Treatment of nonpulmonary infections due to Mycobacterium fortuitum and Mycobacterium chelonei on the basis of in vitro susceptibilities

One hundred twenty-three patients with nonpulmonary infections due to Mycobacterium fortuitum or Mycobacterium chelonei were treated by wound debridement and with chemotherapy on the basis of in vitro susceptibilities of the organism. Of 76 patients with infections caused by M. fortuitum, 13 required no therapy or were adequately treated with surgery alone. Patients with active localized disease received single drug therapy (usually with a sulfonamide) for a mean period of 10.6 weeks for cellulitis and seven months for osteomyelitis. Patients with extensive disease received amikacin or amikacin plus cefoxitin (mean, four weeks) followed by a sulfonamide (mean, six months). The 47 patients with infections caused by M. chelonei received no therapy or were treated with surgery alone (6); with amikacin (10), erythromycin (6), doxycycline (3), or cefoxitin (1); or with amikacin plus cefoxitin followed by cefoxitin alone for a total of 10-12 weeks (20); or other multiple-drug regimens (1). Surgery was performed on 74 (60%) patients. Schlichter tests or serum drug levels were determined for 81 (66%) patients. Response to therapy was excellent; 68 (90%) infections with M. fortuitum and 34 (72%) with M. chelonei were successfully treated. Cultures became negative within six weeks of chemotherapy, except for sternal osteomyelitis, for which cultures were not negative until up to 14 weeks. Follow-up for a mean period of 12 months following therapy was possible in 80% of cases. Relapses were rare except in patients with disseminated disease, and drug resistance developed in only one patient. These studies demonstrate the value of routine susceptibility testing of these mycobacterial species and the benefit of chemotherapy on the basis of in vitro susceptibilities.     

Amikacin therapy for gram-negative septicemia

Amikacin was administered to 18 patients with gram-negative septicemia. Ten of the patients had blood culture isolates highly resistant to gentamicin; six of these patients had persistent bacteremia while receiving gentamicin alone or in combination with other agents. Fourteen of the 18 patients were cured with amikacin therapy and adjunctive measures. Nine of the 10 patients with gentamicin-resistant pathogens were cured. The occurrence of nephrotoxicity in four patients with elevated amikacin serum levels and serious underlying disease indicates the desirability of monitoring serum amikacin levels. Minor ototoxicity occurred in two patients and was associated with prolonged therapy and high serum amikacin levels. Amikacin is a highly effective agent for treating patients with gram-negative bacteremia; it is the agent of choice in the therapy of patients with suspected or documented gram-negative bacteremia caused by pathogens resistant to gentamicin and susceptible to amikacin.     

Endocarditis due to streptomycin-susceptible Enterococcus faecalis with high-level gentamicin resistance

A case of community-acquired endocarditis caused by Enterococcus (Streptococcus) faecalis with high-level resistance to gentamicin sulfate but not to streptomycin sulfate is described. Killing curves performed using achievable serum levels showed synergistic killing when streptomycin but not gentamicin, tobramycin, or amikacin was combined with penicillin G sodium or vancomycin hydrochloride. Combination therapy with vancomycin and streptomycin resulted in cure. Serum bactericidal levels indicated activity of the synergistic, as well as a nonsynergistic (vancomycin plus gentamicin), combination. Routine screening of blood isolates for high-level resistance to streptomycin and gentamicin can provide guidance for selection of therapeutic combinations in serious enterococcal infections, including endocarditis.     

Amikacin in the treatment of gram-negative pneumonia

A clinical efficacy study of amikacin in the treatment of 15 adults with nonbacteremic, gram-negative bacillary pneumonia is presented. All patients had serious underlying illnesses (11 organic heart disease, five chronic obstructive pulmonary disease, one cancer); 11 had undergone major surgical procedures. All had required respiratory assistance during their hospitalization and all had recently received other antibiotics. Thirteen of 15 patients showed clinical improvement with amikacin therapy; the pathogen was also eradicated in 10 of the 13. The mean minimum inhibitory concentration of amikacin for the 17 isolated pathogens was 3.13 μg/ml. The mean peak serum concentration of amikacin was 17.7 μg/ml. No evidence of ototoxiclty or nephrotoxicity was seen.     

Soluble CD14 levels in the serum, synovial fluid, and cerebrospinal fluid of patients with various stages of Lyme disease

Levels of circulating soluble CD14 (sCD14) in patients with various stages of Lyme disease (LD) were examined. Patients with early or untreated late LD had significantly higher levels of sCD14 than did healthy controls (P=.0001 and .0007, respectively); levels returned to normal within 3 months after antibiotic therapy. Patients with persistent posttreatment symptoms of LD had sCD14 levels equivalent to those of healthy controls. Differences in the serum sCD14 levels in patients with various stages of LD are likely to be directly correlated with differences in bacterial burden, suggesting that posttreatment symptoms may not require continued presence of the organism. sCD14 levels in the cerebrospinal fluid (CSF) of patients with any stage of LD were no different from those of control subjects. Levels of synovial fluid sCD14 from patients with Borrelia burgdorferi in their joints were elevated, compared with levels in normal serum, and may play a role in the pathogenesis of arthritis.     

Significance of serum bactericidal activity in gram-negative bacillary bacteremia in patients with and without granulocytopenia

Serum bactericidal activity was determined routinely in 89 patients with gram-negative bacillary bacteremia, 79 of whom were analyzed because they had granulocyte counts either below 100/mm3 or above 1,000/mm3. A peak (one hour after the administration of the antibiotics) serum bactericidal titer of 1:8 or more in non-granulocytopenic patients or 1:16 or more in severely granulocytopenic patients could be correlated with a favorable clinical response, in 98 percent (44 of 45) (p less than 0.0001) and 87 percent (20 of 23), (p less than 0.001) respectively. Granulocytopenic patients required a statistically significantly higher serum bactericidal activity for a favorable response. Serum bactericidal activity appears to be a useful and simple method to monitor antibiotic treatment in gram-negative bacillary bacteremia, especially when combination therapy is used.     

Chronic idiopathic and secondary neutropenia: clinical and serological investigations

Clinical data on 49 patients with chronic idiopathic neutropenia (CIN) and 42 patients with neutropenia secondary to a well-defined immunological disorder (SN) were collected and related to serological parameters. In 47% of the patients with CIN and 53% of those with SN, a positive direct immunofluorescence test was obtained with granulocytes from the patients. In the sera from the patients in the two groups, antibodies against donor granulocytes were detected by the indirect immunofluorescence test, the leucoagglutination test and/or the granulocytotoxicity test in 15%, 19% and 15%, respectively. The results of the above tests could not be correlated with any clinical or haematological parameter. Immune complexes in the serum were detected by the 125I-Clq-binding test in 29% of patients with CIN and in 58% of those with SN. The presence of serum immune complexes correlated well with the existence of a low neutrophil count, but not with the presence of recurrent infections, with bone-marrow abnormalities, or with positive reactions in other serological tests. The sera of eight out of 14 patients with CIN and seven out of 12 patients with SN had inhibitory activity for myeloid colony formation in vitro (CFU-GM). This CFU-GM inhibitory activity was correlated with the presence of recurrent infections and with hypoplasia of the myeloid compartment of the bone marrow, but not with positive reactions in other tests. We conclude that the 125I-Clq-binding test probably detects circulating immune complexes that induce a shift neutropenia, whereas serum activity inhibitory for CFU-GM possibly relates to clinically more serious forms of neutropenia. The significance of neutrophil-bound Ig and granulocyte-reactive antibodies in the serum is not clear.     

Gentamicin/amikacin-resistant gram-negative bacilli at Detroit General Hospital, 1975–1976

During a consecutive 10 month period from November 1975 through August 1976, all gram-negative bacilli isolated at Detroit General Hospital were tested for gentamicin and amikacin resistance on Mueller-Hinton agar using 10 μg discs utilizing Bauer-Kirby methods. Amikacin-resistant strains (and many gentamicin-resistant bacilli) were similarly tested using tube dilutions in Mueller-Hinton broth. The two methods correlated well for gentamicin but did so imperfectly with amikacin. In analyses for amikacin susceptibilities, values for minimal inhibitory concentration(s) and minimal bactericidal concentrations obtained in broth were subsequently employed. In this survey, 4,640 gram-negative bacilli were isolated; 1,199 strains (26 per cent) and 37 strains (0.8 per cent) were resistant to gentamicin and amikacin, respectively. Thirty-six of the strains had combined gentamicin/amikacin resistance, and they represented 3.1 per cent of all of the gentamicin-resistant isolates. Gentamicin/amikacin-resistant gram-negative bacilli were widely spread throughout medical and surgical services of the hospital. These organisms clustered in the adjacent intensive and respiratory care units. Amikacin-resistant bacilli were recovered from sputum (15 times), wounds (12 times), urine (five times) and blood (five times). Pseudomonas aeruginosa was isolated six times, Ps. cepacia 13 times and Serratia marcescens six times. These strains were usually susceptible to chloramphenicol, tetracycline and trimethoprimsulfamethoxazole but were regularly resistant to amikacin, gentamicin, tobramycin, kanamycin, streptomycin, carbenicillin and cefoxitin.     

Meta-analysis: combination of meropenem vs ceftazidime and amikacin for empirical treatment of cancer patients with febrile neutropenia

Background:Meropenem monotherapy vs ceftazidime plus amikacin have been approved for use against febrile neutropenia. To assess the effectiveness and safety of them for empirical treatment of cancer patients with febrile neutropenia, we conducted a meta-analysis of randomized controlled trial.Methods:Randomized controlled trials on ceftazidime plus amikacin, or/and monotherapy with meropenem for the treatment of cancer patients with febrile neutropenia were identified by searching Cochrane Library, PubMed, Science Direct, Wiley Online, Science Citation Index, Google (scholar), National Center for Biotechnology Information, and China National Knowledge Infrastructure. Data on interventions, participants’ characteristics and the outcomes of therapy, were extracted for statistical analysis. Seven trials fulfilled the inclusion criteria.Result:The treatment with ceftazidime plus amikacin was more effective than meropenem (OR = 1.17; 95% CI 0.93–1.46; 1270 participants). However, the treatment effects of the 2 therapy methods were almost parallel in adults (OR = 1.15; 95% CI 0.91–1.46; 1130 participants older than 16). Drug-related adverse effects afflicted more patients treated with ceftazidime plus amikacin (OR = 0.78; 95% CI 0.52–1.15; 1445 participants). The common responses were nausea, diarrhea, rash, and increased in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin.Conclusion:Ceftazidime plus amikacin should be the first choice for empirical treatment of cancer patients with febrile neutropenia, and meropenem may be chosen as a last defense against pathogenic bacteria.     

Antimicrobial therapy of septicemia due to Klebsiella pneumoniae in neutropenic rats.

Three different isolates of Klebsiella pneumoniae, highly sensitive to amikacin but varying in susceptibility to cefazolin, were injected intraperitoneally into neutropenic rats. Animals were treated every 8 hr for 72 hr with saline (controls), cefzolin (full dose, 40 mg/kg; one-fourth dose, 10 mg/kg), amikacin (full dose, 8 mg/kg; one-fourth dose, 2 mg/kg), or a combination of both drugs at either full dose or one-fourth dose. All drugs were given intramuscularly. Combination therapy with full doses produced higher mean bactericidal titers in serum and more rapid clearance of bacteria from blood and peritoneal washings. However, cumulative mortality at 72 hr in rats treated with amikacin plus cefazolin in full doses (24%, 23%, and 44%) was not significantly different from mortality in rats treated with amikacin alone (34%, 17%, and 62%). Results with cefazolin alone were not significantly different from the mortality in control animals for two of the three challenge organisms. When the minimal inhibitory concentration of cefazolin was less than or equal to 8 micrograms/ml, in vivo synergy was suggested by the similar survival rate obtained with a combination of a one-fourth dose of each agent and with amikacin alone in a full dose. These results demonstrate the relative ineffectiveness of cefazolin for therapy of klebsiella septicemia and suggest that in vivo antimicrobial synergy occurs in combination therapy against strains of bacteria relatively sensitive to cephalosporins.     

Studies on multi-antibiotic resistant strains of staphylococcus aureus

Twenty-seven isolates of Staphylococcus aureus were found to be resistant to methicillin, nafcillin, tobramycin, gentamicin, amikacin, cefoxitin, clindamycin, erythromycin and chloramphenicol by disc diffusion testing and tube dilution studies; they were sensitive to cefamandole, cephalothin and vancomycin by disc testing. A discrepancy between minimum inhibitory and bactericidal concentrations was noted for the cephalosporins which was not appreciated on disc testing. All isolates were very sensitive to rifampin (minimum bactericidal concentration 0.3 mg/l). All isolates were susceptible to phage type 83A. A subpopulation of variant small-colony forms of Staphylococcus aureus was recovered when superinhibitory amounts of aminoglycosides and methicillin were used. The variant Staphylococcus aureus strains retained the same antibiotic susceptibility patterns and phage type as their parent strain of Staphylococcus aureus. Further studies are in progress concerning these isolates and their impact on the hospital flora at our institution.     

Clinical analysis of neutropenic fever associated with hematological disorders

We evaluated the efficacy of combination therapy with sulbactam/cefoperazone (SBT/CPZ) and amikacin sulfate (AMK) in eligible patients with hematological disorders of neutrophil count less than 1,000/microliter. The clinical efficacy rate in 157 evaluated patients was 65.6%. The clinical efficacy rates were related to neutrophil counts and serum albumin levels at the 1 week later. The clinical efficacy rates were 87.1% in patients with neutrophil counts over 500/microliter and 34.8% in patients with serum albumin levels under 3 g/dl after 1 week. G-CSF treatment were not significant but tended to be more effective in patients with sepsis, and the neutrophil counts increased significantly. The group using G-CSF before the antibiotic treatment had a high clinical efficacy rate. It is suggested that G-CSF is effective in patients with neutropenia with the high risk to infection and in those who already have severe infections.     

Amikacin treatment of pulmonary infections involving gentamicin-resistant gram-negative bacilli

Twelve patients with pulmonary infections presumably involving gentamicin-resistant gram-negative bacilli were evaluated for their response to amikacin therapy. All patients had hospital-acquired infections for which they had been previously treated and were considered therapeutic failures with gentamicin or tobramycin. Assessment of response to amikacin therapy showed objective evidence of clinical improvement in 11. The gentamicin-resistant organism was eradicated in nine patients although, in the majority, other gram-negative bacilli persisted in respiratory tract secretions both during and after treatment. There was one clinical failure.     

Mycobacterium fortuitum pulmonary infection associated with an antigen-selective defect in cellular immunity

In this study we describe the first example of a well documented case of pulmonary infection caused by Mycobacterium fortuitum shown to be associated with an antigen-selective defect in cellmediated immunity to this organism. Immunologic parameters were evaluated before, during and after antibiotic treatment with amikacin. A defect in cellular immunity to purified protein derivative from Myco. fortuitum, shown to be antigen-selective as indicated by normal responsiveness to purified protein derivative from Mycobacterium tuberculosis and several other common recall antigens, accompanied the prolonged infection by this organism. During the first three months of treatment with amikacin, the patient's clinical status improved coincident with the eradication of the organism from the sputum. During the next three months of therapy with amikacin, however, a generalized defect in cellular immunity developed, and the lung disease again progressed. The deteriorating clinical condition was presumably related to a generalized cellular immune anergy or hyporesponsiveness induced by the amikacin therapy. After three more months of treatment, the organism became resistant to the drug and reappeared in sputum cultures. Since amikacin therapy was discontinued, the patient's general immune responsiveness returned to normal. He did, however, remain unresponsive to purified protein derivative from Mycobacterium fortuitum.     

Influence of rifampin therapy on serum bactericidal activity in the presence of cloxacillin and vancomycin

In this study the effect of rifampin on serum inhibitory and serum bactericidal titres was examined. Sera were prepared from pooled human serum to contain vancomycin (10 mg/L), cloxacillin (5 mg/L) or rifampin (1 mg/L), and the combinations cloxacillin/rifampin and vancomycin/rifampin. These five sera were tested by a microtitre method for serum inhibitory power and serum bactericidal titre against 11 strains of Staphylococcus aureus. A 48 h incubation period was required to detect full colony growth for subculture plates. It was found with all strains that the effect of the addition of rifampin to the other two antibiotics was to increase the serum inhibitory power, lower the serum bactericidal titre, increase the inhibitory/cidal ratio, and slow colony growth on subculture. In the clinical part of the study it was shown that only three of 38 sera (8%) from patients receiving betalactam or vanomycin but not rifampin gave an inhibitory/cidal ratio greater than 8, but that nine of 10 sera (90%) from patients receiving rifampin in addition to betalactam or vancomycin gave a ratio greater than 8 (P<0.001). The study verified that the effect of rifampin in serum was to increase inhibitory power and decrease bactericidal titre. The clinical significance of these results is not known and it is suggested that a high ratio of inhibitory to bactericidal titre in the presence of rifampin is to be expected, and that a low bactericidal titre under these circumstances is not necessarily an indication to modify therapy.     

Serum levels of GM-CSF are elevated in patients with thrombocytopenia

Serum levels of GM-CSF, IL-3 and IL-6 were measured in patients with immune thrombocytopenia (ITP), non-immune thrombocytopenia (NIT), autoimmune haemolytic anaemia (AIHA) and neutropenia. 8/10 children with ITP had elevated serum levels of GM-CSF (mean 18.4 pg/ml) while thrombocytopenic, but only two had detectable levels (mean 4.5 pg/ml) after normalization of the platelet count. In patients with NIT a significant inverse correlation between platelet count and serum levels of GM-CSF was observed. IL-3 and IL-6 levels were not significantly elevated in thrombocytopenic patients and only two of the nine patients with either AIHA or neutropenia had detectable levels of GM-CSF. Thus, GM-CSF may play a role in the response to severe thrombocytopenia.     

Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration

In an examination of the relationships among plasma aminoglycoside concentrations, the minimal inhibitory concentration (MIC) for the infecting organism, and therapeutic outcome, data were analyzed from 236 patients with gram-negative bacterial infections who were participants in four clinical trials of gentamicin, tobramycin, and amikacin. Clinical response to therapy occurred in 188 (80%) patients. Elevated maximal and mean peak aminoglycoside concentration/MIC ratios were strongly associated with clinical response (P less than .00001 and P less than .0001, respectively). A graded dose-response effect was found between an increasing maximal peak concentration/MIC ratio and clinical response. By logistic regression the peak concentration/MIC ratios were associated significantly with clinical response after adjustment for underlying severity of illness and other factors correlated with response. These results demonstrate that a high peak concentration relative to the MIC for the infecting organism is a major determinant of the clinical response to aminoglycoside therapy.     

Depression of lymphocyte reactivity by serum from patients with dilated cardiomyopathy

We have investigated the presence of serum factors (serum inhibitory factor and rosette inhibitory factor) which inhibit the blastogenic response to phytohemagglutinin and E-rosette function of normal lymphocytes in patients affected with dilated cardiomyopathy. We found them to be present in significantly higher levels with respect to a "control disease" group (P less than 0.05) and normal subjects (P less than 0.02). Furthermore, serum inhibitory factors were significantly correlated to the functional class of cardiac failure as evaluated according to the New York Heart Association functional classification (P less than 0.05). There was no correlation between serum factors and other immunological parameters investigated (serum IgG, IgA, IgM, C3 and C4 concentrations, alpha-2-macroglobulin levels). Serum inhibitory factors may affect lymphocyte subpopulations, accounting for a T-suppressor functional defect correlated with greater severity of the disease.     

Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma

Despite aggressive and innovative therapy, patients with multiple myeloma (MM) invariably relapse and die of their disease. New options for non-cytotoxic salvage therapy and additional therapeutic strategies are needed. Arsenic trioxide, an antitumour agent with a multifaceted mechanism of action, induces apoptosis in vitro in MM cell lines and freshly isolated cells from MM patients and, in preliminary studies, displayed clinical activity in patients with late-stage MM. A phase 2, multicentre, open-label study of arsenic trioxide was conducted in 24 MM patients; eight had relapsed and 16 were refractory to prior therapy. Patients received arsenic trioxide 0.25 mg/kg/d for 5 d/week during the first 2 weeks of each 4-week cycle. Sixteen patients had grade 3 or 4 neutropenia and one required antibiotics. Reductions (25% or more) in serum M-protein levels occurred in eight of 24 (33%) patients. An additional six (25%) patients had stable disease. The median time to response was 67.5 d, with a median duration of response of 130 d. Arsenic trioxide therapy lowered serum creatinine levels in two patients with high baseline values. These data indicate that arsenic trioxide is active and reasonably well tolerated as a single-agent salvage therapy, even in patients with late-stage, relapsed and refractory MM.     

Anemia of chronic disease is the more frequent type of anemia seen in patients with chronic idiopathic neutropenia of adults

This study describes the frequency and the type of anemia seen in patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA). We found that NI-CINA patients had low hemoglobin levels and increased serum concentrations of erythropoietin (EPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). The hemoglobin levels correlated positively with the number of circulating neutrophils and inversely with the levels of EPO and TNF-alpha but not of IL-1beta. Anemia, defined as the reduction of the hemoglobin below 12.0 g/dl for women and 13.3 g/dl for men, was found in 23 out of 148 patients studied, a proportion of 15.5%. Two of the anemic patients had iron deficiency anemia (8.7%), 11 had anemia of chronic disease (ACD; 47.8%) presenting with normal or slightly reduced erythrocytic indices, low serum iron, and increased serum ferritin, and the remaining ten had anemia of undefined pathogenesis (AUP; 43.5%) with normal or slightly decreased erythrocytic indices, serum iron ranging from 43 to 88 microg/dl, and ferritin values ranging from 12 to 50 ng/ml. We conclude that ACD is the more frequent type of anemia seen in patients with NI-CINA, and that pro-inflammatory cytokines, notably TNF-alpha, may be involved in the pathogenesis of both ACD and AUP, given that serum levels of the cytokine were significantly increased and that the EPO response to anemia was blunted in these patients. These findings further support our previously reported suggestion for the possible existence, in NI-CINA patients, of an unrecognized low-grade chronic inflammatory process that may be involved in the pathogenesis of the disorder.