Amikacin therapy for serious gram-negative bacillary infections.

Amikacin is a new aminoglycoside antibiotic pharmacologically similar to kanamycin. It has a wide range of activity against Gram-negative bacilli, including many resistant to gentamicin. Thirty-six serious Gram-negative bacillary infections were treated with amikacin. Twenty-nine patients (80-6%) responded (cured or improved). Twelve of 13 patients with gentamicin-resistant pathogens responded. Minor ototoxicity occurred in 6 patients and was associated with prolonged therapy or previous aminoglycoside therapy. Possible nephrotoxicity with amikacin was found in 6 patients. Amikacin should be used primarily to treat suspected or known gentamicin-resistant pathogens.     

Review of 152 patients with bacteremias treated wih amikacin

The efficacy of amikacin treatment of 152 patients with bacteremia was reviewed from case reports submitted by 53 investigators. Eighty-one per cent of these patients had a favorable outcome; 73 per cent were cured and 8 per cent partially cured. Analysis of the 29 treatment failures revealed that the majority (21) were in patients with either pneumonia, leukemia or mixed aerobic-anaerobic infections. Forty-five patients were infected with gentamicin-resistant organisms; 66 per cent of these patients were cured following amikacin therapy, and 14 per cent had a partial cure. These results indicate that amikacin is effective in the therapy of gram-negative bacteremia, even in seriously ill patients with gentamicin-resistant pathogens.     

Gentamicin resistance among gram-negative bacillary blood isolates in a hospital with long-term use of gentamicin

Between 1977 and 1985, gentamicin was the only formulary aminoglycoside at the Buffalo Veterans Administration Medical Center. During this time, there was a significant increase in the amount of gentamicin purchased. Amikacin represented 11% or less of the total aminoglycoside purchased in the same period, but purchases of this agent also significantly increased. Because of this long-term use of gentamicin, a retrospective analysis of gentamicin resistance among gram-negative bacillary blood isolates was performed. The results of this review revealed no significant change in the overall incidence of gram-negative bacteremia; approximately 75% of these bacteremic episodes were hospital acquired. The mean yearly gentamicin-resistance rate of gram-negative blood isolates was 13.2% (range, 6% to 18%) with no significant change in the rate for the period reviewed. However, for certain strains there were fluctuations in the percentage of resistance from year to year, suggesting that clusters of infections due to these organisms had occurred. Bacteremic infection due to resistant organisms was a major contributor to the overall level of gentamicin resistance among blood isolates. Amikacin resistance among gram-negative blood isolates was rare. In conclusion, despite the predominant use of gentamicin there was no change in the gentamicin resistance rate among gram-negative bacillary blood isolates during a nine-year period. The rate of gentamicin resistance among blood isolates appeared to be related to outbreaks/clusters of infections due to resistant strains rather than the frequency of use of gentamicin.     

An overview of pediatric experience with amikacin

Amikacin is an important agent in the treatment of gram-negative bacillary infections in infants and children. Frequently, these infections are nosocomial. Pediatric patients especially at risk are premature infants, infants of low birth weight, patients requiring invasive procedures and those who are immunocompromised. Amikacin has been shown to be effective in vitro and in vivo against organisms (Enterobacterlaceae and Pseudomonas) multiply-resistant to kanamycin, gentamicin and tobramycin. To date, 458 infants and children have received amikacin for the treatment of infection in a variety of sites; respiratory tract, urinary tract, blood, skin and soft tissues, abdomen, central nervous system, bone and joints. Case reports on 122 of these patients could be evaluated for efficacy. Eighty-seven patients were cured, 20 demonstrated a clinical response, but the causative agent was not eradicated, and 15 failed to respond to amikacin therapy. The dose administered intravenously or intramuscularly was usually 10 mg/kg as an initial dose, followed by 7.5 mg/kg every 12 hours. Satisfactory levels have been demonstrated in blood, viscera, soft tissue, joint spaces, bone, the peritoneal space and urine. Cerebrospinal fluid levels have been erratic when the parenteral route was employed alone. The drug is well tolerated. Immediate side effects have not been a problem. Studies for assessment of possible ototoxicity and nephrotoxicity are in progress.     

Use of aztreonam in the treatment of serious infections due to multiresistant gram-negative organisms, including Pseudomonas aeruginosa

Aztreonam is a novel antimicrobial agent belonging to the monobactam class of antibiotics. It inhibits both beta-lactamase-producing and non-beta-lactamase-producing aerobic gram-negative bacilli, but it has no activity against gram-positive species or against anaerobic species. The efficacy of aztreonam in the treatment of infection in 76 patients and its safety in 87 patients was evaluated. The majority (91 percent) of patients had significant underlying disease, and 47 percent were critically ill. Aztreonam produced an overall clinical response of 86 percent, with 10 of 11 cases of bacteremia cured, including four due to Pseudomonas aeruginosa, seven of eight cases of pneumonia, and seven of nine episodes of osteomyelitis. Infections due to bacteria resistant to ampicillin, carbenicillin, cefazolin, cefamandole, cefoxitin, and gentamicin were cured. Although 15 of 18 patients with exacerbations of pulmonary infection due to P. aeruginosa showed clinical improvement, bacteriologic cure was not achieved, as has been noted with other drugs. Similarly, patients with major underlying structural abnormalities of the urinary tract showed early relapses of bacteriuria. Aztreonam combined with antistaphylococcal, antistreptococcal, or antianaerobic agents provided an alternative to aminoglycoside use in these non-neutropenic patients. Administration of 1 or 2 g every eight hours yield serum bactericidal levels well in excess of 1:8 against all Enterobacteriaceae and some P. aeruginosa strains. There was a low incidence of adverse side effects, none serious. Overall, aztreonam is a useful alternative to the drugs available for use in hospital-acquired gram-negative infections and provides a chance for more directed therapy.     

Antibiotic resistance patterns during aminoglycoside restriction

When amikacin first became available its use was restricted to prevent the emergence of resistant strains of gram-negative bacilli to this new agent. Gentamicin was the aminoglycoside most widely used at this time, and the incidence of gentamicin-resistant bacteria was 14%, while only 2.4% were resistant to amikacin. For a period of 15 months gentamicin use was restricted, and amikacin was used almost exclusively. Amikacin use was associated with a fall in the incidence of gentamicin-resistant bacteria to 9.2% (p less than .00005), while amikacin resistance remained unchanged at 2.2% (NS). During a period of 21 months after all aminoglycoside restrictions were lifted, gentamicin use again increased, and was accompanied by a return of gentamicin resistance to the baseline level of 15.3%. During this period, amikacin resistance also increased to 4.0% (p less than .0000001) but was due primarily to an increase in resistant Pseudomonas aeruginosa. Escherichia coli was the most frequently isolated gram-negative bacillus during all three periods, and it remained sensitive to both antibiotics regardless of the drug in use. In contrast, P. aeruginosa showed a high level of resistance to gentamicin, which fell when this antibiotic was restricted, only to return to a high level with reinstitution of gentamicin. While there was also an increase in amikacin resistant strains of P. aeruginosa with unrestricted aminoglycoside use, there was no apparent shift in the pattern of aminoglycoside modifying enzymes among a small random selection of amikacin-resistant bacteria. Impaired uptake of antibiotic was the predominant mechanism responsible for P. aeruginosa resistance among strains that did not produce aminoglycoside acetyltransferase (AAC)(6').     

Amikacin therapy of gram-negative bacteremia

Treatment with amikacin was evaluated in 15 patients with gram-negative bacteremia. The sources of sepsis were urinary tract (in six patients), abdomen (in five) and miscellaneous sites (in four). Sixteen bacterial pathogens were recovered, including three gentamicin-resistant organisms. All isolates were susceptible to amikacin. Eleven of the 14 patients who could be evaluated fulfilled the criteria for cure, including the three patients with gentamicin-resistant organisms. Three patients failed to respond to amikacin therapy. Monitoring untoward effects revealed eighth nerve toxicity in one patient and nephrotoxicity in one patient. These results indicate that amikacin is effective in the treatment of patients with gram-negative bacteremia, even when caused by gentamicin-resistant bacteria.     

Amikacin therapy of gram-negative bacteremia and meningitis. Treatment in diseases due to multiple resistant bacilli.

The therapeutic efficacy of amikacin was evaluated in patients with serious hospital-acquired infections caused by Gram-negative bacilli susceptible to amikacin, but usually resistant to kanamycin, gentamicin, and tobramycin. The infections for which amikacin was given were Gram-negative bacteremia in 15 patients and Gram-negative meningitis in two patients. Therapy with amikacin resulted in a cure in 13 patients, improvement in 1, and failure in 3. Continuous intravenous infusion of amikacin yielded a high cerebrospinal fluid to serum ratio of amikacin in one case of meningitis and intrathecally administered amikacin yielded high ventricular fluid levels in another case of meningitis. The emergence of resistance to amikacin was noted in one patient treated with amikacin in whom Serratia bacteremia persisted. Treatment with amikacin was usually tolerated well. This study indicates that amikacin is an effective antibiotic in the treatment of serious Gram-negative infections caused by gentamicin-resistant organisms.     

Alterations in the microbial flora and in the incidence of bacteremia at a university hospital after adoption of amikacin as the sole formulary aminoglycoside.

Because of the rapid emergence of resistance to gentamicin and tobramycin among isolates of aerobic and facultative gram-negative bacteria at our university hospital, we designed a prospective study to track aminoglycoside resistance, bacteremic episodes, and bacteremia-associated deaths before and after the institution of amikacin as the sole formulary aminoglycoside. From June 1984 through June 1987 (immediately before this policy change), amikacin accounted for only 20% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin among aerobic and facultative gram-negative bacterial isolates were 12.8%, 10.8%, and 5.9%, respectively. During the next 30 months (immediately after the change in policy), amikacin accounted for 98% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin were 6.3%, 5.0%, and 3.3%, respectively. Furthermore, during the latter 30 months, the incidence of both bacteremia and bacteremia-associated death decreased significantly. Hospitals at which resistance to gentamicin or tobramycin is increasing among the gram-negative flora may benefit from the use of amikacin as the principal aminoglycoside.     

Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia

To determine the association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia, the case reports of 37 patients from four prospective, randomized, controlled trials of gentamicin, tobramycin, and amikacin were analyzed. Twenty (54 percent) of these patients had a favorable outcome. Patients with maximal one-hour postinfusion (peak) levels of 7 micrograms/ml or greater for gentamicin and tobramycin or 28 micrograms/ml or greater for amikacin more often had successful outcomes (14 of 20, 70 percent) than those with levels less than this (six of 19, 32 percent) (p less than 0.006). Patients with overall mean peak levels of 6 micrograms/ml or greater for gentamicin and tobramycin or 24 micrograms/ml or greater for amikacin more often had successful outcomes than those with levels less than this (six of 17, 35 percent) (p less than 0.04). The initial patient temperature, serum urea nitrogen/creatinine ratio, initial polymorphonuclear leukocyte count, and age were also associated with outcome; but by multivariate analysis, achieving an adequate peak concentration was the most important discriminating factor. These results suggest the potential importance of achieving adequate aminoglycoside levels in patients with gram-negative pneumonia.     

Amikacin therapy of patients with multiply antibiotic-resistant Serratia marcescens infections: development of increasing resistance during therapy.

Over a recent 22 month period, 222 patients in two adjacent hospitals became infected with a multiply antibiotic-resistant strain of Serratia marcescens; 13 were bacteremic. Nineteen patients with clinically significant infections received amikacin. Nine of 11 patients with urinary tract infections were cured. In contrast, only one of eight patients with pneumonia or other deep tissue infections was cured and four died. These eight patients were severely ill; many had infections with multiple microorganisms. In four of five patients in whom the infection failed to clear promptly. Serratia strains became increasingly resistant to amikacin during therapy and these strains contributed to the death of two of these patients. Amikacin proved useful in treating patients with infections due to gentamicin-resistant S. marcescens organisms, especially urinary tract infections. However, the capacity of some strains of S. marcescens to develop resistance to amikacin may limit the usefulness of this antibiotic in the treatment of deep tissue infections which involve this microorganism.     

Comparative antimicrobial susceptibility of aerobic and facultative bacteria from community-acquired bacteremia to ertapenem in Taiwan

Background  

Ertapenem is a once-a-day carbapenem and has excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. The susceptibility of isolates of community-acquired bacteremia to ertapenem has not been reported yet. The present study assesses the in vitro activity of ertapenem against aerobic and facultative bacterial pathogens isolated from patients with community-acquired bacteremia by determining and comparing the MICs of cefepime, cefoxitin, ceftazidime, ceftriaxone, ertapenem, piperacillin, piperacillin-tazobactam, ciprofloxacin, amikacin and gentamicin. The prevalence of extended broad spectrum β-lactamases (ESBL) producing strains of community-acquired bacteremia and their susceptibility to these antibiotics are investigated.     

Cefotaxime plus amikacin as empiric therapy in the treatment of febrile episodes in neutropenic patients with hematologic malignancies

Summary Between October 1980 and October 1981, cefotaxime plus amikacin were used in the treatment of 131 febrile episodes that occurred in 108 neutropenic patients with hematologic malignancies. The overall clinical response was 86.2%. Fevers of unknown origin and clinically or microbiologically documented infections responded in 88.8 and 84.4% of the cases, respectively. Renal toxicity occurred in 3.8% of the cases.In vitro studies showed that cefotaxime and amikacin were active against 78.7 and 94.7% of the pathogens, respectively, despite the high frequency (31%) of multiply resistant strains ofPseudomonas aeruginosa (defined asin vitro simultaneously resistant to carbenicillin, gentamicin, tobramycin and sisomicin) isolated from blood and infected sites. Synergy studies performed against 35 gram-negative bacilli isolated from blood revealed the presence of synergism between cefotaxime and amikacin in 54% of the cases. The peak levels of bactericidal activity in the serum of patients receiving cefotaxime plus amikacin showed median values of 1:128 and 1:8 againstEscherichia coli andP. aeruginosa septicemias, respectively.

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Cefotaxim plus Amikacin als empirische Therapie bei febrilen Episoden neutropenischer Patienten mit malignen hämatologischen Erkrankungen

Zusammenfassung Zwischen Oktober 1980 und Oktober 1981 wurden 131 fieberhafte Episoden bei 108 neutropenischen Patienten mit hämatologischen Neoplasien mit Cefotaxim plus Amikacin behandelt. Insgesamt wurde bei 86,2% der Fälle ein klinischer Erfolg erzielt. Bei Fieber unbekannter Ursache sprachen 88,8% und bei klinisch oder mikrobiologisch dokumentierten Infektionen 84,4% der Patienten auf die Therapie an. Bei 3,8% der Fälle kam es zur toxischen Nierenschädigung.In vitro-Studien zeigten, daß Cefotaxim und Amikacin gegen 78,7% beziehungsweise 94,7% der pathogenen Erreger aktiv waren, obwohl multiresistentePseudomonas aeruginosa-Stämme (definiert als simultane Resistenzin vitro gegen Carbenicillin, Gentamicin, Tobramycin und Sisomycin) 31% der aus Blut und von Infektionsstellen isolierten Erreger ausmachten. Bei 35 Isolaten von grampositiven Stäbchen aus Blut wurden Synergismus-Studien mit Cefotaxim und Amikacin durchgeführt; gegen 54% der Stämme war eine synergistische Aktivität der Kombination nachzuweisen. Die höchste bakterizide Aktivität im Serum nach Gabe von Cefotaxim plus Amikacin betrug im Mittel gegen von Septikämie-Patienten isolierteEscherichia coli 1:128 und gegenP. aeruginosa 1:8.

     

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.     

Comparative efficacy and toxicity of amikacin/carbenicillin versus gentamicin/carbenicillin in leukopenic patients: a randomized prospective trail

Between July 1974 and August 1976, 157 leukopenic patients who had a neoplastic disease or bone marrow failure syndrome were assigned at random to receive either amikacin (7.5 mg/kg every 8 hours)/carbenicillin (100 mg/kg every 4 hours) or gentamicin (2 mg/kg loading, 1.5 mg/kg every 8 hours)/ carbenicillin on admission to the hospital or on completion of a previous course of antibiotic therapy. Fever and evidence suggesting gram-negative rod infection prompted initiation of therapy, and its duration was determined by the patient's clinical course and culture data. A total of 155 courses of amikacin therapy and 140 courses of gentamicin therapy were given. The over-all clinical response rate was 75 per cent for both antibiotic regimens. Cure of urinary tract or soft tissue infections was observed in over 90 per cent of the cases. In gram-negative bacillemias only 15 of 23 patients (65 per cent) treated with amikacin and 10 of 17 patients (59 per cent) given gentamicin survived. Two bacteremic patients with gentamicin-resistant (but amikacin-sensitive) rods were assigned at random to receive gentamicin; they died. Improved survival in both treatment groups was associated with the use of combinations of drugs that interacted synergistically in vitro. There was no significant difference in the incidence of ototoxicity and nephrotoxicity. For patients with infections due to an organism susceptible to both amikacin and gentamicin, a regimen which incorporates carbenicillin and either drug is equally effective, but empiric use of amikacin is indicated when there is a reasonable possibility of infection due to gentamicin-resistant organisms.     

Antibiotic susceptibility profiles of 941 gram-negative bacteria isolated from septicemic patients throughout Canada. The Canadian Study Group.

The choice of antimicrobial therapy for the treatment of bacteremia is often empirical and based on the knowledge of antibiotic susceptibility profiles of the most common bacteria causing such infections. It therefore is crucial to survey the susceptibility of bacteria causing sepsis. This study examines the susceptibility profiles of 941 gram-negative bacteria, isolated from septic patients in 10 Canadian hospitals, to 28 antimicrobial agents. Among the isolates, 30 different species were represented; Escherichia coli dominated, representing 52.5% of isolates. More than 50% of all bacteria were resistant to ampicillin. Only 67% of the E. coli isolates were susceptible to ampicillin, while 30% of all strains were resistant to ticarcillin. Of the cephalosporins, ceftazidime and cefoperazone/sulbactam were the agents to which isolates were the most susceptible (90%). Only 51% of the E. coli strains were susceptible to cephalothin, while 91% were still susceptible to cefazolin. A total of 93% and 98% of the strains were susceptible to aztreonam and imipenem, respectively. Aminoglycosides were highly active against most isolates, in general in the following order: netilmicin greater than tobramycin greater than gentamicin greater than amikacin. Tobramycin was the most active against Pseudomonas aeruginosa. Nearly all isolates were susceptible to the quinolones. Tolerance (MBC/MIC ratio, greater than or equal to 32) was rarely observed. This survey of the susceptibility of gram-negative bacteria causing sepsis provides valuable information for implementing the chemotherapy for gram-negative septicemia and demonstrates that several older and newer agents, alone or in combination, can be used as adequate initial therapy for gram-negative sepsis in Canada.     

Gentamicin resistance in gram-negative bacilli: occurrence of modifying enzymes and their influence on susceptibility testing

Among 272 gram-negative bacilli, regarded as strains with reduced susceptibility to gentamicin by the disc test, 156 strains were resistant (greater than or equal to f microgram/ml) by the agar dilution method. Altogether 76% of the 156 strains were cross-resistant to tobramycin, kanamycin, streptomycin and amikacin. Amikacin showed the highest antibacterial activity in vitro. 32 of the resistant strains produced acetylating or adenylylating enzymes, which caused resistance. The production of enzymes was not limited to any genera. Complete cross-resistance to aminoglycoside antibiotics was recorded in 45%, 98% and 22% respectively, of Pseudomonas aeruginosa, Ps. maltophilia and other gram-negative rods. Enzyme-producing strains were not cross-resistant to all aminoglycosides. Changes in MICs and inhibition zones with different inocula among enzyme-producing strains emphasize the importance of standardized inocula in susceptibility testing.     

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.     

Incidence of trimethoprim-sulfamethoxazole-resistant enterobacteriaceae among transplant recipients

Of 114 recipients of pancreatic, renal, and bone marrow transplants who were given trimethoprim-sulfamethoxazole (TMP-SMZ) for antimicrobial prophylaxis, 44 (39%) had a total of 52 fecal isolates of TMP-SMZ-resistant gram-negative bacilli. In most of these 44 patients, the resistant isolate was found at a concentration of greater than or equal to 10(6) organisms/ml of feces. Escherichia coli was the most frequent of the isolates, and Citrobacter freundii was the next most frequent. Eight of the 114 transplant recipients had gram-negative bacteremia; in six of these eight patients, a TMP-SMZ-resistant gram-negative bacillus was the etiologic agent of bacteremia. Four of the latter six patients had stool cultures analyzed prior to the detection of bacteremia; all four had high concentrations (greater than or equal to 10(8)/ml) of fecal TMP-SMZ-resistant E. coli one to 20 days before they were found to have E. coli bacteremia. In each of these instances, the E. coli isolates from the stool and the blood had similar antibiograms. These findings indicated that resistance to TMP-SMZ is becoming more prevalent and that the screening of patients for the presence of fecal TMP-SMZ-resistant Enterobacteriaceae prior to initiation of long-term therapy with this antimicrobial agent may be worthwhile.     

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.