Treatment of pseudomonas and serratia infections with ceftazidime

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1 Journal of Antimicrobial Chemotherapy (95) 5, 6-6 Treatment of pseudomonas and serratia infections with ceftazidime Colleen J. Bergin, Peter Phillips, obert. T. Chan, John uedy and Erica P. Crichton Departments of edicine and Laboratories, t. Paul's Hospital, Vancouver, B.C., Canada V6Z Y6 The effectiveness and safety of parcnterally administered ceftazidime were assessed in 0 patients with infections caused by Pseudomonas aeruginosa or erratia marcescens. There were six infections involving the urinary tract, six wound infections, one respiratory tract infection, three septicaemias, one empyema, one mastoiditis and two infections of the epididymis. ixteen of the isolates were resistant to at least one aminoglycoside antibiotic. ifteen patients were clinically and bacteriologically cured, two patients improved, but had relapses and three patients showed no response. The lack of clinical response was due to the development of resistance by P. aeruginosa in two patients with osteomyelitis, one of whom also had diabetes mellitus. The third patient who had chronic lymphocytic leukaemia developed post-operative osteomyelitis and septicaemia with serratia. he did not respond to treatment. ide effects consisted of a positive direct Coomb's test without evidence of haemolysis in two patients and a mild maculopapular rash in one patient. Introduction Pseudomonas and erratia species are important nosocomial pathogens. Therapy for infection with these organisms has relied heavily on aminoglycoside antibiotics. Newer cephalosporins have an increased antibacterial spectrum against aerobic Gram-negative bacilli, but many are not effective against Ps. aeruginosa. Ceftazidime has a wide antibacterial spectrum in vitro, including activity against Pseudomonas and erratia with inhibition of growth in vitro often being achieved with lower concentrations than with other cephalosporins and aminoglycosides (Phillips et al., 9; Bint et al., 9; Chow & Bartlett, 9). Pharmacokinetic studies have shown a half-life of - h, low protein binding, good serum and extracellular fluid levels and predominantly renal excretion (Harding et al., 9; Wittman et al., 9). Animal studies suggest safety of the drug in dosages proposed for human use and human trials to date have shown good tolerance to the drug (Capel-Edwards et al., 9; Zuccoli etal., 9; Deandre etal., 9;Gordts, Bad & Butzler, 9; anders et al., 97). This study concentrated on infections with Ps. aeruginosa and er. marcescens because these infections are notoriously difficult to treat and frequently require antimicrobial agents which have important dose-related adverse effects. Twenty patients with infections due to Pseudomonas or erratia are presented. ost of these patients had significant underlying disease and had already failed to respond to aminoglycoside therapy. eprint requests to. Dr E Crichton, Laboratory, t. Paul's Hospital, 0 t. Paul's Hospital, Vancouver, BC.V6ZY6, Canada. 6 0O5-75/5/05O6+O9 $0.00/0 95 The British ociety for Antimicrobial Chemotherapy Downloaded from on arch 0

2 6 C. J. Bergin rt a/. aterial and methods Twenty patients received courses of intravenous ceftazidime from August 9 to December 9. The patients were over the age of 6 years with infections of the respiratory tract, urinary tract, wounds or septicaemia. Criteria for exclusion were: pregnancy, history of serious allergy to penicillin, concurrent antimicrobial therapy, or marked impairment of renal function (G less than loml/min). Written informed consent was obtained in all cases. Prior to therapy a full clinical and laboratory investigation was carried out. Clinical assessments including vital signs were documented daily. The following specimens were obtained for analysis before, during and after treatment: blood specimens for complete blood count, platelet count, direct Coomb's test, BUN, total protein, albumin, creatinine, alkaline phosphatase, GOT and LDH; urine for protein, cells and glucose; and exudates, urine and blood for bacteriological investigation. ensitivity testing was performed according to the Kirby-Bauer method using 0 and 0 ug discs for ceftazidime and 00 ug discs for carbenicillin. The two discs were used for ceftazidime because there was insufficient information about zone sizes related to ICs. ICs were determined by plate dilution for ceftazidime and by the microtitre method for the other antimicrobial agents. Ceftazidime was supplied by Glaxo Canada Ltd. in the pentahydrate form with sodium carbonate. The drug was dissolved in sterile water for injection and administered over 5-0min at a dose ranging from 0-5 to g rv qh except for one patient with impaired renal function who received g of ceftazidime intravenously qh. The duration of treatment ranged from 7- days. Patients were withdrawn from treatment if there was bacteriological evidence that the causative organism(s) was resistant, or if serious adverse effects were noted. esults There were patients with infections caused by Ps. aeruginosa, nine of whom were considered clinically cured; in seven of these the bacteria were also eliminated (Table I and Table III). The most severe infection was in an elderly man who grew Pseudomonas from an empyema, from the skin surrounding the drainage tubes and in the urine (case ). He had a complicated course requiring two courses of ceftazidime. The empyema which had not responded to gentamicin or tobramycin resolved with ceftazidime. The urine cleared of Pseudomonas, but a suprapubic catheter was necessary in the patient's management and the organism returned. The urinary infection again cleared after the second course of ceftazidime. treptococcus faecalis was grown transiently after the second course of ceftazidime, but did not require treatment with antibiotics. At the time of his discharge, the patient was cured clinically, but a susceptible Ps. aeruginosa was still isolated from the superficial wound through which the chest tube had been inserted. There were five patients in whom Pseudomonas complicated wound infections. These consisted of a femoral popliteal graft wound, a buttock ulcer in a patient with chronic lymphocytic leukaemia, a foot ulcer in a patient with longstanding plantar warts and two patients in whom the wound infection resulted in osteomyelitis. Ceftazidime was effective in curing the three soft tissue infections clinically. The Pseudomonas was not eliminated from the plantar warts, however, and in the patient with chronic lymphocytic leukaemia, the buttock ulcer was subsequently infected with other coliform bacteria. In Downloaded from on arch 0

3 Ceftazidime for pseodomonas and serratia infections 65 Table I. Infections with Ps. aeruginosa. Clinical Age ex Infection Associated conditions Ceftazidime Dose (g) Duration qh iv (days) Clinical response st course (l)empyema () nd course () Empyema () st course nd course Wound oot wound Wound astoiditis Wound oot ulcer G. I. bleeding Urinary retention uprapubic catheter Pneumonitis enal impairment Coronary artery disease Heal-conduit ubdural haematoma Burn wounds Alcoholism Pneumonia Urethral catheter emoral popliteal bypass Longstanding Plantar warts Chronic lymphocytic leukaemia Chronic mastoiditis Ankle fracture Osteomyelitis Osteomyelitis Diabetes mellitus (qh) but No response Developed resistance No response Developed resistance the two patients with associated osteomyelitis of the lower limbs, resistance of Ps. aeruginosa developed in two and seven days respectively. Neither of these patients responded clinically. Ceftazidime was also used in one patient with chronic mastoiditis. His condition improved clinically and the Ps. aeruginosa disappeared during therapy but recurred subsequently. The organism remained sensitive to ceftazidime. Downloaded from on arch 0

4 66 C. J. Bergin et at. Table II. Infections with er marcescens. Clinical Age ex Infection Associated Conditions Ceftazidirne Dose (g) Duration qh iv (days) Clinical response () epticaemia () Empyema & sternal Osteomyelitis epticaemia related to iv device epticaemia related to iv line Pneumonia Wound heumatic Heart Disease Valve replacement Chronic Lymphocytic Leukaemia Congestive Heart failure Alcoholism itral Valve eplacement enal Impairment Post-cardiac surgery Abdominal Aortic Aneurysm Post coronary bypass enal Impairment Hepatic failure Lymphoma prostate 5 I No response No response elapsed Ceftazidime proved effective in the urinary tract. In three patients urinary tract infections with Ps. aeruginosa followed urethral catheterization. In each of these patients the organism disappeared and the symptoms resolved within three days of starting ceftazidime. One patient, however, required an indwelling urinary catheter and the Pseudomonas was again isolated from the urine after discontinuing the drug. esistance did not develop. Two patients with epididymitis were cured clinically, but again in one of these patients a urinary catheter remained in the bladder after the organism had been eliminated from the urine. He had recurrence of Ps aeruginosa bacteriuria which was cured after removal of the catheter and a second course of ceftazidime. The organism again remained sensitive. Eight patients were infected with er. marcescens, six of whom were cured clinically and bacteriologically (Table II and Table III). There were three patients with urinary tract infections persisting after prolonged catheterization. In all three patients the organism cleared rapidly but one patient with prostatic lymphoma and radiologically demonstrated urethral abnormalities had two clinical relapses over a period of six months. Each septic presentation responded to ccftazidime. Two of three patients with septicaemia were rapidly cured with elimination of the organism. The third patient with Downloaded from on arch 0

5 Ceftazidime for pseudomonas and serratia infections 67 an underlying lymphocytic leukaemia had developed an empyema and sternal osteomyelitis following a cardiac bypass operation. he had no clinical response to two courses of ceftazidime although the organism remained sensitive. Acinetobacter species were also isolated from her empyema. In another patient with a post operative sternal wound infection the organism was eliminated within four days of starting ceftazidime and the wound healed well. The last patient developed pneumonia with er. marcescens isolated from her sputum in pure culture. he had required assisted ventilation for one week after mitral valve replacement. The organism disappeared within two days of starting ceftazidime. ide-effects were noted in three patients. One patient developed a mild pruritic maculopapular rash which resolved in three days despite continuation of the drug. In two patients the Coomb's test became positive but there was no evidence of haemolysis. One of these patients had underlying leukaemia. No changes were observed in renal or hepatic function during therapy. Bacteriological investigations revealed that many of the isolates which were susceptible to mg/ or less of ceftazidime were resistant to aminoglycoside antimicrobials (Table III). However, all isolates of Ps. aeruginosa were susceptible to ticarcillin (6 mg/ or less) and the eight isolates of er. marcescens were susceptible to amikacin (6 mg/ or less). During therapy with ceftazidime two strains of Ps. aeruginosa became resistant to ceftazidime and also to carbenicilhn and ticarcillin, but they remained susceptible to tobramycin. One strain of er. marcescens also became resistant to carbenicilhn and ticarcillin while it remained sensitive to ceftazidime, amikacin and netilmicin usceptibility of Pseudomonas and erratia species to ceftazidime was independent of susceptibility to the aminoglycoside antibiotics. It was also noted that there was a good relationship between zone size and IC determinations. A zone size greater than 0 mm with the 0 ug disc corresponded with an IC of less than mg/. The development of resistance with an IC of 5 mg/ corresponded with the disappearance of any zone around the 0 ug disc. Discussion Nosocomial infections frequently complicate prolonged hospitalization. The infecting bacteria are often er. marcescens and Ps. aeruginosa which typically show resistance to many antimicrobial agents (tevens et al., 9). Twelve of the patients in this study had already failed to respond to other antimicrobial therapy including gentamicin and tobramycin. The average length of the hospital stay in this study was 55 days. any of the patients had multisystem problems and half of the patients were treated in the Intensive Care Unit at some time during their illness. Nosocomial infections frequently involve the urinary and respiratory tracts and are often associated with the presence of chest tubes, urinary catheters and endotracheal tubes (Turck et al., 9). infections usually respond well to treatment with any antimicrobial agent to which the organism is susceptible. In this study all but one of the urinary tract infections were cured both clinically and bacteriologically after urinary catheters were removed. The exception was the patient with lymphoma of the prostate. The two patients with epididymitis also responded rapidly to ceftazidime. espiratory tract and soft tissue infections are often much more difficult to treat and empyema and abscesses pose special problems. In this series, eight such infections were cured and the organism eliminated including one patient with Ps. aeruginosa complicating a chronic Downloaded from on arch 0

6 Organism Istcoursef Ps. aeruginosa E. coli Ps. aeruginosa E coli nd coursef Ps aeruginosa tr.faecalis Ps. aeruginosa tr.faecalis Ps. aeruginosa Ps. aeruginosa Ps. aeruginosa Pr. morganii 5 Ps. aeruginosa 6 st course Ps aeruginosa nd course Ps aeruginosa Ps aeruginosa Ps. aeruginosa 0 ug disk zone (mm) ug disk zone (mm) Ceftazidime activity IC before treatment Table III. Laboratory findings IC after treatment Days to Eliminate Organism 5 6 persisted on skin Gentamicin > > > > Tobramycin > > > < ensiuvities (IC)* NetiLmicin 6 < ^ O ^ 0 < i 6 6 Amikacin 6 >6 6 > 6 6 ^ o ^ o s 6 Carbeniciilin Cephalothin > 6 6 > 6 ^ O ^ o 6 > 6 > 6 > 6 >6 ^* o ^ o Ticarallin > > Downloaded from on arch 0 I s s

7 *ICs (mg/) ceflazidime determined by agar plate dilution method ICs to other antimicrobials determined by icro can system (Alpkem) Carbenicillin sensitivities determined by Kirby-Bauer method -resistant, I-intermediate, -sensitive. tcfer to Table I ^ b ^ O 6 ^ ] o ^ o > 6 > 6 ^ o ^ o ^ u ^ 0 ^ 0 ^ o ^ o ^ o >6 6 6 >6 < < 6 < > < < > > > > 9 Ps aeruginosa 0 Ps. aeruginosa Ps aeruginosa Ps. aeruginosa Ps. aeruginosa Ps aeruginosa er marcescens er. marcescens Acinetobacter sp. er marcescens Acinetobacter sp 5 er marcescens 6 er. marcescens Ps. cepacia 7 er. marcescens er. marcescens 9 er. marcescens 0 er. marcescens developed resistance 7 days after start of therapy developed resistance days after start of therapy 6 persisted persisted persisted > > > > <0-5 > > > > > > > > > 6 6 > o > ID i < i 6 6 < 6 6 > 6 >6 on Downloaded from on arch 0

8 60 C. J. Bergin tt aj. empyema who had failed to respond to one month of therapy with gentamicin and tobramycin. Ceftazidime eliminated the organism from the pleural fluid and the chest tube could be removed. The reasons for failure of therapy in three patients are worth considering. All three patients had osteomyelitis, but this was not evident at the time therapy was started. In two patients the infection was caused by Ps. aeruginosa which became resistant during therapy. The third patient had osteomyelitis, an empyema and septicaemia caused by er. marcescens as well as underlying chronic lymphocytic leukaemia. All three patients had received only g ceftazidime/ h. Clearly, this dosage is inadequate to treat osteomyelitis but we have no data to show whether the inadequate dosage was responsible for the development of resistance. In treating bacterial infections, the development of resistance to antimicrobial agents may present a problem. In this series, resistance to ceftazidime developed only in the two patients with osteomyelitis treated with an inadequate dose. Cross-resistance developed to carbenicillin and ticarcillin. One erratia isolate also developed resistance to carbenicillin and ticarcillin during therapy but it remained sensitive to ceftazidime. No organism developed resistance to aminoglycosides during therapy. This suggests that the appropriate aminoglycoside may be a suitable alternative in case of therapeutic failure with ceftazidime. It is of interest that resistance to ceftazidime did not develop in the presence of urinary catheters and chest tubes. Treatment of Pseudomonas and erratia infectious in the past has relied heavily on aminoglycoside therapy with its well known side-effects of renal and ototoxicity. This small trial shows the effectiveness and relative lack of adverse effects of ceftazidime in the treatment of severe soft tissue infections caused by Ps. aeruginosa and er. marcescens. If these findings are supported by other clinical trials, this drug may replace the more toxic aminoglycosides in the management of these infections. eferences Bint, A. J, Yeoman, P., Kilburn, P., Anderson, & tansfield, E. (9). The m-vitro activity of ceftazidime compared with that of other cephalosponns. Journal of Antimicrobial Chemotherapy, uppl. B, 7-5 Capel-Edwards, K, Losty, C.., Tucker,. L. & Pratt, D. A. H. (9). Preclinical evaluation of ceftazidime. Journal of Antimicrobial Chemotherapy, uppl. B, 7-9. Chow, A. W. & Bartlett, K H. (9). Comparative in-vitro activity of ceftazidime and other ^-lactamase stable cephalosponns against anaerobic bacteria. Effect of inoculum size and divalent cation supplementation. Journal of Antimicrobuil Chemotherapy, uppl. B, 9-5 De andre, G., Corrocher,., Gabrielli, G. B. & Ho, I. (9). Clinical experience with ceftazidime for lower respiratory tract infections. Journal of Antimicrobial Chemotherapy, uppl. B, 07-. Gordts, B., Bad, I. & Butzler, J. P. (9). Ceftazidime in cystic fibrosis. The Lancet i, 55. Harding,.., Ayrton, J., Thornton, J. E., unro, A J. & Hogg,. I. J. (9). PharmacokineUcs of ceftazidime in normal subjects. Journal of Antimicrobial Chemotherapy, uppl. B, 6-7 Phillips,., Warren, C, hannon, K., King, A. & Hanslo, D. (9). Ceftazidime: in-vitro antibacterial activity and susceptibility to /J-lactamascs compared with that of cefotaxime, moxalactam and other /actam antibiotics. Journal of Antimicrobial Chemotherapy, uppl. 5,-. anders, W. E., Johason, J. E. rd & Taggart, J. G. (97). Adverse reactions to cephalothin and cephapirin. New England Journal of edicine 90,-9. tevens, G. P., Jacobson, J. A. & Burke, J. P. (9). Changing patterns of hospital infections with antibiotic use. Archives of Internal edicine,57-9. Downloaded from on arch 0

9 Ceftazidime for psendomonas and serratia infections 6 Turck,. & tamm, W. (9). Nosocomial infections of the urinary tract. American Journal of edicate 70,65^*. Wittman, D. H., chassan, H.-H., Kohler,. & eibert, W. (9). Pharmacokinetic studies of ceftazidime in serum, bone, bile, tissue fluid and peritoneal fluid. Journal of Antimicrobial Chemotherapy, uppl. B, 9-7. Zuccoli, P., Ho, I., ergoni,. & elley, L. (9). Evaluation of ceftazidime in the treatment of severe infection Journal of Antimicrobial Chemotherapy, uppl. B, -. (anuscript accepted 5 October 9) Downloaded from on arch 0