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Keywords:

  • neutropenia;
  • infection;
  • prophylaxis;
  • ciprofloxacin;
  • colistin

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Following a 2-year study, the combination of oral ciprofloxacin and colistin has been used continuously for 10 years without the emergence of resistance. During a 2-year period (1987–1989), we compared ciprofloxacin + colistin (CIP + COL) with neomycin + colistin (NEO + COL) in a randomized trial – combinations chosen because of the potential for prophylaxis of Gram-negative infection by ciprofloxacin, with colistin given to reduce the risk of emergence of resistance. Sixty-four patients with similar demographics in each arm were evaluable for efficacy analysis. Patients on CIP + COL had a significantly lower proportion of neutropenic days with fever (P < 0·001) and neutropenic days on intravenous antibiotics (P < 0·001) than patients on NEO + COL. A total of 54 (15 bacteriologically documented) pyrexial episodes occurred in patients on CIP + COL and 77 (41 bacteriologically documented) in patients on NEO + COL. Only two Gram-negative bacterial infections occurred in the CIP + COL arm compared with 16 in the NEO + COL arm. No Staphylococcus aureus infections occurred in the CIP + COL group compared with 10 in the other patients. Two CIP-resistant Gram-negative bacilli were isolated from patients on CIP + COL compared with 13 NEO-resistant Gram-negative bacilli from patients on NEO + COL. Following a subsequent decade of unchanged use of this prophylactic strategy in neutropenic patients, a 2-year follow-up study between 1 January 1998 and 31 December 1999 showed 66 significant infections during 350–400 neutropenic episodes. Eight of the 111 (7·2%) isolates were with ciprofloxacin-resistant organisms, involving 2% of the neutropenic episodes, indicating that the strategy of combining colistin with ciprofloxacin has been effective in the prevention of Gram-negative sepsis in neutropenic patients without the emergence of significant resistance despite widespread concurrent hospital and community use of the quinolones.

Infection has been, and remains, the major cause of morbidity and mortality in neutropenic patients (Young, 1983; Rossi & Klastersky, 1996,Riley et al, 1999; Hargrave et al, 2001). As the outcome of therapy for acute leukaemia has improved, the number of patients experiencing prolonged (> 10 d), profound (neutrophils < 0·1 × 109/l) neutropenia has also increased (Schimpff, 1980; Gratwohl et al, 1998; Jagarlamundi et al, 2000). Patients with leukaemia who receive chemotherapy usually have concurrent gut and respiratory tract mucosal damage, and percutaneous vascular access catheters, all of which can be portals of entry for infecting organisms. The majority of bacterial infections are caused by endogenous organisms or acquired Gram-negative bacteria which colonize the gastrointestinal tract (Schimpff et al, 1972).

Over the past three decades, numerous studies have examined ways of suppressing potential pathogens already colonizing the patient and reducing the acquisition of new organisms. Attention has focused chiefly on the use of laminar air flow systems (O'Donnell et al, 1994) and attempts to achieve either total gut decontamination using oral antibiotics (Storring et al, 1977; Watson et al, 1982) or ‘selective’ gut decontamination based on Van de Waaij's concept of colonization resistance (van der Waaij & Berghuis, 1974). Some authors (Wade et al, 1981; Watson et al, 1982) have suggested that, despite colonization resistance, systemic prophylaxis by absorbable cotrimoxazole prevented infection more effectively than the simple suppression of intestinal bacteria by non-absorbable agents.

Ciprofloxacin (CIP), a 4-quinolone antibiotic, is active against most Gram-negative and some Gram-positive bacteria (Fass, 1983). It rapidly eliminates aerobic Gram-negative organisms from the gut after oral administration and is also absorbed, reaching systemic therapeutic levels within 1–2 h (Bergan et al, 1988). Ciprofloxacin has little effect on the anaerobic flora of the gut and may preserve colonization resistance (Rozenberg-Arska et al, 1985).

Several small studies have investigated ciprofloxacin in the prevention of bacterial infection in neutropenic patients, but the emergence of ciprofloxacin-resistant organisms has been a concern (Rozenberg-Arska et al, 1985; Dekker et al, 1987; Young, 1987; Cometta et al, 1994; Yeh et al, 1999). It has previously been suggested that it is possible to limit the emergence of resistant strains by the concomitant use of another antibiotic (Rozenberg-Arska et al, 1983). We previously conducted an in vitro study (Mannan et al, 1988) which excluded antagonism between ciprofloxacin and colistin (COL) when tested against strains of Pseudomonas aeruginosa isolated from neutropenic patients, suggesting a possible role in prophylaxis for this regimen. Hence, in the comparative trial, the combination of ciprofloxacin with colistin was evaluated by comparing it with what, at that time, was a standard prophylactic regimen of neomycin (NEO) plus colistin (Storring et al, 1977). Subsequent to this trial, the intention was to put the best arm of the study into practice and assess the risk of emergence of resistant organisms over the next decade of use in a unit managing approximately 350–400 neutropenic episodes in patients with haematological malignancy per annum.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Randomized trial patient selection Between 1987 and 1989, adults aged ≥ 18 years who were likely to be made neutropenic for at least 7 d were eligible for study entry. They were either receiving cytotoxic chemotherapy for treatment of a haematological malignancy or undergoing intensive chemo/radiotherapy prior to bone marrow transplantation (BMT). Patients could be re-enrolled during subsequent neutropenic episodes. Informed consent was required prior to the trial entry and the protocol was approved by the Royal Free Hospital ethical practices subcommittee. Exclusion criteria included known quinolone allergy, a history of convulsions, antibiotics usage within the previous 7 d, serum creatinine level of > 240 µmol/l and patients who were already febrile. Patients who were neutropenic for < 7 d or pyrexial within 48 h of starting prophylaxis were excluded from the efficacy analysis. Safety analysis was performed on all patients who had received the study medications for at least 72 h.

Antimicrobial prophylaxis Patients were stratified into BMT and chemotherapy groups and randomized at the onset of chemotherapy or conditioning for BMT to receive oral CIP (500 mg) + COL (1·5 MU) twice daily or NEO (500 mg) + COL (1·5 MU) twice daily. All patients received oral amphotericin B suspension 500 mg four times/d plus ketoconazole 200 mg twice daily or subsequently fluconazole 100 mg once a day. BMT patients were nursed in protective isolation in single rooms with high efficacy particulate air (HEPA) filters. Chemotherapy patients were nursed in similar single rooms or occasionally in four-bedded rooms. The prophylactic regimen was continued until the neutrophil count reached 1·0 × 109/l or for a maximum of 30 d. Patients were assessed daily for compliance (using nursing records and random patient cross-checks), adverse events and symptoms, and signs of infection.

Monitoring of development of resistance Microbiological surveillance to assess the effect of 10 years of antibiotic prophylaxis with ciprofloxacin and colistin was carried out 10 years after the study end, between 1 January 1998 and 31 December 1999. During that period all neutropenic in-patients continued to receive the modified regimen and all bacteria from microbiologically proven infection cultures were assessed for sensitivity to ciprofloxacin.

Microbiological methods Weekly surveillance cultures were taken from nose, throat, urine, faeces and the central catheter exit site. Nose, throat and catheter swabs were cultured on blood agar and sabouraud agar. Faeces were cultured on MacConkey, deoxycholate citrate (DCA), blood, campylobacter and sabouraud agar, and inoculated into selenite F broth which was subcultured on to DCA after overnight incubation. Urine was cultured semiquantitatively, using a 3-mm standard loop, on cysteine lactose electrolyte-deficient (CLED) agar. All Gram-negative bacilli were identified using API procedures (Bio Merieux SA, 69280 Marcy-I'Etoile, France), and other organisms according to standard laboratory techniques. Antibiotic sensitivity testing was carried out using the modified Stokes' method (Stokes & Ridgeway, 1987). Minimum inhibitory concentrations were determined for significant isolates using agar dilution techniques (Waterworth, 1978).

When infection was suspected, in addition to the above, cultures were taken from probable sites of sepsis and blood. Blood was cultured using aerobic and anaerobic Bactec bottles (660).

Biochemical and haematological methods Haemoglobin, differential white cell and platelet count, plasma urea and electrolytes, liver function tests and serum creatinine were monitored at least twice weekly.

Systemic antimicrobial therapy When patients developed a fever, or infection was suspected, they were randomized in a concurrent empirical antibiotic study to receive intravenous (IV) amikacin plus azlocillin or vancomycin plus aztreonam. Antimicrobial prophylaxis was discontinued during systemic therapy. Empiric antifungal therapy was given throughout the period and applied after 96 h of antibiotic therapy for patients with unresponsive fever of unknown origin, using amphotericin B or liposomal amphotericin B.

A subsequent cohort of all neutropenic patients treated within the unit over a 2-year period from the beginning of 1998 until the end of 1999 were monitored for microbiologically documented infections and, in all cases, microbiological sensitivity testing of all organisms was carried out. The number of neutropenic episodes was estimated by reviewing the weekly inpatient diagnostic lists.

After the initial study, all subsequent neutropenic patients on the unit received the CIP + COL regimen, the dose of colistin being increased in 1993 to 3·0 MU twice daily (the then recommended dose). The follow-up study patients also received antifungal prophylaxis with fluconazole and oral amphotericin B or, subsequently, itraconazole.

During the follow-up study Bactec 9000 bottles were used (Becton Dickinson Europe, 38241 Meylan Cedex, France).

The empiric regimens following the initial trial included piperacillin with or without amikacin, ceftazidime plus amikacin, imipenem, meropenem and, currently, piperacillin/tazobactam alone.

Definitions A pyrexial episode was defined as a temperature of at least 38°C persisting for at least 2 h. Infections were classified in accordance with European Organization for Research and Treatment of Cancer (EORTC) criteria (EORTC International Antimicrobial Therapy Project Group, 1978). Colonization was defined as the isolation of an organism on one or more occasions from a mucosal site > 72 h after initiating prophylaxis. Compliance was assessed as good (omission of up to one dose in any 7-d period), moderate (omission of two doses in any 7-d period but not on the same day) or poor (omission of two doses in any 1 d or > 2 doses in any 7-d period). Diarrhoea was defined as > 3 soft or liquid stools/d. Renal dysfunction was classified as moderate (50–100% increase in baseline creatinine) or severe (> 100% increase in baseline creatinine). Hepatic dysfunction was classified, based on elevations above the upper limit of normal bilirubin or liver enzyme levels, as mild (≤ 50% increase), moderate (50–300% increase) or severe (> 300% increase).

Statistical analysis Non-categorical demographic and safety variables were tested for normality using the Shapiro–Wilk test. Treatment groups were compared for the proportion of days with fever and IV antibiotics using the Wilcoxon two-sample test. Comparison for episodes of fever and organism isolated was performed using Fisher's Exact test.

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Clinical data

A total of 150 neutropenic episodes were assessed in the trial of which 128 were evaluable for efficacy analysis and 148 for safety analysis (Table I). Twelve episodes in the CIP + COL arm (exclusion criteria present: eight, pyrexial within 48 h of starting prophylaxis: two, cancellation of BMT: one, did not develop neutropenia: one) and 10 episodes in the NEO + COL arm (exclusion criteria present: five, pyrexial within 48 h of starting prophylaxis: two, protocol violation: two, neutropenic for < 7 d: one) were excluded from efficacy analysis. Therefore, there were 64 evaluable episodes in the CIP + COL arm and 64 in the NEO + COL arm. Patient characteristics were similar in both arms, as was the duration on the study and the duration of neutropenia.

Table I.   Clinical data.
 CIP + COLNEO + COL
Number randomized7674
Number evaluable for safety7573
Number evaluable for efficacy6464
Mean age (range)34·5 (18–72)36 (18–74)
Non-transplant3940
Transplant2524
 Autograft1412
 Allograft1112
Mean days on study (range)28 (14–30)26·5 (9–30)
Mean days of neutropenia (range)22 (8–30)21·5 (7–30)

Pyrexial episodes and use of parenteral antibiotics

Patients on CIP + COL had a significantly lower proportion of neutropenic days on parenteral antibiotics than patients on NEO + COL (0·36 versus 0·60; P < 0·001). There was also a significant difference in the proportion of neutropenic days with fever (CIP + COL: 0·14, NEO + COL: 0·26; P = 0·003) between the two groups. Seventeen out of 64 patients in the CIP + COL arm did not develop a pyrexia compared with only six out of 64 in the NEO + COL arm (P = 0·02) (Table II). The total number of febrile episodes during the neutropenic period was lower in patients on CIP + COL than in patients on NEO + COL. This was owing to the difference in bacteriologically documented episodes between the two groups: the number of non-bacteriologically documented episodes was similar in both arms.

Table II.   Nature of pyrexial episodes during neutropenic period.
 CIP + COL n = 64NEO + COL n = 64
  • *

    One episode with mixed bacteraemia and fungaemia.

Total number of pyrexial episodes5477
Bacteriologically documented15*41
Clinically documented1115
Possible bacterial2015
Non-bacterial6*5
Infection doubted31
Total number of patients with pyrexial episodes4758 (P = 0·02)

Compared with patients on CIP + COL, patients on NEO + COL had more episodes of pulmonary (nine versus two) and soft tissue (26 versus 13) infections. Other sites of infection were the oropharynx (NEO + COL: five, CIP + COL: two) and the urinary tract (NEO + COL: one, CIP + COL: 0).

Microbiological data

Fourteen out of 64 patients on CIP + COL and 39 out of 64 patients on NEO + COL developed a bacteriologically documented infection (Table III). The incidence of Gram-negative infection was significantly lower (P > 0·001) in patients on CIP + COL than in patients on NEO + COL. There was also a significant difference in Gram-positive infections between the two groups (P = 0·03). This was mainly as a result of the lack of Staphylococcus aureus infections in the CIP + COL arm.

Table III.   Bacterial isolates from documented infections.
 CIP + COL n = 64NEO + COL n = 64
  • *

    One patient on CIP + COL and three patients on NEO + COL with polymicrobial infections. One patient on CIP + COL and two patients on NEO + COL each with two episodes of bacteriologically documented infections.

  • CNS, coagulase-negative staphylococcal.

Total isolates1644
Gram-positive
 Staphlococcus aureus010 (P = 0·001)
 CNS46
 α haemolytic streptococci98
 Others11
 Total Gram-positive1425 (P = 0·03)
Gram-negative
 Acinetobacter sp.10
 Enterobacteriaceae07
 Pseudomonas aeruginosa04
 Stenotrophomonas maltophilia13
 Others02
 Total Gram-negative216 (P < 0·001)
Anaerobic bacteria03
Total patients14*39* (P < 0·001)

Colonization with Gram-negative bacilli was significantly lower in patients on CIP + COL than in patients on NEO + COL (P < 0·001). Five patients on CIP + COL were colonized with Gram-negative bacilli while receiving prophylaxis compared with 25 patients on NEO + COL. The majority were isolated from the gut (CIP + COL 0 versus NEO + COL 18) with six infections due to these organisms in the NEO + COL group of patients. One patient on CIP + COL with Acinetobacter sp. nasal colonization developed a Hickman site soft tissue infection with the same organism.

Compared with patients on NEO + COL, there was a significantly lower number of patients on CIP + COL from whom resistant colonizing Gram-negative bacilli were isolated (P < 0·01). Two patients on CIP + COL were colonized with CIP-resistant Acinetobacter sp. In the NEO + COL arm eight patients were colonized and six patients infected with NEO-resistant Gram-negative bacilli (this included one infection due to a colonizing Escherichia coli).

Colonization with yeasts was similar in both groups (CIP + COL: 15, NEO + COL: 13). There were no documented fungal infections in the NEO + COL arm compared with four in the CIP + COL arm. However, two patients on CIP + COL developed their infections prior to prophylaxis. One patient had a recrudescence of her disseminated aspergillosis. The second patient with Candida guillermondii fungaemia had developed a transient pyrexia on admission with isolation of Candida guillermondii from one set of blood cultures, but this was thought to be a contaminant at the time and not treated. Of the other two patients, one had polymicrobial Candida krusei and Streptococcus mitis bacteraemia and the other candidosis due to Candida albicans.

Adverse events and compliance

Adverse events (mainly hepatic dysfunction and diarrhoea) occurred in both arms (Table IV) but could not be directly attributed to the study regimens. However, fewer patients on CIP + COL had diarrhoea. Two patients on CIP + COL developed convulsions, but there was an underlying cause for this in each case.

Table IV.   Adverse advents.
 CIP + COL n = 75NEO + COL n = 73
  • *

    Focal convulsions as a result of cortical thrombophlebitis and grand mal convulsions secondary to metabolic disturbance.

  • **

    Pseudomonas aeruginosa and Stenotrophomonas maltophilia pulmonary infections.

Renal dysfunction710
 Moderate34
 Severe46
Hepatic dysfunction2122
 Mild1111
 Moderate68
 Severe43
Rash98
Diarrhoea918
Convulsions2*0
Deaths12
 Following infection02**
 Cause unclear10
Total patients3133

Good compliance was achieved in 59 (92%) patients on CIP + COL and 54 (84%) patients on NEO + COL. Compliance was moderate in four patients on CIP + COL and nine patients on NEO + COL, and poor in one patient in each arm.

Long-term surveillance for development of ciprofloxacin resistance

Between 1 January 1998 and 31 December 1999 there were 66 episodes of microbiologically documented infection in 47 patients out of approximately 700 neutropenic episodes (Table V). Twenty-eight of these episodes involved Gram-negative rods (with or without other organisms). There were five ciprofloxacin-resistant Gram-negative organisms isolated, none of which led to a fatal conclusion. During the same period 80 (11·4%) patients were colonized with Gram-negative organisms and 25 of these (32%) had organisms resistant to ciprofloxacin (Table VI). Although occasional patients on the unit have been colonized with ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus(MRSA) and vancomycin-resistant Enterococcus (VRE), the majority of these have been imported. The incidence of bacteraemias with haemolytic streptococci (which are also ciprofloxacin resistant) has declined with time and there has been little change in the incidence of infections with coagulase-negative staphylococci.

Table V.   Blood culture isolates in the follow-up study.
Microbiologically documented infections in 47 patients66
Gram-negative rods with or without other organisms28
Ciprofloxacin-resistant organisms5
 Pseudomonas aeruginosa2
 Escherichia coli1
 Stenotrophomonas maltophilia1
Table VI.   Colonization with ciprofloxacin-resistant gram-negative organisms during the follow-up study.
OrganismsNumber
Escherichia coli8
Enterobacter cloacae7
Stenotrophomonas maltophilia6
Pseudomonas aeruginosa4
Citrobacter freundii1
Enterobacter agglomerans1
Enterobacter sp.1
Acinetobacter sp.1
Coliform sp.1
Total30
Sites of resistant organismsNumber
Stool17
Throat6
Wound swab1
Hickman exit site2
Perineum1
Throat and nose1
Stool & throat1
Wound & nose1
Total30

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Selective oral gut decontamination is now widely, but not universally, used for the prevention of infections caused by Gram-negative bacilli in neutropenic patients, although its role is controversial (Young, 1987), and most studies have only shown a significant benefit when combined with a protective environment. It is, perhaps, now more widely used in the intensive care setting, in which meta-analysis has shown a reduction in ventilator-associated pneumonia and in mortality, particularly in acute trauma patients (D'Amico et al, 1998).

A number of antimicrobial agents such as colistin, cotrimoxazole and the 4-quinolones have the capacity to suppress gut enterobacteriaceae without reducing the anaerobic flora (Rozenberg-Arska et al, 1985). Many studies have investigated the use of cotrimoxazole, but there has been concern about its potential for marrow suppression (Wade et al, 1983) and the incidence of adverse reactions (Watson et al, 1982). More recent studies show faster neutrophil recovery with ciprofloxacin prophylaxis compared with cotrimoxazole prophylaxis (Imrie et al, 1995). Further trials have demonstrated encouraging results for the quinolones with a reduction in the incidence of Gram-negative sepsis and febrile episodes (Dekker et al, 1987; Karp et al, 1987; Warren et al, 1990; GIMEMA Infection program, 1991; Schmeiser et al, 1993; Lew et al, 1995; Ford et al, 1998) and further confirmation of its safety and efficacy is provided by this study.

The CIP + COL regimen provided better prophylaxis against bacterial infection than NEO + COL, with a greater number of patients on CIP + COL remaining afebrile during their period of neutropenia. This study also provides convincing evidence of the reduction in duration of fever and use of parental antibiotics with CIP + COL prophylaxis. In part, this is related to the difference in the number of soft tissue and pulmonary infections between the two regimens. Patients on NEO + COL had more of these types of infection which took longer to respond and necessitated longer periods on parenteral antibiotics. CIP is well absorbed and achieves good tissue levels (Fass, 1983), suggesting that it should be a good agent for preventing infections originating in the respiratory tract and skin.

Only 14 patients on CIP + COL had bacteriologically documented infections compared with 39 patients on NEO + COL. It has been argued that the use of oral absorbable agents could prevent the recovery of organisms from culture specimens and give rise to misleading results. However, this does not appear likely as there was an equivalent number of non-bacteriologically documented pyrexial episodes between the two groups, evidence reinforced by the observation of fewer febrile episodes in the CIP + COL group.

The CIP + COL regimen was effective in preventing infections with Gram-negative bacilli and S. aureus. There were no S. aureus infections in the CIP + COL arm and only two patients developed infections with Gram-negative bacilli. Both were Hickman catheter exit site infections which responded following treatment with IV ceftazidime and amikacin and removal of the Hickman catheters. In contrast, 25 patients on NEO + COL developed bacteraemias, soft tissue or pulmonary infections with Gram-negative bacilli or S. aureus. These results reflect the antibacterial spectrum of the antibiotics and the local microbial ecology. In our institution, Pseudomonas aeruginosa had previously accounted for about 30% of Gram-negative infections, with 59% mortality, in neutropenic patients and there had also been a high incidence of S. aureus infection. The spectrum of infection in neutropenic patients is changing (Kibbler & Prentice, 1999) and factors influencing this include prophylactic antimicrobials, the use of long-term central venous catheters (Lowder et al, 1982) and mucosal damage following intensive cytotoxic therapy (McWhinney et al, 1991). It is important that the choice of strategies for antimicrobial prophylaxis in the neutropenic patient is guided by the prevalent pathogens and their antimicrobial susceptibility.

In our institution, 50–55% of E. coli isolated from our neutropenic patients were resistant to neomycin. This may account for the difference in rates of isolation of resistant Gram-negative bacilli between the two regimens. NEO-resistant Gram-negative bacilli were isolated from 13 patients on NEO + COL compared with only two CIP-resistant Gram-negative bacilli from patients on CIP + COL. However, only one of the eight gut isolates of NEO-resistant enterobacteriaceae caused bacteraemia.

As illustrated by the long-term surveillance study, the emergence of CIP-resistant Gram-negative bacilli during therapy remains an infrequent event in our patient population. Resistant strains have been reported from a number of centres (Cometta et al, 1994; Kern et al, 1994; Yeh et al, 1999) and have led to concerns that quinolone prophylaxis should be discontinued. Similar problems were encountered in the past with co-trimoxazole prophylaxis and it was found that the acquisition rate and number of infections due to resistant enterobacteriaceae may be reduced by the addition of a concomitant antibiotic such as colistin (Rozenberg-Arska et al, 1983). Although the dose of colistin used in the initial study was lower than the currently recommended daily dose of 4·5–9 MU, it may have contributed to the prevention of selection of resistant organisms. We believe that the subsequent increased colistin dose has maintained this effect.

In our initial study, neither of the two cases of Gram-negative infection in patients receiving CIP + COL were with ciprofloxacin-resistant organisms and two out of five colonizing organisms were resistant. This compares favourably with a recent published meta-analysis of trials mostly performed during that era, showing an incidence of infections with quinolone-resistant Gram-negative organisms of 3·0% (Engels et al, 1998). After 10 years further use of our regimen, the incidence of infections with ciprofloxacin-resistant Gram-negative organisms is 1·2% and there has been no increase in the incidence of colonization with ciprofloxacin-resistant Gram-negative organisms (31% versus 40% of isolated Gram negative).

Both regimens were well tolerated. Fewer patients on CIP + COL had diarrhoea, which may relate to the lower use of IV antibiotics for patients in this arm. In general, compliance was good with both regimens, a factor of great importance with regard to the usefulness of prophylactic therapy. Another useful effect of antibiotic prophylaxis is in the reduction of acute graft-versus-host disease (GvHD) following allogeneic bone marrow transplantation (allo-BMT) (Beelen et al, 1999). The hypothesis is that the intestinal bacterial microflora are involved in the pathogenesis of GvHD through the LPS (lipopolysaccharide)-mediated enhancement of the cytokine storm (Ferrera, 1993) and that the addition of anti-anaerobic agents such as metronidazole to ciprofloxacin might reduce the incidence of GvHD. The randomized trial carried out by Beelen et al (1999) demonstrated a reduced incidence of severe acute GvHD but no effect on chronic GvHD or survival.

In conclusion, ciprofloxacin provides effective prophylaxis against Gram-negative infection in adults. Our study shows that careful use, combining it with colistin in the setting of good infection control practices to prevent the spread of imported resistance, has maintained its effectiveness. Thus, in the absence of any superior strategy, this approach continues to be used and recommended.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We would like to thank the late Paul Noone for his contribution to the design of the original study and for his many other contributions to the fight against infection in neutropenic patients.

This work was undertaken by the Royal Free Hospital NHS Trust, which received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive.

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  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
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