amphotericin B (Table 11), the disadvantage of the latter being the occurrence of toxic side effects.

    triazolic systemic antimycotics - fluconazolum
    - itraconazolum
    polyenic antimycotics - amphotericinum B
    - amphotericinum B lipid Complex
    - nystatinum
    - natamycinum
    polyenic antimycotics - ketoconazolum
    - miconazolum
    other antimycotics - flucytosinum
    Tab. No.11 - Specific therapy of Candida spp. infections.
    Application of Amphotericin B as the route of choice is currently better practicable thanks to the availability of a new Amphotericin B preparation with a lipid complex substantially reducing its nephrotoxicity. In order to be able to evaluate the significance of mycotic infections in critically ill patients hospitalized at the resuscitation department and the surgical intensive care unit a retrospective review of the incidence of mycotic infections was made, including their susceptibility to antimycotics, as well as of certain risk factors occurring in surgical patients with mycotic colonization.

    Patients and Methods

    In the period from 1 January 1999 to 30 June 2003, the Department of Microbiology examined blood cultures from 336 patients hospitalized in the Intensive Care Unit of the Department of Surgery, and from 2136 patients hospitalized in the Department of Anaesthesiology and Resuscitation, 3rd Faculty of Medicine, Charles University, Prague (hereafter DAR) (Table 12).

      Number (%)
      Surgery DAR
    Number of sampled BC 336 2136
    Number of positive BC 48 (14) 338 (18.2
    Gram + cocci(staphylococci, streptococci viridantes) 33 (9.8) 246 (11.5)
    Gram - bacilli (E. coli, Klebsiella sp., Pseudomonas aeruginosa, Enterobacter cloacae, Serratia sp.) 14 (4.2) 114 (5.3)
    Yeasts
    Candida albicans
    Candida non albicans
    1 (0.03)
    1
    30 (1.4)
    28
    2
    Tab. No.12 - Results of blood cultures (BC) from patients in the ICU of the Departments of Surgery and Anaesthesiology & Resuscitation (from 1 January 1999 till 30 June 2003)

      Number (%)
    Species Surgery DAR
    Candida albicans 28 (93) 90 (88.2)
    Candida nonalbicans 2 (7) 12 (17.8)
    Total 30 102
    Tab. No.13 - Yeast colonisation in patients admitted to the ICUs of the Departments of Surgery and Anaesthesiology & Resuscitation (DAR) from 1 January 1999 till 30 June 2003

    The most frequently isolated pathogens in both groups were Gram-positive cocci and Gram-negative bacilli. Infections caused by yeasts were found more frequently in patients of the resuscitation department. Colonization with yeasts was detected in 30 patients of the Department of Surgery, and in 102 patients of the DAR. The most frequent finding was Candida albicans (88.2 - 93%). The most frequent sites of yeast colonization were the airways and efferent urinary tract (Table 14).

      Incidence rate (%)
    Localization Surgery DAR
    Airway 57 56
    Urine 14 35
    Other (aspirates, bile, vascular catheters) 29 9
    Tab. No.14 - Yeast colonization in patients in the Intensive Care Units of the Departments of Surgery and Anaesthesiology & Resuscitation (Period from 1 January 1999 till 30 June 2003)

    The isolated Candida species were tested for resistance to single antimycotic preparations (Table 15).

      Resistance rate (%) CAAL (Surgery) Resistance rate (%) CAAL (DAR) Resistance rate (%) CANA (DAR)
    ANTIMYCOTIC
    Nystatin 12 6 9
    Clotrimazole 0 14 28
    Ketoconazole 0 10 19
    Fluconazole 0 6 19
    Flurocytosin 87 64 68
    Amphotericin B 0 1 1
    Miconazole 37 50 65
    Pimaricin 0 9 5
    Otraconazole 0 2 16
    Econazole 33 33 55
    Tab. No.15 - Rate of resistance to antimycotics in recovered Candida spp. (Candida albicans - CAAL, Candida nonalbicans - CANA)

    The lowest resistance rate was found in Amphotericin B. Long-term antibiotic therapy as well as overload resulting from certain interventional procedures could be identified as risk factors in relation to Candida spp colonization (Table 16).

    Risk factors Number (%)
    Malignant tumours 18 (56.2)
    Antibiotic therapy 32 (100)
    Intra-abdominal operations
    - acute (inflammatory and obstructive acute abdomen)
    - elective (GIT tumours)
    25 (78.1)
    19
    6
    Injury 7 (21.8)
    Central vein cannulation 29 (90.6)
    Parenteral nutrition 28 (87.5)
    Tracheostomy 7 (21.8)
    Indwelling urinary catheter 26 (81.3)
    Diabetes mellitus 6 (18.7)
    Tab. No.16 - Risk factors in patients with yeast colonization - Intensive Care Unit of the Department of Surgery

    A file of 30 patients with yeast colonization hospitalized in the ICU of the Department of Surgery was covered by pre-emptive fluconazole administration. In this file, not a single case of candidaemia occurred.

    Conclusion

    1. Infections caused by yeasts are a further source of nosocomial contagion in a group of patients in surgical intensive care.
    2. Yeast colonization and candidaemia in the critically ill patient is most frequently caused by the fungus Candida albicans (88.2 - 93 %).
    3. Most frequent colonization sites are the airways and the efferent urinary tract.
    4. Among all antimycotics, Amphotericin B is the one to which Candida species show the lowest resistance rate.
    5. In addition to the risk of long-term antibiotic therapy, overload resulting from certain interventional therapeutic procedures (long-term central vein cannulation, parenteral nutrition, indwelling urinary catheter) as well as postoperative intra-abdominal inflammatory complications, operations of malignant tumours, serious injuries with posttraumatic inflammatory complications, and tracheostomy with artificial ventilation are further risk factors in critically ill patients in surgical intensive care who moreover have evidenced yeast colonization.
    6. In concomitant occurrence of risk factors and proven Candida spp. colonization the route of choice is starting prevention: prophylactic/pre-emptive treatment with an antimycotic (fluconazole or Amphotericin B if there is evidence of resistance to the former).
    7. In the treatment of most serious mycotic infections Amphotericin B is recommended as the first choice. Regarding the risk of toxic effects, fluconazole or the Amphotericin B lipid complex is preferred.

    References

    1. Aikawa, N., Sumiyama, Y., Kusachi, S., Hirasawa, H., Oda, S., Yamazaki, Y.: Use of antifungal agents in febrile patients non-responsive to antibacterial treatment: the current status in surgical and critical care patients in Japan. J Infect Chemother, 2002, 8 (3), 237- 41.
    2. Alvarez-Lerma, F., Nolla, J., Palomar, M., Leon, M.A.: Treatment approach for fungal infections in critically ill patients admitted to intensive care units: result of multicenter survey. Enferm Infecc Microbiol Clin 2003, 21 (2), 83-8
    3. Blumberg, H.M., Jarvis, W.R., Soucie, J.M., Edwards, J.E., Patterson, J.E., Pfaller, M.A., Rangel-Frausto, M.S., Rinaldi, M.G., Saiman, L., Wiblin, R.T., Wenzel , R.P.: Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study of the National Epidemiology of Mycosis Survey. Clin Infect Dis , 2001, 33 (2), 177-86.
    4. Dupont, H.: Fungal infections in intensive care units: a cross- survey . Ann Fr Anesth Reanim , 2001, 20 (4), 413-7
    5. Garbino,J., Lew, D.P., Romand, J.A., Hugonnet, S., Auckenthaler, R., Pittet, D.: Prevention of severe Candida infections in non-neutropenic, high-critically ill patients: a randomized , double-blind, placebo-controlled trial in patients treated by selective digestive decontamination. Intensive Care Med. 2002, 28 (12), 1708-17.
    6. Geldner, G., Ruhnke, M., Leper, P., Penk, A., Wiedeck, H., Essig, A., Trautmann, M.: Invasive Candida infection in surgical patients: a valid clinical entity. Anesthesiol Intensivmed Notfallmed Schmerzther , 2000, 35 (12), 744-9
    7. Holzheimer, R.G., Dralle, H.: Management of mycoses in surgical patients- review of the literature. Eur J Med Res. 2002, 7 (5) , 200-26.
    8. Lyytikainen, O., Lumio, J., Sarkkinen, H., Kolho, E., Kostiala, A. : Nosocomial bloodstream infections in Finnish hospital during 1999-2000. Clin Infect Dis , 2002, 35 (2) , 14 - 9
    9. Patterson, T.F.: Role of newer azoles in surgical patients. J Chemother , 1999, 1 (6), 504-12.
    10. Tapia. C., Gonzales, P., Diaz , M.C., Corvalan, V., Gaete, M., Cuenca-Estrella, M., Rodriguez- Tudella, J.L.: Systemic yeast infections in a general hospital. Correlation between study of susceptibility in vitro, and patient survival to the fungal infection episode. Rev Med Chil, 2002, 130 (6), 661-5.

    Addresse for correspondence:

    Professor František Vyhnánek, MD, PhD.
    Department of Surgery
    The 3rd Faculty of medicine, Prague