Trimethoprim/sulfamethoxazole versus placebo: a double-blind comparison of infection prophylaxis in patients with small cell carcinoma of the lung.

The suppression of pathogenic aerobes and the preservation of anaerobes provides a degree of infection prevention during granulocytopenia. Trimethoprim/sulfamethoxazole (TMP/SMZ) suppresses Enterobacteriaceae and probably maintains colonization resistance through sparing of anaerobes. TMP/SMZ (320/1600 mg/day) treatment was compared to placebo in a double-blind, randomized trial in patients with newly diagnosed small cell carcinoma of the lung during the initial courses of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. Infections were evaluated as microbiologically documented, with or without bacteremia, and clinically documented and were correlated to granulocytopenia. Of the 61 patients evaluated, 32 were given TMP/SMZ and 29 were given placebo; both groups had similar characteristics with regard to disease extent, performance status, age, sex, chemotherapy, and days of granulocytopenia. Incidence of infection at less than 100 granulocytes/microliters was significantly reduced in the TMP/SMZ group (2 infections/100 days) compared to placebo (11 infections/100 days, p = 0.005). Also reduced were the number of bacteremias and the mean proportion of study time on broad-spectrum antibiotics (p less than 0.01). Compared to placebo, TMP/SMZ provided infection prophylaxis without an increase in marrow suppression among patients with small cell carcinoma of the lung receiving intensive chemotherapy.

Microbiology of acute periodontal infection in myelosuppressed cancer patients.

This study characterized the subgingival microbial flora associated with 27 acute exacerbations of preexistent periodontal disease in 24 patients with chemotherapy-induced myelosuppression. All but two acute periodontal infections developed at low granulocyte levels (less than 1,000/microL). Suspected pathogens were detected in high concentrations in subgingival plaque specimens in 17 episodes of acute periodontal infection; a single pathogen was recovered in ten acute infections, and more than one pathogen was recovered in seven acute infections. Staphylococcus epidermidis, Candida albicans, S aureus, and Pseudomonas aeruginosa predominated, with combinations of these detected in some patients. Concomitant bacteremias developed in two of these patients. The subgingival microflora associated with ten acute periodontal infections was characterized by predominantly indigenous microorganisms, which in nine episodes were in abnormal proportions compared with microbial profiles in noncancer patients with similar degrees of periodontal disease. These data demonstrate that pathogens normally associated with infections in myelosuppressed cancer patients, as well as indigenous oral flora, are associated with acute periodontal infections during granulocytopenia. This finding is important, since this body site has not commonly been recognized as a source for acute infection in these patients.

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.

Periodontal infection in patients with acute nonlymphocyte leukemia. Prevalence of acute exacerbations.

From the initiation of chemotherapy until attainment of complete remission, 22 newly diagnosed, hospitalized patients with acute nonlymphocytic leukemia were studied for the prevalence of periodontal disease at admission and for acute exacerbations during myelosuppressive chemotherapy. Consistent with a normal population, all patients had asymptomatic periodontal disease at admission. In these 22 patients, 47 acute infections developed, including 13 of periodontal origin. All but three acute periodontal infections occurred during pronounced granulocytopenia (less than 100 granulocytes per microliter). Although signs and symptoms of inflammation were minimal, all 13 episodes were associated with pain and fever. Asymptomatic periodontal disease is readily overlooked but can be easily diagnosed by thorough clinical and roentgenographic examination. Its occurrence in patients with acute leukemia and its acute exacerbation during granulocytopenia indicate that this oral infection is associated with considerable morbidity during the treatment of acute nonlymphocytic leukemia.

Adherent microorganisms on lumenal surfaces of long-term intravenous catheters. Importance of Staphylococcus epidermidis in patients with cancer.

Using electron microscopy, we prospectively evaluated how frequently adherent microorganisms colonized silicone rubber intravenous (Hickman) catheters removed from patients with cancer. Thirteen (87%) of 15 catheters had gram-positive cocci in glycocalyx adherent to the surface of the catheter lumen. Fungal elements or gram-negative bacilli were mixed with the gram-positive cocci in the glycocalyx on the lumens of three catheters. A consistent morphologic form was adherent to, and the same species was recovered from, the corresponding catheter for six of 27 organisms causing septicemia during catheterization: four of five Staphylococcus epidermidis bacteremias and the only Staphylococcus aureus bacteremia, and one of five candidemias. Three of these six septicemias were successfully treated without removal of the catheter. Although adherent organisms, particularly S epidermidis, were likely to be present on the surface of the lumen of long-term, indwelling, silicone intravenous catheters, septicemias potentially related to these organisms occurred infrequently (fewer than two per 1000 days of catheter use), and the suspect septicemias could sometimes be treated without removal of the catheter.

Safety and tolerability of multiple doses of imipenem/cilastatin.

The safety and tolerability of 1 gm imipenem and cilastatin given together every 6 hours for 10 days was evaluated in a randomized, double-blind, placebo-controlled trial in normal subjects. Nausea was more common in the drug-treated group (five of six subjects) than in the control group (two of six subjects). No consistent changes in hepatic function indices were noted. Although beta 2-microglobulin excretion showed a significant trend of rising over time in the drug group, there were no differences between groups with regard to 24-hour urinary excretion of either N-acetyl-beta-glucosaminidase or beta 2-microglobulin. Urinalysis did not reveal any casts and serial creatinine clearance determinations showed no change in renal function in either the drug- or placebo-treated groups. Pure tone audiograms were performed before and after dosing in 11 of 12 subjects; no changes were noted. We conclude that the combination of imipenem and cilastatin was well tolerated and safe.

Empiric antibiotic therapy for granulocytopenic cancer patients.

Many cancer patients become granulocytopenic as a result of therapy and, as such, are likely to have fever during neutropenic episodes. Approximately 20 percent of these episodes have an associated gram-negative rod bacteremia; these infections occur among the most profoundly granulocytopenic patients and are associated with the highest mortality. Most infections are caused by one of three organisms: Escherichia coli, Pseudomonas aeruginosa, or Klebsiella pneumoniae. The standard approach to therapy has been the empiric utilization of an antibiotic combination, most often an aminoglycoside with either an anti-Pseudomonas penicillin or a cephalosporin. In patients for whom concern about aminoglycoside-associated nephro- or ototoxicity is high, a double beta-lactam combination has been considered. Also, with the introduction of increasingly active, exceptionally broad-spectrum antimicrobials, empiric therapy with single agents has been considered. Beta-lactam/aminoglycoside combinations more often than not are synergistic, although antagonism can be detected on occasion. Some double beta-lactam combinations demonstrate antagonism, whereas in other cases, synergism, or at least partial synergism, can be observed. Antibiotic combinations can be evaluated through in vitro models, such as the capillary model system, or through animal models designed to mimic the neutropenic state with gram-negative bacteremia, to determine potential agents or combinations of agents for this patient population. These preclinical approaches have suggested that some agents may prove effective as monotherapy and, indeed, have been comparable in activity to some of the standard antibiotic combinations. However, clinical trials have had insufficient numbers of particularly high-risk patients with profound, persistent granulocytopenia and gram-negative rod bacteremia to be able to assess their usefulness in such patients. In general, it still appears to be advantageous to use combinations such as those used in the most recent European Organization for Research on Treatment of Cancer antimicrobial trial, which compared azlocillin/amikacin with ceftazidime/amikacin. In order to reduce aminoglycoside toxicity, patients were randomly assigned to receive amikacin either for a short period or for the entire length of therapy. The study should help to determine whether it is possible to maintain the advantages of two-drug combinations while reducing the disadvantages of prolonged aminoglycoside therapy.

Staphylococcus aureus bacteremia in patients with acute leukemia.

The natural history and outcome of Staphylococcus aureus bacteremia in patients with acute leukemia were studied over a 10 year period at the Baltimore Cancer Research Program. There were 370 patients at risk; 32 (9 percent) had 37 episodes. Granulocytopenia (less than 1,000/microliters) was present in 95 percent of the episodes. The sites of origin of bacteremia were identified in 32 episodes and were usually the skin and lower respiratory tract. Initially, broad-spectrum antimicrobials were used empirically in 30 episodes and specific antistaphylococcal therapy was used in the remaining seven episodes. The median duration of therapy was 14 days of intravenous therapy and seven days of oral therapy, a total of 21 days. There was improvement during therapy in 31 of the 37 episodes (83 percent) although, among the subgroup of six patients with shock, only one improved (p less than 0.001). There was no clinical or postmortem evidence of endocarditis in any patient. Since endocarditis complicating Staph. aureus bacteremia appears to be rare in patients with acute leukemia, a shorter course of therapy than that usually recommended for endocarditis may be justified.

Combined modality treatment of Hodgkin's disease confined to lymph nodes. Results eight years later.

Eighty-seven patients with newly diagnosed Hodgkin's disease, pathologic stages IA, IIA, IIB and IIIA, were assigned at random to receive either extended field radiotherapy alone or that therapy followed by six cycles of MOPP (nitrogen mustard, Oncovin, procarbazine, prednisone) chemotherapy. Patients were entered into the study from January 1970 to January 1974. Patients were followed for a median of 69 + months from the end of all treatments. Patients whose disease was less than stage IIIA had a 31 per cent relapse rate with radiotherapy alone compared to a 6 per cent relapse rate with combined modality treatment (P = 0.04). No deaths from Hodgkin's disease have occurred in patients who received combined modality therapy, whereas 24 per cent of the patients who received radiotherapy alone have died with active disease. However, three patients with stage IIIA disease who were treated with both modalities have died from other causes (myocardial infarction, adenocarcinoma of lung, acute leukemia). Combined modality therapy of patients with early Hodgkin's disease may be superior to radiotherapy alone, especially for certain subgroups of patients discussed in detail.

Herpes zoster and impaired cell-associated immunity to the varicella-zoster virus in patients with Hodgkin's disease.

Thirty-two patients with Hodgkin's disease and 12 normal donors were studied for their in vitro lymphocyte responsiveness to a membrane-associated varicella-zoster (VZ) antigen. When compared to the normal donors, patients with Hodgkin's disease in whom radiotherapy was recently completed and those with active, recurrent disease had markedly impaired cell-associated immunity to VZ antigen. In addition, there was a suggestion that patients in long-term remission who had received primary combined modality therapy (radiotherapy plus chemotherapy) had an impaired response when compared to normal persons or to patients who had received single modality therapy. Newly diagnosed, untreated patients with Hodgkin's disease did not differ significantly from normal persons as a group but two of six were unresponsive to the VZ antigen whereas all normal subjects were responsive. Most patients in remission for at least one year following therapy had normal in vitro responsiveness. In two patients herpes zoster developed after the demonstration of absent in vitro lymphocyte reactivity to the VZ antigen.

Improved prognosis for granulocytopenic patients with gram-negative bacteremia.

The grave prognosis associated with gram-negative bacteremia occurring in granulocytopenic patients with cancer suggests that granulocyte transfusions are frequently indicated. We have evaluated 67 episodes of gram-negative bacteremia, studied in four consecutive antibiotic trials, in order to correlate prognostic determinants of recovery. These patients had a median absolute granulocyte count of 100/microliter at the time of bacteremia. Empiric antibiotic regimens were begun at the first evidence of suspected infection. Granulocyte transfusions were employed only as clinically indicated by inadequate patient response to antibiotic therapy. Among the 29 patients who had an increase in their granulocyte count of greater than or equal to 100/microliter over the subsequent 14 days, 27 (93 per cent) recovered whereas among 38 patients who had no appreciable increase in their granulocyte count, 21 (55 per cent) improved (p = 0.006). In this latter group of patients with no granulocyte recovery, the susceptibility of the pathogen(s) to the initial empiric antibiotic regimen was of major importance. None of four patients responded when the pathogen was resistant to both antibiotics initially utilized, six of 14 (44 per cent) patients responded when there was susceptibility to one antibiotic, and 15 of 20 (75 per cent) patients responded when there was susceptibility to both antibiotics (p less than 0.025). We conclude that patients with gram-negative bacteremia and persistent granulocytopenia will often respond to antimicrobial therapy alone provided the initial choice of empiric antibiotics is appropriate and that their use is instituted promptly. Granulocyte transfusions need not be added unless clinical evaluation indicates inadequate response.

The emergence of coryneform bacteria as a cause of nosocomial infections in compromised hosts.

Corynebacterium species that are normally abundant on the skin and mucous membranes rarely cause infections and are susceptible to most antibiotics. The report in 1976 of four cases of sepsis at the National Institutes of Health caused by a hitherto undescribed corynebacterium that is highly antibiotic resistant, but uniformly susceptible to vancomycin, alerted the medically oriented scientific community to the emergence of these organisms as a possible new cause of nosocomial infections. Although we have always performed antibiotic susceptibility tests on all microorganisms recovered from normally sterile body fluids, our first recovery of these organisms was in August 1977. Since then we have recovered 52 such strains from 39 patients, most frequently from the rectum, followed by the groin, blood, lesions and urine in order of predominance. Characterization by API 50 L strips revealed that most, but not all strains resemble the JK group of Riley et al. [1]. Cell wall studies and DNA base ratios further confirmed their status as corynebacteria. Hospital acquisition has been proved; cross infection between patients is the most likely mode of spread. Their recognition is necessary for optimal preventive and therapeutic care of patients with compromised host defenses.

Infections in 92 splenectomized patients with Hodgkin's disease. A clinical review.

Infections that occurrred in 92 previously untreated patients with Hodgkin's disease were reviewed from the time of laprotomy and splenectomy. Pneumonias occurred in nine patients with urinary tract infections in twelve during the immediate postoperative period. Severe bacterial infections did not occur in any patients during initial radiation therapy, adjuvant chemotherapy (stages I through IIIA), initial intensive chemotherapy (stages IIIB and IV) or during remission. Severe infections occurred in eight profoundly granulocytopenic patients with recurrent Hodgkin's disease. Streptococcus (Diplococcus) pneumoniae and Hemophilus spp infections were distinctly uncommon during the remission period. Herpes zoster, however, was very common developing in 22 of 92 (24 per cent) patients. Predisposing factors to herpes zoster included sex (female more than male), therapy (radiation plus chemotherapy more than chemotherapy alone), and age (less than 30 years of age more often than 30 to 50 years of age). Severe infection was uncommon in these patients except in ascociation with specific predisposing factors such as the immediate postoperative state of prolonged granulocytopenia associated with recurrent Hodgkin's disease or its therapy. Splenectomy per se did not affect either the incidence or the severity of infection during this period of 12+ months of observations per patient.

Torulopsis glabrata infections in patients with cancer. Increasing incidence and relationship to colonization.

Torulopsis glabrata, an opportunistic pathogen, was found to be the etiologic agent of infections in patients with cancer. This observation prompted a retrospective review to determine the incidence and underlying factors of infection with this organism. This study showed that T. glabrata had been cultured frequently and that the incidence of infection has been progressively increasing. During a 48-month period (9/70-8/74), T. glabrata was cultured from routine surveillance and diagnostic cultures in 167 patients, 27 of whom had either presumed or documented infection. Review of clinical and necropsy records implicated T. glabrata infections as a contributory factor in the death of 14 of the 27 patients. Etiologic diagnosis of infection was established antemortem in only three patients. Pulmonary isolation in pure growth occurred in 24 of the 27 patients. Seventeen of 19 infected patients who had prior routine surveillance cultures were colonized prior to infection. Infection occurred in the setting of far advanced malignancy or leukopenia and followed the use of systemic, broad spectrum antibiotics. T. glabrata is a frequently overlooked opportunistic pathogen which, in the proper setting, appears to be producing increasing numbers of infections.

Can antibacterial therapy be discontinued in persistently febrile granulocytopenic cancer patients?

It has been suggested that empiric broad-spectrum antibiotics, instituted for fever in the presence of granulocytopenia, should continue to be administered, even when infection is not demonstrable, to those patients who remain persistently febrile and granulocytopenic. Therefore, the consequences of discontinuing antibiotics when the presence of infection is doubted in this setting were evaluated. In 16 (3.7 percent) of 429 episodes of fever and granulocytopenia for which empiric antibiotic therapy was instituted, after approximately four days, persistence of both fever and granulocytopenia was found, and yet infection was prospectively classified at that time as "doubtful." The initial empiric antibiotic regimen was therefore discontinued after a mean of 4.8 (median 5.0) days. Discontinuation of antibiotics proved appropriate for half of the patients; eight patients received no systemic therapeutic antibiotics with no evidence of infection during a period of at least two weeks. The other eight patients had antibacterial antibiotics reinstituted within a mean of 2.4 days; six infections were subsequently demonstrable. Six of these eight patients also required or were believed to require antifungal therapy with intravenous amphotericin B for presumed fungal infections. Patients with relapsed leukemia or lymphoma and those with a likelihood of continued profound granulocytopenia (counts below 100/microliters) or both were the ones who tended to require reinstitution of antibiotics. Discontinuation of antibiotics when infection was considered doubtful despite persistence of both fever and granulocytopenia was, therefore, successful in eight of 16 patients. Reinstitution of antibiotics was required in the eight remaining patients. No definite rule appears to be applicable to all patients.

Piperacillin or ticarcillin plus amikacin. A double-blind prospective comparison of empiric antibiotic therapy for febrile granulocytopenic cancer patients.

Piperacillin plus amikacin was compared in a prospective randomized double-blind trial with our standard regimen of ticarcillin plus amikacin as empiric therapy of fever in patients with granulocytopenia. Profound persistent granulocytopenia (fewer than 100/microliter polymorphonuclear leukocytes without any rise during therapy) was present in 60 percent of the patient trials in both treatment groups. Of 38 microbiologically and clinically documented infections treated with piperacillin plus amikacin, 22 (58 percent) showed improvement. Of 34 microbiologically and clinically documented infections treated with ticarcillin plus amikacin, 19 (56 percent) showed improvement. There was no difference in response between groups according to the site of infection or infecting pathogen. Toxicity was minimal, with an equivalent incidence of immediate reactions, nephrotoxicity and superinfection. Patients receiving ticarcillin plus amikacin became colonized with more resistant gram-negative bacilli (17) than did those receiving piperacillin plus amikacin (3). Despite the monosodium structure of piperacillin, hypokalemia was not reduced for patients who received piperacillin plus amikacin. Although piperacillin has a wider in vitro antibacterial spectrum than ticarcillin, the clinical efficacy and toxicity of the combination of piperacillin plus amikacin were similar to those of ticarcillin plus amikacin as empiric therapy.

Antibiotic synergism and response in gram-negative bacteremia in granulocytopenic cancer patients.

To determine whether antimicrobial synergism affects the outcome of gram-negative bacteremia among profoundly (less than 100/microliter) neutropenic cancer patients, the clinical courses of 75 such patients who received empiric therapy with combination, broad-spectrum antibiotics were analyzed. Twenty-nine of 34 (85 percent) patients whose granulocyte count increased to more than 100/microliter during therapy improved, whereas only 12 of 41 (29 percent) patients with no increase in granulocyte count showed improvement (p = 0.0002). The critical group for further analysis was, therefore, those patients with persistent, profound granulocytopenia. Among these 41 patients, synergism was associated with a substantially better response rate: eight of 18 (44 percent) improved compared with none of 13 in whom synergism was not detected (p = 0.005); presence or absence of synergism could not be assessed for the pathogens isolated from the remaining 10 patients because the organisms were exquisitely susceptible to one of the two antibiotics used. Further evaluation of these persistently neutropenic patients indicated that synergism appeared critical even when the pathogen was susceptible to both antibiotics. Thus, seven of 11 (64 percent) showed response when the two drugs were synergistic in activity, compared with none of six when synergism was not present (p = 0.01). These data again demonstrate the importance of granulocyte recovery to patient response and further indicate that synergistic combinations of antibiotics are indicated for cancer patients with gram-negative bacteremia and persistent, profound granulocytopenia.

Hepatitis in patients with acute nonlymphocytic leukemia.

Three consecutive groups (University of Maryland Cancer Center protocols 7110, 7405, and 7802) of patients with acute nonlymphocytic leukemia who achieved a complete hematologic remission with similar antileukemic therapy were reviewed for the development of hepatitis. Ninety-four (73 percent) experienced viral hepatitis; eight had type B hepatitis and 86 had non-A/non-B hepatitis. The hepatitis was mild in all patients. Hepatitis secondary to cytomegalovirus, herpes simplex virus, Epstein-Barr virus, or Toxoplasma gondii was not observed. Antibody to type A hepatitis was common, but acute infection could not be substantiated. All cases of type B hepatitis in which the surface antigen could be serotyped were found to have the less frequently observed ayw marker, suggesting a common donor as the source of infection. The median duration of complete remission was longer (p = 0.03) for patients in Group II (protocol 7405) who contracted hepatitis (247 days) compared with patients without hepatitis (125 days). Median overall survival was also longer (p = 0.01) for these patients in whom hepatitis developed (672 days versus 372 days, respectively). No prolongation of complete remission duration or survival could be demonstrated for patients from Group I (protocol 7110) or Group III (protocol 7802) who contracted hepatitis. In patients with hepatitis, the height of transaminase serum bilirubin levels or duration of abnormal results of liver function tests did not correlate with the duration of complete remission or survival. Hepatitis, a common infection in those patients with acute nonlymphocytic leukemia who undergo induction therapy, had an inconsistent effect on the duration of complete remission interval and overall survival.

Infection among 210 patients with surgically staged Hodgkin's disease.

To determine the incidence and types of infections in Hodgkin's disease, particularly those related to the overwhelming pneumococcal sepsis syndrome, 210 consecutive patients with previously untreated Hodgkin's disease who underwent staging laparotomy with splenectomy from March 1968 to October 1979 were reviewed. For 178 patients (85 percent) alive at the end of the study, the mean follow-up time was 68.1 months. Eighty-two serious infections occurred among 59 (28 percent) of the patients; 47 (57 percent) serious infections were microbiologically documented and 35 (43 percent) were clinically documented. Forty-seven microbiologically documented serious infections occurred in 34 patients and consisted of 23 episodes of pneumonia, 10 cases of bacteremia, seven wound infections, two cases of disseminated herpes zoster, one subphrenic abscess, and four miscellaneous infections. Microbiologically documented serious infections occurring during initial treatment or remission had lower incidences of leukopenia (29 versus 58 percent) (p = 0.09) and death (11 versus 53 percent) (p = 0.005) than those occurring after relapse of Hodgkin's disease. Of the microbiologically documented serious infections, 76 percent were associated with a predisposing factor(s) (leukopenia, postoperative state, steroids, peripheral neuropathy, leukemia), of which 34 percent were fatal. Microbiologically documented serious infections unassociated with a predisposing factor were never fatal, including the only episode of pneumococcal sepsis in the series. In contrast to microbiologically documented serious infections, only 14 percent of clinically documented serious infections (versus 38 percent) were fatal. The overwhelming pneumococcal sepsis syndrome and other infections thought to be associated with the asplenic state are uncommon problems in patients with Hodgkin's disease after splenectomy.

Randomized trial of empiric antibiotic therapy with ticarcillin in combination with gentamicin, amikacin or netilmicin in febrile patients with granulocytopenia and cancer.

A randomized trial of ticarcillin plus gentamicin (group 1), ticarcillin plus amikacin (group 2) and ticarcillin plus netilmicin (group 3) as empiric antibiotic therapy in patients with granulocytopenia and cancer was carried out at the Baltimore Cancer Research Center. The response rate for all infections was 97 per cent in group 1, 91 per cent in group 2 and 95 per cent in group 3. Patients with bacteremias showed improvement in 93 per cent (group 1), 78 per cent (group 2) and 82 per cent (group 3) of cases. All failures were among patients with gram-negative bacteremias. Both antibiotic susceptibility of the bacteremic organism and granulocyte recovery correlated with patient improvement. Nephrotoxicity and ototoxicity were rare and were not significantly different in three groups of patients. Therefore, ticarcillin plus gentamicin, ticarcillin plus amikacin and ticarcillin plus netilmicin appear to be equally efficacious and minimally toxic in this patient population. Excellent over-all results can be expected with these combinations provided the etiologic agent is susceptible.