The treatment of severe intra-abdominal infections: The role of piperacillin/tazobactam

Intra-abdominal infections require treatment effective against both aerobic and anaerobic bacteria. Piperacillin/tazobactam, a beta-lactam/beta-lactamase-inhibitor combination, has a spectrum that includes Gram-positive and Gram-negative aerobic and anaerobic organisms. In one comparative study of piperacillin/tazobactam and gentamicin/clindamycin, 88% of patients treated with piperacillin/tazobactam had a favorable clinical outcome at endpoint compared to 74% of patients treated with gentamicin plus clindamycin. Bacteriological response at endpoint was 87% in the piperacillin/tazobactam group and 74% in the gentamicin plus clindamycin group. In a comparative trial of piperacillin/tazobactam versus imipenem/cilastatin, the clinical cure rate was 91% in the piperacillin/tazobactam group and 69% in the imipenem/cilastatin group (p=0.005). Among microbiologically evaluable patients, the infecting organism was eradicated in 93% of piperacillin/tazobactam-treated patients compared to 76% eradication among imipenem/cilastatin-treated patients (p=0.029). Results of these clinical trials and others have shown that piperacillin/tazobactam is a safe and effective alternative to either combination or monotherapy for intra-abdominal infections.     

Use of ciprofloxacin in the treatment of hospitalized patients with intra-abdominal infections

BACKGROUND: Numerous combination and single-agent antimicrobial regimens are available for the treatment of intra-abdominal infections. Selection of empiric agents must be directed at providing reliable activity against endotoxin-generating Escherichia coli, other gram-negative facultative bacteria, and anaerobes such as Bacteroides fragilis. Safety profiles, pharmacokinetic profiles, and cost-effectiveness must also be considered. Use of fluoroquinolones for the treatment of intra-abdominal infections has recently been advocated. METHODS: We review 2 prospective, comparative clinical trials conducted between 1992 and 2002 that evaluated the efficacy and safety of IV ciprofloxacin in patients with intra-abdominal infections. Separate pharmacoeconomic analyses conducted for each study are also reviewed. RESULTS: A total of 4 ciprofloxacin studies (2 clinical, 2 pharmacoeconomic) comprise the database. The combination of ciprofloxacin plus metronidazole was at least as effective as imipenem/cilastatin and clinically more effective than piperacillin/tazobactam therapy, based on clinical success end points. In 1 trial, treatment success for the clinically valid population was reported for 84% (93/111) of patients treated with IV ciprofloxacin/metronidazole, 86% (91/106) of those treated with IV/oral ciprofloxacin/metronidazole, and 81% of those treated with IV imipenem/cilastatin (91/113). The IV/oral ciprofloxacin/metronidazole regimen had a statistically significant lower mean infection-related cost than the IV only ciprofloxacin/metronidazole plus imipenem groups (difference of approximately 1100 US dollars; P = 0.029). In the second clinical trial, clinical resolution rates were statistically different for patients receiving IV/oral ciprofloxacin/metronidazole (74%) versus IV piperacillin/tazobactam therapy (63%; P = 0.047). Ciprofloxacin/metronidazole was more cost-effective compared with piperacillin/tazobactam (2200 US dollars-3600 US dollars lower cost-effective ratios per patient) regardless of whether the patient had a diagnosis of appendicitis or whether a switch to an oral drug was permissible. CONCLUSIONS: In the studies reviewed herein, the combination of ciprofloxacin plus metronidazole was an effective and safe regimen for the treatment of intra-abdominal infections. This regimen has potential advantages over exclusively IV regimens, including the option of sequential IV/oral therapy, patient convenience, cost savings, and reduced hospital stay.     

Piperacillin-tazobactam versus imipenem-cilastatin for treatment of intra-abdominal infections.

In order to compare the clinical and microbiological efficacies and safety of piperacillin plus tazobactam with those of imipenem plus cilastatin, 134 patients with intra-abdominal infections (73 patients with appendicitis) participated in an open randomized comparative multicenter trial. A total of 40 men and 29 women (mean age, 53 years; age range, 18 to 92 years) were enrolled in the piperacillin-tazobactam group and 40 men and 25 women (mean age, 54 years; age range, 16 to 91 years) were enrolled in the imipenem-cilastatin group. The patients received either piperacillin (4 g) and tazobactam (500 mg) every 8 h or imipenem and cilastatin (500 mg each) every 8 h. Both regimens were given by intravenous infusion. A total of 113 patients were clinically evaluable. Of 55 patients who received piperacillin-tazobactam, 50 were clinically cured, while 40 of 58 patients in the imipenem-cilastatin group were clinically cured. The differences were significant (Wilcoxon test; P = 0.005). There were 4 failures or relapses in the piperacillin-tazobactam group and 18 failures or relapses in the imipenem-cilastatin group. The microorganisms isolated were eradicated in similar proportions in the two patient groups. Adverse reactions, mainly gastrointestinal disturbances and nausea, were noted in 13 patients who received piperacillin-tazobactam and in 14 patients who received imipenem-cilastatin. Results of the present study show that piperacillin-tazobactam is effective and safe for the treatment of intra-abdominal infections.     

Comparative in vitro antimicrobial activity of a novel quinolone, garenoxacin, against aerobic and anaerobic microbial isolates recovered from general, vascular, cardiothoracic and otolaryngologic surgical patients

OBJECTIVES: The aim of the study was to analyse the susceptibility of unique and non-duplicate aerobic and anaerobic isolates from surgical patients to a novel des-F(6)-quinolone (garenoxacin) and other selected antimicrobial agents. METHODS: Eleven hundred and eighty-five aerobic and anaerobic isolates from general, vascular, cardiothoracic and otolaryngologic surgical patients were tested for susceptibility to garenoxacin and seven other antibiotics (ciprofloxacin, moxifloxacin, levofloxacin, piperacillin/tazobactam, imipenem, clindamycin and metronidazole) using the referenced microbroth and agar-dilution method. RESULTS: Garenoxacin exhibited greater antimicrobial activity than comparator quinolones such as ciprofloxacin, levofloxacin and other antimicrobials when tested against selected gram-positive organisms. The in vitro aerobic and anaerobic activity of garenoxacin was similar to that of moxifloxacin. All fluoroquinolones tested were effective against most gram-negative facultative anaerobes including Escherichia coli. Garenoxacin and moxifloxacin demonstrated similar in vitro antimicrobial activity against selected anaerobic gram-positive and gram-negative anaerobic bacteria such as members of the Bacteroides fragilis group. Overall, the in vitro activity of the advanced spectrum quinolones against anaerobic surgical isolates compared favourably with selected comparator agents, metronidazole, imipenem and piperacillin/tazobactam. CONCLUSIONS: These findings suggest that 82.4% of aerobic surgical isolates were susceptible to a concentration of garenoxacin < or = 1.0 mg/L, whereas 84.5% of the anaerobic isolates were susceptible to a garenoxacin concentration < or = 1.0 mg/L. Garenoxacin may be a valuable surgical anti-infective for treatment of serious head and neck, soft tissue, intra-abdominal and diabetic foot infections.     

Piperacillin/Tazobactam versus Imipenem: A Double-Blind,Randomized Formulary Feasibility Study at a Major Teaching Hospital

With the introduction of piperacillin/tazobactam to the North American market, hospitals have been faced with the task of making a decision regarding its formulary role. In view of its broad spectrum of activity, piperacillin/tazobactam could be considered as a formulary alternative to imipenem. To evaluate the formulary feasibility of substituting piperacillin/tazobactam for imipenem, a comparative assessment of these agents in the empiric treatment of serious bacterial infections was undertaken at this tertiary care hospital. This trial was conducted as a randomized, double-blind, single-center study. Consenting adult patients (>16 years of age) who were prescribed imipenem were randomized to receive either 4 g of i.v. piperacillin/tazobactam or imipenem 500 mg of i.v. Q6H with or without concurrent antibiotics. Doses were adjusted according to renal function. There were no restrictions regarding the use of nonstudy antibiotics before and during the study period. Patients with β-lactam allergies or meningitis or who had received greater than 72 h of previous imipenem therapy were excluded. Patients were evaluated at the end of treatment, at discharge, and at 30 days postdischarge. Endpoints included both clinical and microbiologic efficacy as well as drug toxicity. Over the 433-day study period, 360 imipenem treatment courses were initiated. Of these, 150 treatment courses (75 piperacillin/tazobactam courses and 75 imipenem courses) met study criteria and were subsequently randomized. The distribution of prescriber services for enrolled patients was similar to that for all patients receiving imipenem during the study period (p = 0.15). Also, there were no statistically significant differences in demographic parameters between enrolled and excluded patients. For those patients enrolled in the study, demographic characteristics, treatment course indication(s), and accompanying antibiotics were similar across treatment arms. The mean duration of study drug therapy was 7.7 days (SD, 6.2) for imipenem and 7.5 days (SD, 6.7) for piperacillin/tazobactam (p = 0.84). In the majority of cases, treatment discontinuation occurred as a result of a favorable treatment course outcome, stepdown to a narrower spectrum parenteral agent, or stepdown to an oral agent and did not differ between study drugs (p = 0.73). Clinical and microbiologic treatment course outcomes were also similar across treatment arms. Clinical outcome was deemed successful or improved for 68% of imipenem and 70% of the piperacillin/tazobactam treatment courses (p = 0.54). Fifty-three percent of treatment courses were microbiologically confirmed. Of the 58 courses that were assessed for microbiological outcome, 93% demonstrated successful eradication of the causative pathogens. There was no difference between study drugs (96% imipenem; 90% piperacillin/tazobactam; p = 0.61). The proportion of treatment courses with at least one adverse event was similar between the study drugs (p = 1.0). Nausea and/or vomiting were/was observed more commonly in the imipenem arm (p = 0.03). Discontinuation of therapy due to drug toxicity occurred in 16% of imipenem and 5% of piperacillin/tazobactam treatment courses (p = 0.06). There was no statistically significant difference between the mean treatment course cost for imipenem ($762; range, $55–$3192) versus piperacillin/tazobactam ($696; range, $79–$2967; p = 0.59). In summary, piperacillin/tazobactam seems to represent a suitable alternative to imipenem for several clinical indications including intra-abdominal infections, pneumonia, febrile neutropenia, and skin/soft tissue infections in which the causative pathogens are susceptible. However, in view of the prevalence of multiresistant Gram-negative aerobic pathogens at this institution, we do not believe that imipenem can be removed from the drug formulary. In addition, at the currently studied dosing regimen, there seems to be no evidence of a direct cost advantage associated with the use of piperacillin/tazobactam as an alternative to imipenem.     

Piperacillin–tazobactam: a β-lactam/β-lactamase inhibitor combination

Piperacillin–tazobactam is a β-lactam/β-lactamase inhibitor combination with a broad spectrum of antibacterial activity that includes Gram-positive and -negative aerobic and anaerobic bacteria. Piperacillin–tazobactam retains its in vitro activity against broad-spectrum β-lactamase-producing and some extended-spectrum β-lactamase-producing Enterobacteriaceae, but not against isolates of Gram-negative bacilli harboring AmpC β-lactamases. Piperacillin–tazobactam has recently been reformulated to include ethylenediaminetetraacetic acid and sodium citrate; this new formulation has been shown to be compatible in vitro with the two aminoglycosides, gentamicin and amikacin, allowing for simultaneous Y-site infusion, but not with tobramycin. Multicenter, randomized, double-blinded clinical trials have demonstrated piperacillin–tazobactam to be as clinically effective as relevant comparator antibiotics. Clinical trials have demonstrated piperacillin–tazobactam to be effective for the treatment of patients with intra-abdominal infections, skin and soft tissue infections, lower respiratory tract infections, complicated urinary tract infections, gynecological infections and more recently, febrile neutropenia. Piperacillin–tazobactam has an excellent safety and tolerability profile and continues to be a reliable option for the empiric treatment of moderate-to-severe infections in hospitalized patients.     

Antimicrobial susceptibility of common pathogens isolated from postoperative intra-abdominal infections in Japan

The principle of empirical therapy for patients with intra-abdominal infections (IAI) should include antibiotics with activity against Enterobacteriaceae and Bacteroides fragilis group species. Coverage of Pseudomonas aeruginosa, Enterobacter cloacae, and Enterococcus faecalis is also recommended for hospital-associated IAI. A nationwide survey was conducted to investigate the antimicrobial susceptibility of pathogens isolated from postoperative IAI. All 504 isolates were collected at 26 institutions and referred to a central laboratory for susceptibility testing. Lower susceptibility rates to ciprofloxacin and cefepime were demonstrated in Escherichia coli. Among E. coli, 24.1% of strains produced extended-spectrum β-lactamase (ESBL). Carbapenems, piperacillin/tazobactam, cephamycins/oxacephem, aminoglycosides, and tigecycline had high activity against E. coli, including ESBL-producing isolates. Among E. cloacae, low susceptibility rates to ceftazidime were demonstrated, whereas cefepime retained its activity. P. aeruginosa revealed high susceptibility rates to all antimicrobials tested except for imipenem. Among B. fragilis group species, low levels of susceptibility were observed for cefoxitin, moxifloxacin, and clindamycin, and high susceptibility rates were observed for piperacillin/tazobactam, meropenem, and metronidazole. Ampicillin, piperacillin, and glycopeptides had good activity against E. faecalis. Imipenem had the highest activity against E. faecalis among carbapenems. In conclusion, we suggested the empirical use of antimicrobials with the specific intent of covering the main organisms isolated from postoperative IAI. Piperacillin/tazobactam, meropenem, or doripenem, are appropriate in critically ill patients. Combination therapy of cefepime (aztreonam in patients with β-lactam allergy) plus metronidazole plus glycopeptides, imipenem/cilastatin or cephamycins/oxacephem plus ciprofloxacin plus metronidazole are potential therapeutic options.     

Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin for the treatment of patients with nosocomial lower respiratory tract infection. Piperacillin/tazobactam Nosocomial Pneumonia Study Group

An open-label, randomized, comparative, multi-centre study was conducted at 25 centres in the USA and Canada to compare the safety and efficacy of piperacillin/tazobactam plus tobramycin with ceftazidime plus tobramycin in patients with lower respiratory tract infections. Piperacillin/tazobactam (3 g/375 mg) every 4 h or ceftazidime (2 g) every 8 h were administered i.v. for a minimum of 5 days. Tobramycin (5 mg/kg/day) given in divided doses every 8 h was administered to all patients. Patients with Pseudomonas aeruginosa isolated from respiratory secretions at baseline were to continue tobramycin for the duration of the study. Tobramycin could be discontinued in other patients after the baseline culture results were known. A total of 300 patients was randomized, 155 into the piperacillin/tazobactam group and 145 into the ceftazidime group. Of these, 136 patients (78 in the piperacillin/tazobactam group and 58 in the ceftazidime group) were considered clinically evaluable. Both groups were comparable for age, sex, duration of treatment and other demographic features. The clinical success rate in evaluable patients was significantly greater (P = 0.006) in the piperacillin/tazobactam treatment group (58/78; 74%) than in the ceftazidime group (29/58; 50%). Eradication of the baseline pathogen was significantly greater (P = 0.003) in the piperacillin/tazobactam group (66%) than in the ceftazidime group (38%). The clinical and bacteriological responses of those patients with nosocomial pneumonia were similar to the overall results. Twelve (7.7%) piperacillin/tazobactam-treated patients and 24 (17%) ceftazidime-treated patients died during the study (P = 0.03). Seven of the 24 deaths in the ceftazidime treatment group but only one of the 12 deaths in the piperacillin/tazobactam treatment group were directly related to failure to control infection. The majority of adverse events were thought by the investigator to be attributable to the patients' underlying disease and not drug related. In this study, piperacillin/tazobactam plus tobramycin was shown to be more effective and as safe as ceftazidime plus tobramycin in the treatment of patients with nosocomial LRTI.     

Comparative in vitro activities of a new quinolone, WIN 57273, and piperacillin plus tazobactam against anaerobic bacteria.

The in vitro activities of a new quinolone, WIN 57273, and the combination of piperacillin and tazobactam, a beta-lactamase inhibitor, were compared with those of cefoxitin, ceftizoxime, chloramphenicol, clindamycin, imipenem, metronidazole, and piperacillin for 123 clinical anaerobic isolates. Ceftizoxime and cefoxitin had equivalent activities, while metronidazole was active against gram-negative isolates. In the Bacteroides fragilis group, species other than B. fragilis were the most resistant. The combination of piperacillin with tazobactam in a ratio of 8 to 1 was more effective than piperacillin against B. fragilis group organisms when the MIC of piperacillin was greater than or equal to 64 micrograms/ml. Overall, WIN 57273 (i) and imipenem (ii) were the most active agents, with MICs for 50 and 90% of strains of (i) 0.25 and 0.5 and (ii) 0.125 and 2 microgram/ml, respectively.     

Treatment of anaerobic infection

Anaerobic bacteria are the predominant flora in the normal human skin and mucous membranes and are, therefore, a common cause of endogenous infections. Since anaerobic infections are generally polymicrobial, where anaerobes are mixed with aerobic organisms, therapy should provide coverage of both types of pathogens. The isolation of anaerobes requires appropriate methods of collection, transportation and cultivation of specimens. The lack of use of any of these methods can lead to inadequate recovery of anaerobes and inappropriate therapy. Treatment of anaerobic infection is complicated by the slow growth of these organisms and the growing resistance of anaerobic bacteria to antimicrobials. The primary role of antimicrobials is to limit the local and systemic spread of infection. Surgical drainage is of primary importance. This includes debriding of necrotic tissue, draining the pus, improving circulation, alleviating obstruction and increasing tissue oxygenation. The most effective antimicrobials against anaerobic organisms are metronidazole, the carbapenems (imipenem, meropenem and ertapenem), chloramphenicol, the combinations of a penicillin and a β-lactamase inhibitor (ampicillin or ticarcillin plus clavulanate, amoxicillin plus sulbactam, and piperacillin plus tazobactam), tigecycline and clindamycin.     

Treatment of anaerobic infection

Anaerobic bacteria are the predominant flora in the normal human skin and mucous membranes and are, therefore, a common cause of endogenous infections. Since anaerobic infections are generally polymicrobial, where anaerobes are mixed with aerobic organisms, therapy should provide coverage of both types of pathogens. The isolation of anaerobes requires appropriate methods of collection, transportation and cultivation of specimens. The lack of use of any of these methods can lead to inadequate recovery of anaerobes and inappropriate therapy. Treatment of anaerobic infection is complicated by the slow growth of these organisms and the growing resistance of anaerobic bacteria to antimicrobials. The primary role of antimicrobials is to limit the local and systemic spread of infection. Surgical drainage is of primary importance. This includes debriding of necrotic tissue, draining the pus, improving circulation, alleviating obstruction and increasing tissue oxygenation. The most effective antimicrobials against anaerobic organisms are metronidazole, the carbapenems (imipenem, meropenem and ertapenem), chloramphenicol, the combinations of a penicillin and a beta-lactamase inhibitor (ampicillin or ticarcillin plus clavulanate, amoxicillin plus sulbactam, and piperacillin plus tazobactam), tigecycline and clindamycin.     

Comparative activity of clinafloxacin and nine other compounds tested against 2000 contemporary clinical isolates from patients in United States hospitals.

The in vitro activity of clinafloxacin (formerly CI-960, AM-1091, PD-127391) was compared with other fluoroquinolones, cephalosporins, gentamicin, vancomycin, imipenem, piperacillin/tazobactam, clindamycin, and metronidazole against 2000 recent clinical strains from a large number of hospitals in the United States. Overall, clinafloxacin was the most active compound tested. Against Pseudomonas aeruginosa, clinafloxacin and ciprofloxacin demonstrated comparable activity (88% and 80% susceptible, respectively), and were four- to 16-fold more potent than levofloxacin (MIC90, 16 micrograms/ml) or trovafloxacin (MIC90, 32 micrograms/ml). Among anaerobic bacteria, clinafloxacin (MIC50s, 0.25-0.5 microgram/ml) and trovafloxacin (MIC50s, 0.5-2.0 micrograms/ml) were the most active quinolones, whereas metronidazole, imipenem and piperacillin/tazobactam were the most potent comparators. Clinafloxacin demonstrated sustained activity when compared to several available peer drugs against contemporary clinical isolates. The clinafloxacin spectrum against the 15 important pathogens monitored ranged from nil or 4.0% (vancomycin-resistant enterococci) to 100.0% (four different species) susceptible with an average percent susceptibility of 94.0%. This degree of potency and spectrum for clinafloxacin provides a wide potential for use against many species with established resistance to other anti-microbial classes.     

Antibiotic susceptibilities of Gram-positive anaerobic cocci: results of a sentinel study in England and Wales

OBJECTIVE: A sentinel study was carried out to determine the antimicrobial susceptibilities of Gram-positive anaerobic cocci (GPAC) freshly isolated from clinical material in diagnostic laboratories in England and Wales. METHODS: A total of 113 GPAC isolates consisting predominantly of current or former members of the genus Peptostreptococcus was obtained from 17 sentinel laboratories in England and one in Wales. Minimum inhibitory concentrations (MICs) of 10 antimicrobial agents were determined by the Etest method. The agents tested were: penicillin, tetracycline, erythromycin, cefoxitin, clindamycin, chloramphenicol, imipenem, co-amoxiclav, piperacillin/tazobactam and metronidazole. MIC50 and MIC90 values for each drug-species combination were calculated whenever suitable numbers of each species were obtained. RESULTS: Excellent spectra of activity (0% resistance) against GPAC were seen for metronidazole, piperacillin/tazobactam, cefoxitin, imipenem and chloramphenicol. Low degrees of resistance to co-amoxiclav (3.5%), clindamycin (7.1%), penicillin (7.1%) and significant degrees of resistance to tetracycline (41.6%) and erythromycin (27.4%) were detected. Some examples of putative macrolide-lincosamide linked resistance were noted in seven (6.2%) isolates of GPAC. CONCLUSION: This study is one of the largest susceptibility studies specifically on GPAC carried out to date and the resulting data may be of value to those involved in the empirical treatment of infections involving Gram-positive anaerobic cocci.     

Diabetic foot infection

Foot infections are common in patients with diabetes and are associated with high morbidity and risk of lower extremity amputation. Diabetic foot infections are classified as mild, moderate, or severe. Gram-positive bacteria, such as Staphylococcus aureus and beta-hemolytic streptococci, are the most common pathogens in previously untreated mild and moderate infection. Severe, chronic, or previously treated infections are often polymicrobial. The diagnosis of diabetic foot infection is based on the clinical signs and symptoms of local inflammation. Infected wounds should be cultured after debridement. Tissue specimens obtained by scraping the base of the ulcer with a scalpel or by wound or bone biopsy are strongly preferred to wound swabs. Imaging studies are indicated for suspected deep soft tissue purulent collections or osteomyelitis. Optimal management requires aggressive surgical debridement and wound management, effective antibiotic therapy, and correction of metabolic abnormalities (mainly hyperglycemia and arterial insufficiency). Treatment with antibiotics is not required for noninfected ulcers. Mild soft tissue infection can be treated effectively with oral antibiotics, including dicloxacillin, cephalexin, and clindamycin. Severe soft tissue infection can be initially treated intravenously with ciprofloxacin plus clindamycin; piperacillin/tazobactam; or imipenem/cilastatin. The risk of methicillin-resistant S. aureus infection should be considered when choosing a regimen. Antibiotic treatment should last from one to four weeks for soft tissue infection and six to 12 weeks for osteomyelitis and should be followed by culture-guided definitive therapy.     

Levofloxacin in the empirical treatment of patients with suspected bacteraemia/sepsis: comparison with imipenem/cilastatin in an open, randomized trial

An open, randomized, multinational, multicentre study was conducted to compare the efficacy, safety and tolerability of levofloxacin 500 mg twice daily with imipenem/cilastatin 1 g iv three-times daily in the treatment of hospitalized adult patients with clinically suspected bacteraemia/ sepsis. Levofloxacin patients could change from iv to oral administration after a minimum of 48 h iv treatment if clinical signs and symptoms of sepsis had improved. The primary efficacy analysis was based on the clinical and bacteriological response at clinical endpoint. A total of 503 patients were randomized and 499 included in the intent-to-treat population. The per-protocol population comprised 287 patients with bacteriologically proven infection. Clinical cure rates at clinical endpoint in the intent-to-treat population and per-protocol population were 77% (184/239) and 89% (125/140), respectively, for levofloxacin and 68% (178/260) and 85% (125/147), respectively, for imipenem/cilastatin. At follow-up, the cure rates in the per-protocol population were 84% for levofloxacin and 69% for imipenem/cilastatin. The 95% confidence interval for both populations showed that levofloxacin was as effective as imipenem/cilastatin. A satisfactory bacteriological response was obtained in 87% (96/110) of levofloxacin patients and 84% (97/116) of imipenem/cilastatin patients at clinical endpoint. Adverse events possibly related to the study drug were reported in 74 (31%) levofloxacin patients and 79 (30%) imipenem/cilastatin patients. There were no clinically appreciable differences between the treatment groups. Levofloxacin 500 mg twice daily, either iv or as sequential iv/oral therapy, was as effective and well tolerated as imipenem/cilastatin 1 g iv three-times daily in the treatment of hospitalized patients with suspected bacteraemia/sepsis.     

Piperacillin/tazobactam in the treatment of community-acquired and nosocomial respiratory tract infections: A review

Investigators assessed the efficacy and safety of piperacillin/tazobactam therapy in a study of patients with community-acquired lower respiratory tract infections and a study of patients with nosocomial, severe lower respiratory tract infections. Piperacillin 4 g/tazobactam 500 mg was given intravenously every 8 h to 193 hospitalized lower respiratory tract infection patients for a minimum of 5 days. There was a favorable response rate of 97% and eradication of the causative pathogen was documented or presumed in 93% of patients. There was a low incidence of adverse experiences and the combination was well tolerated. Seventy-one intensive care patients with severe lung disease received 4 g piperacillin/500 mg tazobactam intravenously every 6 h; afterward they were given amikacin 7.5 mg/kg every 12 h. Minimum duration of treatment was 5 days. Therapy with piperacillin/tazobactam plus amikacin was well-tolerated, produced a 74% favorable clinical response rate, and eradicated the responsible pathogen in 70% of patients.     

Comparative efficacy of different beta-lactam antibiotics and gentamicin in Klebsiella pneumoniae septicaemia in neutropenic mice

The in-vivo activity of ceftazidime, cefotetan, imipenem/cilastatin, piperacillin and gentamicin against two strains of Klebsiella pneumoniae was evaluated in a model of experimental septicaemia in neuropenic mice. Single agent therapy with the aminoglycoside was highly effective against both strains. Among the beta-lactams, ceftazidime and cefotetan were nearly as active as gentamicin, whereas imipenem/cilastatin was slightly less effective, and the results achieved with piperacillin were markedly inferior.     

Aztreonam therapy in children with febrile neutropenia: a randomized trial of aztreonam plus flucloxacillin versus piperacillin plus gentamicin.

In a prospective, randomized trial in 100 febrile neutropenic children, aztreonam plus flucloxacillin was compared with piperacillin plus gentamicin. At the 72 h clinical assessment there was no statistically significant difference between the two groups. However, in microbiologically documented infections there was a higher response rate in the piperacillin/gentamicin group (57%) than in the aztreonam/flucoxacillin group (41%). This was contributed to by the poorer Gram-positive cover of the aztreonam/flucloxacillin combination. In clinically documented infections and unexplained fevers the response rate of the two antibiotic regimens was identical. There were two deaths; one early death (in the piperacillin/gentamicin arm) and one late death. At the final assessment a successful outcome was obtained in the remaining patients. In the aztreonam/flucloxacillin group 75% of the episodes required modification compared with 59% in the piperacillin/gentamicin group.     

A comparative study of imipenem versus piperacillin plus gentamicin in the initial management of febrile neutropenic patients with haematological malignancies.

Three-hundred and twelve episodes of fever in 234 neutropenic patients with haematological malignancies were treated empirically with either imipenem or a combination of piperacillin and gentamicin. There were no significant differences in the percentages of patients responding to therapy at either 72 h (59% and 56% of assessable episodes in the imipenem and combination groups respectively) or at the end of treatment (55% and 53% of assessable episodes in the imipenem and combination groups respectively). Patients in the piperacillin plus gentamicin group experienced significantly more renal tubular damage whereas those who received imipenem suffered more nausea or vomiting. We conclude that imipenem monotherapy represents an acceptable alternative to piperacillin plus gentamicin as empirical therapy of the febrile neutropenic patient.     

Activity of meropenem and comparators against Pseudomonas aeruginosa and Acinetobacter spp. isolated in the MYSTIC Program, 2002-2004

This study examines the susceptibilities of meropenem and other broad-spectrum antimicrobials tested against bacterial isolates collected from hospitalized patients during 2002-2004 from worldwide medical centers participating in the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program. The in vitro activity of meropenem and 5 comparator antimicrobial agents was assessed against Pseudomonas aeruginosa and Acinetobacter spp. Generally, the susceptibility of Australasian and North American isolates was higher than that of the European and South American isolates. The rank order of activity of the antimicrobial agents tested against a worldwide collection of P. aeruginosa was piperacillin/tazobactam (77.7% susceptible) > meropenem (75.4%) > ceftazidime (70.0%) > imipenem (69.7%) > gentamicin (66.1%) > ciprofloxacin (62.0%). Against a worldwide collection of Acinetobacter spp. meropenem (76.1% susceptible) was the most active compound followed by imipenem (74.7%) > gentamicin (51.9%) > ciprofloxacin (40.5%) > piperacillin/tazobactam (39.8%) > ceftazidime (38.1%). The carbapenems appear to be a valuable option for the treatment of serious nosocomial infections caused by P. aeruginosa or Acinetobacter spp. over a broad geographical region.