British Journal of Haernatolog~.1990, 76, Suppl. 2. 30-34

A comparative efficacy and safety study of teicoplanin plus aztreonam versus gentamicin plus piperacillin in haematology oncology patients with clinically diagnosed septicaemia K. C. SPENCER, A. K . M. TAYLOR A N D D. A. WINFIELD* Departments of Bacteriology and *Haematology, Royal Hallamshire Hospital, Sheffield

Summary. Infections due to Gram-positive bacteria, especially coagulase-negative staphylococci. have been increasing in immunocompromised patients during the last 5 years because of an increased use of Hickman catheters and oral gut decontamination with quinolones. Teicoplanin. a new glycopeptide antibiotic. has a long plasma half-life which allows once-a-day bolus administration, making it a 'user friendly' agent. A randomized comparative evaluation of teicoplanin plus aztreonam versus gentamicin plus piperacil-

lin in leukaemic patients with a clinical diagnosis of septicaemia was undertaken. The objectives of this study were ( 1) to evaluate the efficacy and safety of teicoplanin and aztreonam in comparison to a 'standard antibiotic' regimen and ( 2 ) to assess the local and systemic tolerance of these drugs. Results of the study in more than 70 patients to date are presented, and the role of anti-Gram-positive antibiotics in the management of severe sepsis in immunocompromised patients is discussed.

Patients with profound neutropenia have a greatly increased risk of septicaemia that is associated with significant morbidity and mortality (Bodey et al, 1966). Gram-negative asepticaemia, especially when caused by Pseudonzonus aerugiI I O S ~ is , particularly lethal (Bodey, 1984). It has long been recognized that the early utilization of empirical antibiotic therapy covering the predominant pathogens is required (Young. 1988). The concept of planned progressive therapy has been devised to provide such broad-spectrum cover (Barnes & Kogers, 1987). To achieve the appropriate cover, local susceptibility patterns must be known and the low cost and easy availability of micro-computers makes this local collation of data practicable (Wheat et al, 1985). The use of permanent indwelling i.v. catheters provides easy and re-usable venous access and they have a n essential role in the management of neutropenic oncology patients (Abrahm & Mullen. 1982).The Hickman catheter is the most widely used such catheter, but its use has paralleled an increase in the incidence of infections with Gram-positive bacteria, especially Staphylococcus epiderniidis (Press et al, 1984). At the same time some of the newer quinolone antibiotics have been used successfully in the prevention of infections in cancer patients (Dekker et al, 1987).These two events together have ensured that most cancer treatment centres have experienced increases in infection caused by Gram-positive organisms (Viscoli et ul, 1988). Because some

antibiotic regimens are potentially toxic or there are problems with antibiotic resistance, there has been a continual search for new regimens (Bodey, 1984; Schimpff, 1985). With these factors in mind it was decided to perform a comparative efficacy and safety study of teicoplanin plus aztreonam versus our standard empirical regimen of piperacillin plus gentamicin. in haematology oncology patients with clinically diagnosed septicaemia. Teicoplanin is a new glycopeptide antibiotic (Williams & Gruneberg. 1984).which has been shown to be as effective as vancomycin in treating Gram-positive infections associated with Hickman catheters in patients with various haematological disorders (Webster ~t al, 1987; Smith et al. 1989).Teicoplanin is chemically similar to vancomycin but with important differences. It possesses greater lipophilicity resulting in excellent tissue penetration and a long elimination half-life which means it can be given once a day. It has a slow release from tissue, can be given by bolus injection without 'red-neck syndrome' and there is no evidence of renal toxicity. Aztreonam is a novel monocyclic beta-lactam antibiotic which has been shown to possess in vitro Gram-negative activity (Phillips et n1. 1981) and to be effective in the treatment of Gram-negative infections in neutropenic patients (Jones ef al. 1986).It was hoped that the study would answer the question whether glycopeptides should be used empirically in every pyrexial neutropenic patient with a Hickman catheter or added later once the

30

Teicoplanin and Septicaernia diagnosis of Gram-positive infection had been confirmed (Kubin et a / , 1988). The interim results of this study are presented. MATERIALS AND METHODS

Patient selection. Over a 12-month period patients with presumptive septicaemia were prospectively randomized to receive either teicoplanin plus aztreonam (TA) or gentamicin plus piperacillin (GP) in a non-blinded single-centre study. Protocol approval was given by the hospital Ethical Committee and all patients gave informed consent. Inclusion criteria were patients over the age of 18 in whom a diagnosis of presumptive septicaemia was made, and who had not been treated with antibiotics for at least 4 8 h prior to inclusion in the study. Exclusion criteria were any previous hypersensitivity to penicillins or glycopeptides, pregnancy or lactating mothers, and creatinine clearance of < 50 ml/min. A11 antibiotics were given intravenously according to the manufacturer's instructions. Teicoplanin was given as 400 mg twice daily on day 1, then 400 mg daily as a maintenance dose. Aztreonam was given 2 g t.d.s. Piperacillin was given 4 g t.d.s. and gentamicin was administered according to a nomogram (Mawer et ul. 1974). Treatment was given until the patient had become apyrexial for 4 8 h. If the patient did not respond within 48 h, antibiotic treatment was changed to the second-line therapy of ceftazidime plus amikacin. In the gentamicin plus piperacillin group, if a Gram-positive organism had been isolated, resistant to either agent, vancomycin was added to the regimen. All evaluable patients in the study had had single-lumen Hickman catheters inserted under aseptic conditions. Ciprofloxacin 2 50 mg twice daily was given to any patient entering into a phase of severe neutropenia. Clinical assessment. A history of full physical examination was made prior to admission to the study and patients were assessed for clinical response and drug tolerance every day throughout. Clinical response was classified as follows. Cured: clinical signs and symptoms of infection eradicated with no evidence of infection at the end of treatment with the study drugs and without recurrence. Improvement: clinical findings subsided during the period of treatment with the study drugs but with incomplete resolution of infection. Recurrence: initial improvement of signs and symptoms of the infection with a subsequent worsening of the clinical condition due to infection after discontinuing treatment. Failure: no apparent response to antimicrobial therapy. Not evaluable: any reason which, in the opinion of the investigator, rendered the case not evaluable. Routine haematology, biochemistry and urine analysis were assessed before, during and following cessation of treatment. Microbiological assessment. Blood and, where appropriate, urine, sputum and soft-tissue cultures were taken prior to entering into the study. These were repeated after 4 8 h at appropriate intervals during treatment and on completion. All potential pathogens were identified according to the routine laboratory methods and susceptibility to antibiotics determined by a n agar-incorporated break-point method.

31

The values for teicoplanin were 8 mg/l, aztreonam 8 mg/l, gentamicin 2 mg/l and piperacillin 64 nig/l. The microbiological responses were classified as follows. Elimination: causative organism(s) absent at or immediately after termination of therapy or complete disappearance of the infection so that follow-up culture is impossible. Elimination with recurrence: causative organism(s) absent a t or immediately after termination of therapy, but reappearance of the same organism(s) at the same site on follow-up. Elimination with re-infection: causative organism(s) absent at or immediately after termination of therapy but appearance of another infecting organism(s) at the same site on follow-up. Persistence: continued presence of causative organism(s) at the end of therapy. Indeterminate: evaluation of the bacteriological response to the study is not possible, e.g. no potential microbial pathogens isolated. Superinfection: presence of a new infecting organism during therapy or on the days after termination of therapy at a culture site that is normally sterile, or clinically significant numbers of a new organism accompanied by fever or clinical evidence of infection at the culture site that is not normally sterile. Colonization: both the presence of a new micro-organism in clinically insignificant numbers at a culture site that is not normally sterile and an absence of fever or clinical evidence of infection at the site. RESULTS The demographic details of all evaluable patients are shown in Table I. Clinical The preliminary clinical findings of this open comparative study showed both antibiotic regimens to be equally efficacious. Table I1 shows that in the TA group 19/29 (66%) of

Table I. Demography of evaluable patients

No. patients Male :female Mean age (SD)

Teicoplanin taztreonam

Piperacillin + gentamicin

29 13:16 48.3 (20.6)

30 16: 14 44.5 (18.3)

Underlying disease Acute myeloid leukaemia 1 9 Chronic myeloid leukaemia 3 Acute lymphatic leukaemia 1 Non-Hodgkin's lymphoma 3 Hodgkin's disease 3 Myeloma 0 Neutrophil count ( loy/]) Range (mean) No. patients with < 1 Antibiotic treatment (days) Range Mean Mode

20 0

0 6 2 2

0.1-3'8 (1.1) 0-3.9 ( 1 . 2 ) 17 16 1-8 4.59 4

1-7 4.13 3

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R. C. Spencer, A. K. M.Taylor and D. A. WinJield Table 11. Clinical and bacteriological responses Teicoplanin Piperacillin +aztreonam +gentamicin Clinical Cure Improve Recurrence Failure Not evaluable

I*} 5 * 0 5 5

Bacteriological 10 Eliminated Eliminated + recurrence 2 Persist 0 Indeterminate 16 Superinfection I

3

*

3 11

2 9 0 2 18 1

* Fisher’sexact text. Chi-squared= 2 . 1 3 (not significant at 10% level).

Table 111. Microbiological findings of study groups No. in teicoplanin No. in piperacillin

Micro-organism

+ aztreonam

Sfph. hnemo&cxs Staph. epidermidis Staph. simulans Staph. aurerrs

Strep. mitis Group G beta-haem. strep. Enterococci J-K diphtheroids E. coli Ent. ar’rogenes K . pneumoniae S. typhirnuriurn P. aeruginosa

+ gentamicin 1

5 (I)* 1 1 5 1 0 0

1 1 1 1

* Superinfection in one patient.

patients were cured or improved compared with 14/30 (47%) in the GP group. Owing to the small numbers evaluated to date, the difference is not statistically significant (Fisher’s exact test: chi-squared = 2 . 1 3 , not significant at 10%).In the TA group five patients were not evaluable, two because of protocol violation, one death, one developed a rash and one had diminishing renal function. All were withdrawn from the study. In the GP group two patients with decreasing renal function were not evaluable. One patient in each treatment group died as a result of disease. The length of treatment was short in both groups, an average of 4.59 d on TA, compared with 4 . 1 3 d on GP. However, patients receiving TA generally received antibiotics for 1 extra day, compared to the GP group, to achieve fever defervescence.

Apart from suspected septicaemia other possible sites of infection were: in the TA group: two patients with exit-site infections, two with urinary infedtions. one with pharyngitis and one with pneumonia. In the GP group three patients had suspected urinary tract infections and two each with exit-site infections and pharyngitis. Adverse events occurred in three TA patients: renal impairment (l),skin rash (1)and death (1).In GP patients four had adverse events: renal impairment ( 3 ) and death (1).However, in both cases death was due to underlying disease. Bacteriology The bacteriological response in both treatment groups was very similar (Table 11). As expected in such studies, no potential pathogens were isolated from a majority of patients. In two cases Streptococcus niitis persisted in the blood in the GP group and vancomycin treatment was necessary. In the TA group Staph. simulans and Staph. epiderinidis, susceptible to teicoplanin, were eradicated from one patient but recurred following cessation of antibiotic treatment. Superinfection with Staph. epidermidis occurred in one GP patient. and one TA patient had superinfection with P. aeruginosa and Staph. epidermidis. Table I11 shows the bacteria isolated from the patients. In the TA group I 6 bacterial isolates were obtained from 1 2 patients. All 12 had positive blood cultures with two also having exit site wounds (Staph. huemolyticus) and two patients with two micro-organisms in the blood. Blood cultures were again positive in all 12. three had two bacterial species in their blood, urine was positive in one case (Klebsidla pneurnoniae) and two patients had exit-site wounds infected with the same micro-organisms (Staph. epiderrnidis). In vitro susceptibility tests showed that all Gram-positive bacteria were susceptible to teicoplanin (MIC < 8 mg/l) and all Gram-negative isolates were susceptible to aztreonam (MIC < 8 mg/l), gentamicin (MIC < 2 mg/l) and piperacillin (MIC < 64 mg/l). However, gentamicin had in vitro activity only against 6/29 (2 1%)Gram-positive isolates whilst piperacillin was active only against 7/29 (24%) of strains. Eflect of ciprofloxacin In the TA group eight patients were also given ciprofloxacin 2 5 0 mg b.d. as prophylaxis against sepsis during severe neutropenia. Clinical cure or improvement occurred in four ( 50%).In the GP group 10 patients received ciprofloxacin of whom three (30%) were said to have had a clinical cure. These figures. though lower, are similar to the clinical response in the overall group. Again, small numbers mitigate against any conclusions at this time. No Gram-negative pathogens were isolated from any of the patients receiving ciprofloxacin. DISCUSSION This preliminary report shows TA or GP antibiotic treatment to be equally efficacious and safe. However. more numbers are obviously needed to make any definitive conclusions. No tunnel infections were seen in either group, a condition which does not always respond to antibiotic therapy alone (Smith et al. 1989). Four exit-site infections, two in each

Teicoplanin and Septicaemia group, did however respond to antibiotics alone. It could be said that our patients were not treated with antibiotics for long enough, with the average treatment of around 4 d in both groups. However, because of the pressure on beds in our hospital, with a n overall bed occupancy for 1988/89 of 86.9% (cf. provincial average of 78.6%) this is the only way our Haematology Unit can function. In examining the role of ciprofloxacin prophylaxis it can obviously decrease the incidence of Gram-negative septicaemia. However, its use does not appear to affect the eventual outcome of infective episodes. If gentamicin plus piperacillin is used, then Gram-positive infections are sub-optimally treated, because only 49% of strains were susceptible to either agent. However, does this matter? Our study suggests not. Although Gram-negative infections are still common in cancer patients, Gram-positive organisms now predominate causing up to 70% of documented infections in some reports (Pizzo et al, 1986). Most standard antibiotic regimens, as we have shown, do not contain adequate coverage against Gram-positive bacteria. especially coagulase-negative staphylococci and Corynebactrriuni jeikeium. Karp et a1 ( 1 9 8 6 ) have recommended including an antimicrobial agent specific for Gram-positive bacteria in the initial empirical antibiotic regimen in febrile neutropenic patients with a Hickman line in situ. The availability of teicoplanin, which has been shown to be efficacious in treating such infections (Webster et al, 1987: Smith et a]. 1989). makes this policy possible, as we have demonstrated. However, our preliminary study shows no differences in the eventual clinical cure/improvement rates if specific anti-Gram-positive antibiotics are not included. Would it be appropriate to withhold anti-Gram-positive antibiotics until the pathogen has been identified, as argued by Rubin et 01 (1988)?In their study, delaying treatment with vancomycin did not appear to influence the eventual outcome. Thus, rather than use glycopeptide antibiotics with resulting increased cost, could not these agents be added once definitive bacteriological diagnosis is established? The empiric use of vancomycin has resulted in the development of tolerance by some Gram-positive species (Saito e t al, 1987). The threat ofresistance is always a possibility. In dealing with Gram-negative infection, little, if any, margin for error or delay in prompt therapy exists. Ultimately the decision regarding the appropriate antibiotic regimen rests with each hospital. Hospitals have different microbial pathogens and different antibiotic susceptibility patterns (Wheat et 01. 1985). Antibiotic resistance must be taken into consideration. Regardless of which antibiotic(s) are selected, physicians must be prepared to modify their initial choice in the light of microbiological and clinical findings to ensure a successful outcome (Barnes & Rogers. 1987). In conclusion, teicoplanin plus aztreonam has been shown to be a safe and efficacious alternative treatment to gentamicin plus piperacillin for the treatment of presumptive septicaemia in haematology oncology patients. Teicoplanin has several advantages over vancomycin: its ease of administration with subsequent savings in nursing time is a n obvious one. However. the exact timing of the introduction of specific

33

anti-Gram-positive cover in immunosuppressed patients with Hickman catheters still has to be accurately identified.

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R. C. Spencer, A. K. M. Taylor and D. A. Winfield

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