Antibiotic regimens for late-onset neonatal sepsis.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality. It is the third leading cause of neonatal mortality globally constituting 13% of overall neonatal mortality. Despite the high burden of neonatal sepsis, high-quality evidence in diagnosis and treatment is scarce. Due to the diagnostic challenges of sepsis and the relative immunosuppression of the newborn, many neonates receive antibiotics for suspected sepsis. Antibiotics have become the most used therapeutics in neonatal intensive care units, and observational studies in high-income countries suggest that 83% to 94% of newborns treated with antibiotics for suspected sepsis have negative blood cultures. The last Cochrane Review was updated in 2005. There is a need for an updated systematic review assessing the effects of different antibiotic regimens for late-onset neonatal sepsis. OBJECTIVES: To assess the beneficial and harmful effects of different antibiotic regimens for late-onset neonatal sepsis. SEARCH METHODS: We searched the following electronic databases: CENTRAL (2021, Issue 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index - Science on 12 March 2021. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs comparing different antibiotic regimens for late-onset neonatal sepsis. We included participants older than 72 hours of life at randomisation, suspected or diagnosed with neonatal sepsis, meningitis, osteomyelitis, endocarditis, or necrotising enterocolitis. We excluded trials that assessed treatment of fungal infections. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Our primary outcome was all-cause mortality, and our secondary outcomes were: serious adverse events, respiratory support, circulatory support, nephrotoxicity, neurological developmental impairment, necrotising enterocolitis, and ototoxicity. Our primary time point of interest was at maximum follow-up. MAIN RESULTS: We included five RCTs (580 participants). All trials were at high risk of bias, and had very low-certainty evidence. The five included trials assessed five different comparisons of antibiotics. We did not conduct a meta-analysis due to lack of relevant data. Of the five included trials one trial compared cefazolin plus amikacin with vancomycin plus amikacin; one trial compared ticarcillin plus clavulanic acid with flucloxacillin plus gentamicin; one trial compared cloxacillin plus amikacin with cefotaxime plus gentamicin; one trial compared meropenem with standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin); and one trial compared vancomycin plus gentamicin with vancomycin plus aztreonam. None of the five comparisons found any evidence of a difference when assessing all-cause mortality, serious adverse events, circulatory support, nephrotoxicity, neurological developmental impairment, or necrotising enterocolitis; however, none of the trials were near an information size that could contribute significantly to the evidence of the comparative benefits and risks of any particular antibiotic regimen. None of the trials assessed respiratory support or ototoxicity. The benefits and harms of different antibiotic regimens remain unclear due to the lack of well-powered trials and the high risk of systematic errors. AUTHORS' CONCLUSIONS: Current evidence is insufficient to support any antibiotic regimen being superior to another. RCTs assessing different antibiotic regimens in late-onset neonatal sepsis with low risks of bias are warranted.

ANTECEDENTES: La sepsis neonatal es una causa importante de morbilidad y mortalidad. Es la tercera causa de mortalidad neonatal a nivel mundial y constituye el 13% de la mortalidad neonatal total. A pesar de la elevada carga de la sepsis neonatal, la evidencia de alta calidad en el diagnóstico y el tratamiento es escasa. Debido a las dificultades de diagnóstico de la sepsis y a la relativa inmunosupresión del neonato, muchos reciben antibióticos por sospecha de sepsis. Los antibióticos se han convertido en el tratamiento más utilizado en las unidades de cuidados intensivos neonatales, y los estudios observacionales realizados en países de ingresos altos indican que entre el 83% y el 94% de los neonatos tratados con antibióticos por sospecha de sepsis tienen hemocultivos negativos. La última revisión Cochrane se actualizó en 2005. Se necesita una revisión sistemática actualizada que evalúe los efectos de los diferentes regímenes de antibióticos para la sepsis neonatal de inicio tardío. OBJETIVOS: Evaluar los efectos beneficiosos y perjudiciales de diferentes regímenes antibióticos para la sepsis neonatal de inicio tardío. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en las siguientes bases de datos electrónicas: CENTRAL (2021, número 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED y Conference Proceedings Citation Index ­ Science el 12 de marzo de 2021. También se buscaron ensayos controlados aleatorizados (ECA) y cuasialeatorizados en las bases de datos de ensayos clínicos y en las listas de referencias de artículos identificados. CRITERIOS DE SELECCIÓN: Se incluyeron ECA que compararon diferentes regímenes de antibióticos para la sepsis neonatal de inicio tardío. Se incluyeron participantes mayores de 72 horas de vida en el momento de la asignación al azar, con sospecha o diagnóstico de sepsis neonatal, meningitis, osteomielitis, endocarditis o enterocolitis necrosante. Se excluyeron los ensayos que evaluaron el tratamiento de las infecciones micóticas. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron los estudios para inclusión, extrajeron los datos y evaluaron el riesgo de sesgo. Se utilizó el método GRADE para evaluar la certeza de la evidencia. El desenlace principal fue la mortalidad por todas las causas, y los desenlaces secundarios fueron: eventos adversos graves, asistencia respiratoria, apoyo circulatorio, nefrotoxicidad, deterioro del desarrollo neurológico, enterocolitis necrosante y ototoxicidad. El punto temporal principal de interés fue el seguimiento máximo. RESULTADOS PRINCIPALES: Se incluyeron cinco ECA (580 participantes). Todos los ensayos tuvieron alto riesgo de sesgo y evidencia de certeza muy baja. Los cinco ensayos incluidos evaluaron cinco comparaciones diferentes de antibióticos. No se realizó un metanálisis debido a la falta de datos relevantes. De los cinco ensayos incluidos, un ensayo comparó cefazolina más amikacina con vancomicina más amikacina; un ensayo comparó ticarcilina más ácido clavulánico con flucloxacilina más gentamicina; un ensayo comparó cloxacilina más amikacina con cefotaxima más gentamicina; un ensayo comparó meropenem con atención estándar (ampicilina más gentamicina o cefotaxima más gentamicina); y un ensayo comparó vancomicina más gentamicina con vancomicina más aztreonam. Ninguna de las cinco comparaciones encontró evidencia de una diferencia al evaluar la mortalidad por todas las causas, los eventos adversos graves, el apoyo circulatorio, la nefrotoxicidad, el deterioro del desarrollo neurológico o la enterocolitis necrosante; sin embargo, ninguno de los ensayos se acercó a un tamaño de información que pudiera contribuir significativamente a la evidencia de los beneficios y los riesgos comparativos de cualquier régimen antibiótico en particular. Ninguno de los ensayos evaluó la asistencia respiratoria o la ototoxicidad. Los efectos beneficiosos y perjudiciales de los diferentes regímenes de antibióticos aún no están claros debido a la falta de ensayos con un poder estadístico adecuado y al alto riesgo de errores sistemáticos. CONCLUSIONES DE LOS AUTORES: La evidencia actual no es suficiente para apoyar que un régimen de antibióticos sea superior a otro. Se justifica la realización de ECA con bajo riesgo de sesgo que evalúen diferentes regímenes antibióticos en la sepsis neonatal de inicio tardío.

Higher risk of neutropenia associated with piperacillin-tazobactam compared with ticarcillin-clavulanate in children.

BACKGROUND: A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Because neutropenia was seldom observed in children treated with ticarcillin-clavulanic acid (T/C), we conducted a study to determine if there is an increased risk of neutropenia in children exposed to P/T in comparison with T/C. METHODS: Medical records of subjects aged <18 years who received at least 1 dose of P/T or T/C between 1 January 2008 and 30 June 2011 were reviewed. RESULTS: Two hundred ninety-nine episodes of treatment (65 P/T, 234 T/C) met inclusion criteria. Among those episodes, 213 had data allowing complete white blood cell count analysis and were included in the final analysis. Thirteen cases of neutropenia were observed during the study period. The average time to onset was 17.6 days and all patients were aged <13 years. Seven cases (10.8%) occurred in the P/T group and 6 (2.6%) in the T/C group (unadjusted odds ratio, 4.59; 95% confidence interval, 1.48-14.17). Although a statistically significant correlation was observed between age, treatment duration, and total dose and the development of neutropenia (r = -0.121, P = .037; r = 0.267, P < .001; r = 0.260, P < .001, respectively), this was not the case for sex, indications, neutrophil count at initiation, and concomitant drug treatments. CONCLUSIONS: Although our results need to be confirmed, they suggest that children receiving long courses of therapy (>2 weeks) with P/T may be at increased risk of neutropenia, compared with T/C.

Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy.

OBJECTIVES: The objective of this study was to determine whether intra-aural administration of aqueous solutions of marbofloxacin, gentamicin, tobramycin and ticarcillin (used off-licence) was associated with changes in hearing as measured by brainstem auditory evoked responses. MATERIALS AND METHODS: Dogs diagnosed with otitis media (n=37) underwent brainstem auditory evoked response testing and then were treated for their ear disease. First, the external ear canal and middle ear were flushed with sterile saline followed by EDTA tris with 0·15% chlorhexidine. Then, a combination of aqueous antibiotic mixed with an aqueous solution of EDTA tris was instilled into the middle ear. Follow-up examinations were undertaken for each dog, and treatment was continued until there were no detected infectious organisms or inflammatory infiltrate. Brainstem auditory evoked response testing was repeated after resolution of the infection and discontinuation of therapy. RESULTS: Brainstem auditory evoked responses in dogs treated with aqueous solutions of marbofloxacin or gentamicin remained unchanged or improved after therapy of otitis media but were impaired in dogs treated with ticarcillin or tobramycin. CLINICAL SIGNIFICANCE: If off-licence use of topical antibiotics is deemed necessary in cases of otitis media, aqueous solutions of marbofloxacin and gentamicin appear to be less ototoxic than aqueous solutions of ticarcillin or tobramycin.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics.

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.

Antibiotic combination-associated nephrotoxicity in granulocytopenic patients with cancer.

Antibiotic combination-associated nephrotoxicity was reviewed in 491 granulocytopenic patients with cancer and fever. Nephrotoxicity was defined as a rise in the serum creatinine level of more than 0.4 mg/dL. The different aminoglycosides, when combined with ticarcillin disodium, were found to have an equivalent nephrotoxic potential and, for the purpose of analysis, were combined and termed "aminoglycoside plus ticarcillin" (Ags + ticarcillin). Groups treated with gentamicin or amikacin plus cephalothin sodium were combined and termed "aminoglycoside plus cephalothin" (Ags + cephalothin). The rate of nephrotoxicity was statistically less for the Ags + ticarcillin group, eight (3.1%) of 262 patients, than for the Ags + cephalothin group, 23 (18.3%) of 126 patients. Age greater than 50 years was a potentiating factor for the occurrence of nephrotoxicity in the Ags + cephalothin group. We have concluded that for granulocytopenic patients with cancer and fever, the antibiotic combination of the Ags + cephalothin should not be used as empiric antibiotic therapy.

Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillin-clavulanate for complicated skin and skin-structure infections: a randomized, open-label trial.

This study tested whether levofloxacin, at a new high dose of 750 mg, was effective for the treatment of complicated skin and skin-structure infections (SSSIs). Patients with complicated SSSIs (n=399) were randomly assigned in a ratio of 1:1 to 2 treatment arms: levofloxacin (750 mg given once per day intravenously [iv], orally, or iv/orally) or ticarcillin-clavulanate (TC; 3.1 g given iv every 4-6 hours) followed, at the investigator's discretion, by amoxicillin-clavulanate (AC; 875 mg given orally every 12 hours). In the clinically evaluable population, therapeutic equivalence was demonstrated between the levofloxacin and TC/AC regimens (success rates of 84.1% and 80.3%, respectively). In the microbiologically evaluable population, the overall rate of eradication was 83.7% in the levofloxacin treatment group and 71.4% in the TC/AC treatment group (95% confidence interval, -24.3 to -0.2). Both levofloxacin and TC/AC were well tolerated. These data demonstrate that levofloxacin (750 mg once per day) is safe and at least as effective as TC/AC for complicated SSSIs.

Timentin in the treatment of symptomatic complicated urinary tract infections in adult patients.

The safety and effectiveness of Timentin were evaluated in 34 adult patients with symptomatic complicated urinary tract infections, principally due to multiply-drug-resistant bacteria. Although a wide variety of organisms, particularly gram-negative bacilli, were found, Escherichia coli was the most frequent, accounting for 14 of 45 (31 percent) pathogens isolated. Ten (22 percent) isolates were Pseudomonas aeruginosa; 11 (24 percent) were Proteus or Morganella species; three (7 percent) were Citrobacter; one (2 percent) was Klebsiella pneumoniae; two (4 percent) were Staphylococcus aureus; and two (4 percent) were enterococci. Ninety-three percent of all pathogens isolated produced a beta-lactamase. Eight (24 percent) infections were polymicrobial; seven (21 percent) were associated with bacteremia. Clinical improvement occurred in 30 of 34 (86 percent) patients. All bacteremias were cured. Although bacteriologic cure occurred in only 32 percent of patients, control of sepsis and temporary eradication of bacteria (bacteriologic improvement) occurred in 96 percent. Not surprisingly, the rates of relapses and reinfections were high. It was concluded that Timentin is a useful agent in the management of complicated urinary tract infection and offers clinicians an alternative to more toxic antibiotics, such as aminoglycosides.

A controlled study of ticarcillin plus clavulanic acid versus piperacillin as empiric therapy for fever in the immunocompromised host.

Clavulanic acid, a potent beta-lactamase inhibitor, was studied in fixed combination with ticarcillin and used with tobramycin as empiric therapy for fever in the immunocompromised host. Fifty febrile episodes were evaluated in patients with hematologic malignancy and/or neutropenia. Eighty-one percent of evaluable infections treated with the study regimen of ticarcillin, clavulanic acid, and tobramycin responded. Seventy-four percent of evaluable infections treated with the control regimen of piperacillin, tobramycin, and vancomycin responded (p = 0.4). Resistance to piperacillin and ticarcillin were noted in 23.8 percent of 21 isolated organisms. Resistance to ticarcillin and clavulanic acid was noted in only one (4.7 percent) of the isolated organisms (p = 0.092). Untoward reactions, including rash, nephrotoxicity, and superinfection, were unusual and occurred with equal frequency in the study and control groups. Clavulanic acid in combination with ticarcillin was effective and safe in treating fever in the immunocompromised host.

Ticarcillin plus clavulanic acid (Timentin) therapy for osteomyelitis.

Timentin is an exciting new antibiotic agent that is a combination of ticarcillin and clavulanic acid. Forty-seven patients with osteomyelitis received 3.1 g of Timentin intravenously every six hours. The mean duration of therapy was 32 days. The diagnosis was made by bone biopsy; bone biopsy was repeated at the completion of therapy. The bacterial etiology was predominately gram-positive organisms. Of the organisms isolated, Staphylococcus aureus was the most common isolate and represented 39 percent of the total isolates. Streptococcus species were isolated in 13 percent, Group D Enterococcus in 15 percent, Pseudomonas aeruginosa in 10 percent; 23 percent of the isolates were other gram-negative organisms. All but one organism were initially sensitive to Timentin. Three resistant organisms were isolated during therapy. Twenty-seven patients were classified as having a cure, based on no growth on repeat bone biopsy cultures and clinical signs of bone healing. Twenty-two patients returned for follow-up (one to nine months after therapy) and had no evidence of infection; however, because of the short follow-up period, these patients were classified as showing improvement. Six patients had adverse reactions to Timentin: two had mild allergic phenomena and two had prolonged bleeding times. In all four, therapy was discontinued. Two patients had a transient, mild elevation in the level of serum glutamic-pyruvic transaminase (less than twice normal levels). This new agent looks exciting for therapy of both gram-positive and gram-negative bacterial osteomyelitis.

Safety and effectiveness of ticarcillin plus clavulanic acid in the treatment of community-acquired acute pyelonephritis in adult women.

An open study was conducted to evaluate the safety and effectiveness of ticarcillin plus clavulanic acid in the treatment of 18 adult women with community-acquired Escherichia coli acute pyelonephritis. Eleven of the 18 patients had a history of urinary tract infections, primarily acute pyelonephritis. Six patients had blood culture results positive for E. coli in addition to positive urine culture results. Ticarcillin plus clavulanic acid was administered as the 3.2 g formulation to 11 patients and as the 3.1 g formulation to the other seven. The mean duration of treatment was 9.2 days. Five of the 18 (28 percent) patients had clinical and bacteriologic cures; there were 11 (69 percent) relapses or reinfections and two (11 percent) clinical failures. Adverse reactions (all reversible) were reported in 11 (61 percent) patients, the most frequent of which was phlebitis. These results should prompt further investigation into the treatment of acute pyelonephritis with ticarcillin plus clavulanic acid versus other antibiotics.

Safety and effectiveness of ticarcillin plus clavulanate potassium in treatment of lower respiratory tract infections.

The safety and effectiveness of ticarcillin plus clavulanate potassium was evaluated in an open study of 43 patients with community-acquired lower respiratory tract infections. The mean age of the 28 patients in whom bacteriologic evaluations were possible was 55 years; at least two thirds of the patients had a history of alcoholism or chronic obstructive pulmonary disease. A pathogen was isolated from sputum samples in 23 patients; five of these 23 also had documented bacteremia. There were five additional cases of bacteremia associated with clinical signs and symptoms of pneumonia but with no organisms isolated from sputum cultures. Thirty-five pathogens were isolated from the 33 evaluable infection sites, primarily Streptococcus pneumoniae and Hemophilus influenzae. S. pneumoniae was the causative organism in all 10 cases of bacteremia. Ticarcillin plus clavulanate potassium (3 g of ticarcillin and 100 mg of clavulanic acid) was administered intravenously for a mean of six days. All 35 organisms isolated before treatment were eradicated. In one patient a superinfection with Pseudomonas aeruginosa developed after treatment with ticarcillin plus clavulanate potassium. A clinical evaluation was possible for 32 of the 33 infection sites; clinical cure was achieved at 31 sites and improvement was seen at the other site. All 43 patients were monitored for adverse reactions by both clinical observation and laboratory tests. In one patient, reversible thrombocytopenia developed that required discontinuation of ticarcillin plus clavulanate potassium. In another patient, there was a slight decrease in the potassium level during therapy. No systemic adverse reactions occurred, nor was there any instance of local effects associated with the intravenous infusion of the drug.

Comparative study of ticarcillin plus clavulanate potassium versus piperacillin in the treatment of hospitalized patients with urinary tract infections.

The efficacy and safety of ticarcillin plus clavulanate potassium and piperacillin were compared in a clinical trial of 78 hospitalized patients with urinary tract infections. There were 37 evaluable patients in the ticarcillin plus clavulanate potassium-treated group and 39 in the piperacillin-treated group. The 43 infection sites in each group were primarily complicated pyelonephritis or complicated cystitis; six patients in the ticarcillin plus clavulanate potassium-treated group and four in the piperacillin-treated group also had septicemia. Both ticarcillin (3 g) plus clavulanate potassium (200 mg) and piperacillin (125 to 200 mg/kg per day) were administered intravenously. The 43 most common pathogens in each treatment group were Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa from the urinary tract and E. coli from the blood. Eight pathogens in the ticarcillin plus clavulanate potassium-treated group and 11 in the piperacillin-treated group were resistant to ticarcillin in vitro. Eradication was achieved for 39 of the 43 (91 percent) pathogens in the ticarcillin plus clavulanate potassium group, including all six organisms isolated from the blood and eight (89 percent) of the ticarcillin-resistant pathogens. In the piperacillin-treated group, 33 of the 43 (77 percent) pathogens were eradicated, including three of the four blood isolates but only eight (73 percent) of the ticarcillin-resistant pathogens. The rate of reinfection or relapse was similar in both groups. Clinical cure or improvement occurred in 97 percent of the patients in each group. Mild and transient increases in levels of liver enzymes or eosinophilia was reported for 11 patients in the ticarcillin plus clavulanate potassium-treated group and for seven in the piperacillin-treated group. In one patient in the ticarcillin plus clavulanate potassium-treated group, a drug-related rash and nausea developed, and treatment was discontinued.

Safety and efficacy of ticarcillin plus clavulanic acid in the treatment of infections of soft tissue, bone, and joint.

The efficacy and safety of ticarcillin plus clavulanic acid in the treatment of patients with infections of soft tissue, bone, and joint were evaluated in this open study. Clinical diagnoses included osteomyelitis, soft tissue abscess or ulcer, cellulitis, bite wound, traumatic or postoperative cellulitis, necrotizing fasciitis, septic arthritis, septic bursitis, and septic thrombophlebitis. Trauma or underlying disease such as diabetes mellitus or vascular insufficiency was common (more than 50 percent) in the patient population. Clinical efficacy was evaluable in 66 patients who received 3 g of ticarcillin and 0.1 g of clavulanic acid every four or six hours for a mean of 23.4 days. A satisfactory clinical response was observed in 92 percent of the patients. Major pathogens isolated were Enterobacteriaceae, anaerobic cocci, Staphylococcus aureus, and beta-hemolytic Streptococcus. Of the 143 isolates recovered from 55 bacteriologically evaluable cases, 87 percent were eradicated by therapy. Overall, a satisfactory bacteriologic outcome occurred in 93 percent of the patients, and the pathogen(s) persisted in 7 percent. More than 98 percent of the isolates were susceptible to ticarcillin plus clavulanic acid in vitro. Emergence of resistance during therapy occurred with three strains of Pseudomonas aeruginosa. Adverse drug-related reactions required discontinuation of treatment in two patients, although other minor abnormal laboratory findings were common. These results indicate that ticarcillin plus clavulanic acid offers safe and effective therapy for infections of soft tissue, bone, and joint.

Cefoperazone plus tobramycin versus ticarcillin plus tobramycin in febrile granulocytopenic cancer patients.

Cefoperazone plus tobramycin was compared in a prospective, randomized trial with our standard regimen of ticarcillin plus tobramycin as empiric therapy of fever in granulocytopenic patients with cancer. Patients who received cefoperazone were also given vitamin K (5 mg orally twice a week). Of 39 microbiologically and clinically documented infections treated with ticarcillin plus tobramycin, 28 (72 percent) showed improvement. Of 27 microbiologically and clinically documented infections treated with cefoperazone plus tobramycin, 21 (78 percent) showed improvement. The overall response rates were similar (40 of 53, or 74 percent, for ticarcillin plus tobramycin versus 38 of 48, or 79 percent for cefoperazone plus tobramycin). There was no difference in response between groups according to site of infection. Serious side effects were minimal with both regimens. There were no enterococcal superinfections in patients receiving cefoperazone. These results suggest that the overall efficacy and toxicity of study regimens are similar.

A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate.

PURPOSE: The primary purpose of the clinical trial was to assess the safety and efficacy of once-a-day compared with three-times-a-day gentamicin in patients with serious infections who had protocol-determined peak serum aminoglycoside concentrations. PATIENTS AND METHODS: A total of 249 hospitalized patients with suspected or proven serious infections were randomized in a 2:2:1 ratio to gentamicin given three times a day with ticarcillin-clavulanate (TC), gentamicin once a day with TC, or ticarcillin-clavulanate (TC) alone. The gentamicin once-a-day dosage for patients with estimated creatinine clearance values of > or =80 mL/min was 5.1 mg/kg. With lower creatinine clearance estimates, the mg/kg dosage of gentamicin was decreased, and the dosage intervals (once daily or three times a day) were maintained. Evaluability required documentation of achievement of protocol-defined peak serum gentamicin levels. RESULTS: Of the total 175 evaluable patients, there were no significant differences found between treatment regimens with respect to clinical or microbiologic efficacy. Bedside audiometry proved impractical due to the frequency of altered mental state in ill patients. Based on the traditional increase in serum creatinine values from baseline values, no differences in renal toxicity between the treatment groups was identified. When changes in renal function were reanalyzed based on maintaining, as opposed to worsening, of renal function, preservation of renal function was better in the gentamicin once-a-day patients as opposed to the gentamicin three-times-a-day patients, P <0.01. CONCLUSIONS: Gentamicin once a day plus TC, gentamicin three times a day plus TC, and TC alone had similar effects in seriously ill hospitalized patients. The incidence of nephrotoxicity was similar in the three treatment groups. Using a nonvalidated post-hoc analysis, renal function was better preserved in gentamicin once-a-day + TC and TC-only patients as opposed to gentamicin three-times-a-day + TC.

Clinical pharmacology and efficacy of ticarcillin in infants and children.

Ticarcillin was evaluated in 82 neonates and young infants with suspected sepsis and in 16 older children with chronic Pseudomonas infection of the mastoids. The infants also received kanamycin. Individual ticarcillin doses of 75 or 100 mg/kg were given every four, six, or eight hours by intramuscular injection or by a 30-minute intravenous infusion. Mean plasma concentrations one hour after a dose were from 125 to 189 microgram/ml, depending on dosage, age, and maturity. Mean plasma half-lives were approximately 5 hours in the first week of life, 2 hours in infants from 1 to 8 weeks, and 0.9 hours in older children. Volume of distribution was approximately twice as great in infants as in children, and plasma clearance rates correlated inversely with age. Limited efficacy data suggest that ticarcillin is a suitable alternative to ampicillin or carbenicillin, when given concurrently with an aminoglycoside, for newborn infections. When given for several days before mastoidectomy and tympanoplasty, ticarcillin sterilized the mastoids in the majority of patients. A new dosage schedule for ticarcillin in pediatric patients is proposed.

Ticarcillin: a review of its pharmacological properties and therapeutic efficacy.

Ticarcillin is a semisynthetic penicillin for parenteral administration. The antibacterial activity of ticarcillin is similar to that of carbenicillin except that it is two to four times more active in vitro against Pseudomonas aeruginosa, generally less active against Gram-positive cocci and more active against most Gram-negative bacilli. As the pharmacokinetics of ticarcillin and carbenicillin are also similar, ticarcillin should theoretically be clinically effective when administered at a lower dosage than carbenicillin. There is some evidence that ticarcillin is comparable in efficacy with carbenicillin when given in half to two-thirds the dosage, when the drugs are given in combination with an aminoglycoside and in clinical situations where these drugs are agents of choice. Ticarcillin has been used successfully in the treatment of complicated urinary tract infection, pulmonary infection in cystic fibrosis and bacteraemia and is effective when combined with an aminoglycoside in severe infections in patients with granulocytopenia. The efficacy in anaerobic infections is at present poorly documented, although preliminary results are promising. Tolerability has generally been good with hypokalaemia being the most frequently reported side effect. At the dosages used, bleeding and fluid overload have seldom occurred.

A comparative trial of moxalactam plus ticarcillin and clavulanic acid or piperacillin as empiric antibiotic therapy for febrile cancer patients.

Resistance of bacteria to beta-lactam antibiotics remains a difficult clinical problem that can be compounded in infected patients with serious underlying illness, especially those who are immunocompromised. In a prospective randomized safety and efficacy trial, febrile cancer patients received either ticarcillin disodium combined with the beta-lactamase inhibitor clavulante potassium (Timentin, Beecham Laboratories, Bristol, TN) plus moxalactam (T+M), or piperacillin plus moxalactam (P+M) as initial empiric antimicrobial therapy. Sixty-six febrile episodes in 53 patients were studied. In the T+M group, 14 (78%) of 18 clinically evaluable infections in patients with profound granulocytopenia improved as did all 14 (100%) such infections in the P+M group. In the T+M group 17 of 21 (81%) similarly evaluable infections improved irrespective of granulocyte count, as did 14 (88%) of 16 of such infections in the P+M group. These results are not statistically significantly different. Serious side effects were infrequent and comparable with both regimens. There was one antibiotic related hemorrhage in the P+M group and a serious episode of nephrotoxicity in a patient who died without recovering renal function in the T+M group. These results suggest that the overall safety and efficacy of Timentin plus moxalactam, and piperacillin plus moxalactam are comparable and similar to previous empiric antibiotic trials.

Use of probenecid in ticarcillin-induced hypokalemia.

Probenecid has been suggested as a prophylactic treatment of penicillin-induced hypokalemia, the proposed mechanism being that penicillin will be prevented from acting as a nonreabsorbable anion binding potassium and resulting in increased urinary losses. A rapidly occurring hypokalemia, unresponsive to intravenous replacement of potassium, can be explained by redistribution rather than urinary wastage. We report a case where probenecid was administered for ticarcillin-induced hypokalemia without any significant benefits.

Ceftazidime versus a combination of amikacin and ticarcillin in the treatment of severe infections.

Hospital patients with severe gram-negative bacterial infections were randomly assigned to treatment with ceftazidime (2 gm every eight or 12 hours) or a combination of amikacin (500 mg every 12 hours) and ticarcillin (3 gm every six or eight hours). The clinical and bacteriological responses to treatment were satisfactory in most of the patients in both treatment groups. Clinical cure was achieved in 18 of the 20 patients treated with ceftazidime and in 17 of the 20 treated with amikacin-ticarcillin. The bacterial eradication rate was 19 of 21 pathogens in the ceftazidime group and 17 of 20 pathogens in the amikacin-ticarcillin group.