Treatment of serious Pseudomonas infections with azlocillin

Journal of Antimicrobial Chemotherapy (983), Suppl. B, 53-58 Treatment of serious Pseudomonas infections with azlocillin S. Olive, W. J. Mogabgab, B. Holmes, B. Pollock, B. Pauling and R. Beville Tulane University School of Medicine New Orleans, Louisiana. U.S.A. Azlocillin is a semisynthetic acylurcidopcnicillin with increased activity against most strains of Pseudomonas aeruginosa. It was given as the sole antibacterial agent in the treatment of patients with serious pulmonary, wound, bone or joint, or urinary tract infections, endocarditis, or malignant external otitis caused by Pseudomonas sp. In preliminary in vitro tests, azlocillin inhibited 9% of 36 clinical isolates, while carbenicillin and ticarcillin inhibited only 6% and 73%, respectively. Mean MIC of azlocillin against Ps. aeruginosa isolated from the study patients was 9-8 mg/; more than 5% of the strains were inhibited by a concentration of 6-5 mg/. Intravenous administration of the antibiotic at a mean dosage of 7 g/day for 6 to 59 days resulted in an excellent or good clinical response in 9% (9) of the patients treated. Pseudomonas sp. was eliminated from the site of infection in 67% () of the patients. Azlocillin therapy was well tolerated; in only two patients, both of whom had penicillin-type rashes, was it necessary to discontinue therapy. AzlociUin was a safe and effective antimicrobial agent for the treatment of serious infections caused by strains of Pseudomonas sp., primarily Ps. aeruginosa. Introduction Severe nosocomial infections caused by Pseudomonas aeruginosa continue to be a serious problem for patients with impaired host defences (Young et al., 977). The antibiotics currently available for the treatment of such infections include the aminoglycosides (gentamicin, tobramycin, and amikacin) and the penicillins (carbenicillin, ticarcillin, mezlocillin, and piperacilhn). A new class of semisynthetic penicillins, the ureidopenicillins, which are derivatives of ampicillin have increased activity against Ps. aeruginosa. Azlocillin has not only high activity against Ps. aeruginosa, but also activity against a wide variety of Gramnegative bacteria comparable to that of carbenicillin and ampicillin (Fu & Neu, 978). Against Gram-positive bacteria, azlocillin is as active as ampicillin. When used in combination with an aminoglycoside, azlocillin demonstrates synergistic activity in vitro against Gram-negative organisms, particularly Ps. aeruginosa (Neu & Fu, 978). The results of treatment with azlocillin in adult patients with serious infections caused by Pseudomonas sp., primarily Ps. aeruginosa, arc described. Patient enrolment Methods Between August 979 and April 98, hospitalized adult patients with documented infections caused by Pseudomonas sp. were enrolled in a study of azlocillin in New 53 35-753/83/B53+6 S./ 983 The British Society for Antimicrobial Chemotherapy

5 S. Olive et at. Orleans, Louisiana, at the Veterans Administration, Tulane Medical Center, or Charity Hospitals. None of the patients had a history of penicillin allergy, were pregnant, or was found to have an organism resistant to azlocillin. Laboratory determinations, including complete blood count and platelet count, levels of serum electrolytes and hepatic enzymes, and urinalysis, were performed before, during, and after treatment. Radiographs were obtained routinely in patients with osteomyelitis or lower respiratory tract infections and when indicated in patients with other infections. Microbiological studies The causative organisms were isolated using standard techniques. Urine for culture was obtained by catheter or midstream collection and diluted in ten-fold decrements; - ml inocula were streaked on blood agar and incubated at 37 C. Pretreatment urine cultures with colony counts of more than s organisms/ml were considered proof of a urinary tract infection. Specimens from orthopaedic and wound infections for aerobic culture were obtained by swab, aspiration, or bone biopsy, and those for anaerobic culture were obtained by deep aspiration through intact skin and inoculated onto the appropriate transport medium. Swabs or aspirates were streaked onto 5% blood agar plates and incubated at 37 C; colony counts were made from all specimens. Sputum from patients with pneumonia or bronchitis was inoculated on both chocolate and blood agar and incubated in a candle jar. Aerobic and anaerobic cultures were made on blood samples obtained before treatment from all patients and during treatment as appropriate. Species identification of Ps. aeruginosa was made with the N/F System (Flow Laboratories, Roslyn, N.Y.). Bacterial susceptibility of the specimens cultured before treatment to azlocillin was determined by disc diffusion using the modified Kirby-Bauer technique with a 75 /ig azlocillin disc; a zone diameter of S 8 mm was considered susceptible, 5 to 7 mm of indeterminate susceptibility, and ^ mm, resistant. Minimal inhibitory concentrations (MICs) were determined by the standard two-fold dilutions procedure with Mueller-Hinton broth or agar and an inoculum of ^: 5 cfu/ml. Organisms with an MIC of ^6mg/l were considered susceptible to azlocillin. Treatment regimen Azlocillin was administered as the sole antibacterial agent, intravenously as a 3 min infusion. The mean dosage was 7 g/day, given in four to six divided doses. In-vitro susceptibility of Ps. aeruginosa Results Azlocillin was active in vitro against Ps. aeruginosa, inhibiting 9% of 36 clinical isolates obtained from hospital patients. Carbenicillin and ticarcillin inhibited only 6% and 73%, respectively, of these isolates; two of the third-generation cephalosporins, cefoperazone and cefsoludin, were slightly more active than ticarcillin, inhibiting 8% of the isolates. The in-vitro activity of tobramycin was comparable to that of azlocillin (Table I). MIC values of azlocillin against Ps. aeruginosa ranged from 3-3 to 5- mg/, well within the therapeutic range achieved with the recommended clinical dosage of 6 to 8 g/day (Table II).

Serious Pseudomonai infections 55 Table I. Susceptibility of 36 strains of Ps. aeruginosa to azlocillin and various antibiotics by disc diffusion* Class Antibiotic No. sensitive/ no. tested Percentage sensitive Penicillins Azlocillin Pipcracillin Carbenicillin Ticarcillin 35/39 /5 8/3 9/6 89-7 93-3 6 73 Aminoglycosides Third-generation cephalosporins Gentamicin Amikacin Tobramycin Cefotaxime Moxalactam Cefoperazone Ceftizoxime Ccfsoludin Ceftriaxone Ceftazidime 3/7 /5 6/8 8/7 9/ 7/ /7 3/6 7/ /6 85-8 88-9 7 5 8-9 58-8 8 3 58-3 66-7 * Includes strains causing infections treated with azlocillin as well as those screened for consideration of therapy. Table II. MICs of azlocillin for strains of Ps. aeruginosa isolated from patients MIC* mg/ 33 6-5 -5 5 Clinical and bacteriological responses Cumulative percentage of strains inhibited 95 67 86 Mean MIC was 9-8 mg/; more than 5% of the 6-5 mg/ orless. isolates were inhibited by The clinical response of the patients to azlocillin therapy was considered 'excellent' when the signs and symptoms of infection were resolved, 'good' when they improved, and 'poor' if the patient failed to respond clinically. In 9 (9%) of the patients, the clinical response was 'excellent' or 'good' (Table III). Pseudomonas sp. was eliminated from the infection site in (67%) of the patients. It is noteworthy that many of the infections were chronic or recurrent and had been treated previously by other drugs without success, either because the organism became resistant or because adverse effects precluded the continued use of that antibiotic. The clinical and bacteriological responses for each site of infection are discussed below.

56 S. Olive et at. Table ID. Response of various infections Ito azlocillin therapy Infection site and diagnosis Bone and Joint Osteomyelitis Postoperative infection Chronic joint space infection Malignant external otitis Skin and skin structure Surgical wound infection Gangrene Multiple skin abscesses Lower respiratory tract Acute pneumonia Acute bronchitis Empyema Urinary tract Cystitis and prostatitis Bactcraemia Endocarditis Total Bone and joint infections No. of patients IT Clinical response Excellent Good Poor Bacteriological response Eradicated Persisted A total of ten patients were treated with azlocillin for infections of the bone or joint. In eight of these an excellent clinical response was achieved and the causative organism was eliminated. The clinical response for the other two infections was good, but the organisms persisted. Four of these ten patients had osteomyelitis of the hip, humerus, or tibia, and two were completely cured after 8 or days of azlocillin therapy. The third patient improved clinically after 8 days of treatment but the organism persisted. In the fourth patient, the organism became resistant to azlocillin after ten days of treatment. Four other patients developed postoperative infections after total hip or knee replacement, and in each case the clinical response was excellent and Ps. aeruginosa was eliminated after 3 to 37 days of therapy. Another patient had undergone surgery for removal of the femoral head with chronic joint space infection and had been treated with cefamandole for 5 days. Superinfection with Ps. aeruginosa occurred and was resolved after ten days of azlocillin administration. The last patient with a bone infection was an elderly diabetic with malignant external otitis. The infection had developed seven months previously and improved after parenteral treatment with amikacin and tobramycin. Several months later, however, the infection recurred; at that time the patient underwent a right radical mastoidectomy, petrosectomy, and meatoplasty, and was given carbenicillin and gentamicin. Again there was improvement initially, but pain and drainage from the ear recurred. Azlocillin was then administered for days, and at the end of therapy no clinical signs of infection remained, and cultures of the ear drainage were negative. Two months after discharge from the hospital, the cultures were still negative and the patient was asymptomatic. 3

Serious Pseudomonas infections 57 Skin and skin structure infections There were six patients with infections of the skin or skin structure in this study. Three of them had an excellent clinical response with elimination of the causative organism. Each of the other three patients had a good clinical response, and Pseudomonas sp. was eliminated in one but persisted in the other two. Four of the six patients had wound infections. In one patient the infection from an open fracture responded well after debridement, local wound care, and 6 days of azlocillin therapy. Another patient had an open right tibial fracture with almost complete severence of the leg. Infection with Ps. aeruginosa occurred after successful reattachment of the leg. Initially the wound responded well to azlocillin therapy, but after days the organism became resistant. The third wound infection was the result of a gun shot wound to the leg, which required a skin graft. Although the wound improved initially after azlocillin therapy, adequate debridement was impossible and Ps. aeruginosa continued to be cultured from the edge of the graft. This patient left the hospital against medical advice after six days of treatment. The fourth patient with a wound infection had undergone bilateral nephrectomy for chronic renal failure and developed an infection of the renal space; the strain of Ps. aeruginosa cultured from the wound was resistant to both carbenicillin and ticarcillin. After seven days of treatment with azlocillin at varying dosages, in conjunction with dialysis, signs and symptoms of infection resolved; the lesion healed one week later. Another patient had gangrene of the foot, from which not only Ps. aeruginosa, but also Morganella morganii, Proteus rettgeri, and Clostridium sporogenes were cultured. The clinical signs and symptoms of infection improved markedly within the first h of azlocillin therapy, and the lesion healed after five days of treatment. The diagnosis in the sixth patient was multiple posterior cervical and infranuchal abscesses, accompanied by fever and leukocytosis. A similar episode had occurred six years previously, and there had been exacerbations since that time. Betahaemolytic streptococcus, Veillonella sp., as well as Ps. alcaligenes, were cultured from the abscesses. The patient had good clinical response, and the organisms were eliminated by the fifth day of treatment; azlocillin was continued for a total of 8 days. Lower respiratory tract infections Three patients with lower respiratory tract infections were treated, and all had severe underlying pulmonary conditions. Two of the three patients improved clinically, and in one the organism was eliminated. One patient had pneumonia with fever, abnormal chest X-ray, and congestive heart failure; after 8 days of treatment with azlocillin, Ps. aeruginosa was eliminated from the sputum, and there was partial clearing of the infiltrate on the chest X-ray. Another patient, with acute bronchitis, improved clinically after days of azlocillin treatment, but due to severe chronic obstructive pulmonary disease (COPD), the causative organism was not eliminated from the sputum. The third patient had had pneumonectomy for carcinoma with subsequent development of empyema. Previous treatment with tobramycin and ticarcillin for six months and seven weeks, respectively, was unsuccessful. Azlocillin was given for 35 days and the patient underwent surgery to close the draining tract. The incision site collapsed and thoracoplasty was attempted. Despite initial improvement, the organism became resistant to azlocillin and the antibiotic was discontinued.

58 S. Olive et al. Other infections One patient with cystitis and prostatitis caused by Ps. aeruginosa was treated successfully with azlocillin. The infection recurred, however, 3 weeks later. The one patient with bacteremia had a good response to azlocillin therapy. The patient had a history of septicaemia caused by Ps. aeruginosa following third-degree burns over 5% of his body surface area six months previously and was admitted with a diagnosis of endocarditis. The organism became resistant to ticarcillin and carbenicillin, which were administered initially, and aminoglycosides caused ototoxicity and deafness. Azlocillin was administered for 33 days; on the third day of treatment the patient underwent surgery for removal of the tricuspid valve and received oxacillin for the next three days. Complete resolution of the signs and symptoms was achieved, and all follow-up blood cultures were negative. Azlocillin was well tolerated. Adverse effects Azlocillin was well tolerated locally, despite intravenous administration every four or six hours for as long as 59 days. Untoward reactions occurred in four patients and included a macular, pruritic rash in two patients which responded to discontinuation of azlocillin therapy and administration of antihistamines. Two patients complained of mild gastrointestinal discomfort (nausea, vomiting, or diarrhoea) which resolved without discontinuation of azlocillin treatment. Discussion Azlocillin is a ureidopenicillin with excellent bactericidal activity against most Gramnegative and Gram-positive aerobic and anaerobic organisms. Some /Mactamaseproducing bacteria are resistant. Azlocillin is well tolerated and can be administered safely to patients with impaired renal or hepatic function, which can preclude the use of other antibiotics. No adverse reactions other than those associated with the use of other /Mactam antibiotics have been observed in patients treated with azlocillin. Although not done in this study azlocillin can be administered in combination with an aminoglycoside to provide a broader spectrum of antibacterial activity as well as a synergistic effect. Azlocillin represents important progress in the therapeutic approach to pseudomonal infections. In this study, the administration of azlocillin to patients resulted in a complete cure (67%) or significant improvement (%) of serious infections caused by Pseudomonas sp., primarily Ps. aeruginosa. At a dosage of 7 g/day for 6 to 59 days, clinical improvement occurred in all but two patients. References Fu, K. P. & Neu, H. C. (978). Azlocillin and mezlocillin: new ureido penicillins. Antimicrobial Agents and Chemotherapy 3, 93-8. Neu, H. C. & Fu, K. P. (978). Synergy of azlocillin and mezlocillin combined with aminoglycoside antibiotics and cephalosporins. Antimicrobial Agents and Chemotherapy 3, 83-9. Young, L., Martin, W., Mezer, R., Weinstein, L. & Anderson, E. (977). Gram-negative rod bactetemia: microbiologjc, immunologic and therapeutic considerations. Annals of Internal Medicine 86, 56-7.