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PubMedDate not supplied

The emergence of bacterial resistance and its influence on empiric therapy.

The discovery of antimicrobial agents had a major impact on the rate of survival from infections. However, the changing patterns of antimicrobial resistance caused a demand for new antibacterial agents. Within a few years of the introduction of penicillin, the majority of staphylococci were resistant to that drug. In the 1960s the production of the semisynthetic penicillins provided an answer to the problem of staphylococcal resistance. In the early 1960s most Escherichia coli were susceptible to the new beta-lactam antibiotic ampicillin; by the end of that decade, plasmid-mediated beta-lactamase resistance was found in 30%-50% of hospital-acquired E. coli. Use of certain agents resulted in the selection of bacteria, such as Klebsiella, that are intrinsically resistant to ampicillin. The original cephalosporins were stable to beta-lactamase, but the use of these agents was in part responsible for the appearance of infections due to Enterobacter species, Citrobacter species, and Pseudomonas aeruginosa. These bacteria, as well as Serratia, were resistant to many of the available beta-lactam agents. Aminoglycosides initially provided excellent activity against most of the facultative gram-negative bacteria. However, the widespread dissemination of the genes that cause production of the aminoglycoside-inactivating enzymes altered the use of those agents. Clearly, the evolution of bacterial resistance has altered the prescribing patterns for antimicrobial agents. Knowledge that beta-lactam resistance to ampicillin or cephalothin is prevalent is causing physicians to select as empiric therapy either a combination of two or more agents or agents to which resistance is uncommon. The new cephalosporins offer a broad spectrum of anti-bacterial activity coupled with low toxicity. However, physicians must closely follow the changing ecology of bacteria when these agents are used, because cephalosporins can also select bacteria resistant to themselves and thereby abolish their value as empiric therapy.

Aminoglycosides↗

PubMedDate not supplied

Aztreonam in the treatment of bone and joint infections caused by gram-negative bacilli.

Aztreonam was used successfully in 17 of 17 patients with orthopedic infections due to gram-negative bacilli (11, osteomyelitis; six, septic arthritis). Duration of treatment ranged from 14 to 55 days, and the period of follow-up was four to 18 months. Causative organisms included Pseudomonas aeruginosa, Serratia marcescens, Enterobacter gergoviae, Citrobacter diversus, Proteus mirabilis, and Enterobacter aerogenes. Aztreonam was well tolerated. The only definite reactions attributable to aztreonam were asymptomatic increases in serum aspartate aminotransferase (SGOT) and serum alanine aminotransferase (SGPT) in four patients; none of these reactions interfered with completion of therapy. Adverse reactions that were possibly attributable to aztreonam included rash (two patients), diarrhea (one patient), and leukopenia (one patient). All of these patients were receiving antibiotics active against gram-positive organisms in mixed infections in addition to aztreonam. Aztreonam is a promising new monobactam without significant toxicity. It has good activity against gram-negative aerobic bacteria, including P. aeruginosa, and is effective in the treatment of serious infections due to gram-negative aerobes.

Adolescent↗

PubMedDate not supplied

Use of trimethoprim-sulfamethoxazole in pediatric infections: relative merits of intravenous administration.

Trimethoprim-sulfamethoxazole (TMP-SMZ) has traditionally been employed as an oral formulation for infections in ambulatory pediatric patients. However, therapeutic concentrations of TMP and SMZ in serum and CSF are more consistently attained after intravenous administration. Serum half-life increases with the age of the child, and few significant toxic effects are observed with intravenous administration. Either the necessity to optimize bioavailability because of the underlying seriousness of disease or a desire to avoid other drugs that may be responsible for adverse reactions or hypersensitivity should direct the clinician to administer an intravenous preparation. Serious pediatric infections that might warrant the consideration of intravenous TMP-SMZ include shigellosis, salmonellosis, typhoid fever, nocardiosis, gram-negative bacillary septicemia or meningitis, and infections due to Pneumocystis carinii and malarial parasites. Infections due to Listeria will respond to TMP-SMZ, and infections due to Citrobacter diversus, Acinetobacter species, Pseudomonas cepacia, and Flavobacterium meningosepticum are especially susceptible to TMP-SMZ.

Age Factors↗

PubMed2003

Experimental prediction of the evolution of cefepime resistance from the CMY-2 AmpC beta-lactamase.

Understanding of the evolutionary histories of many genes has not yet allowed us to predict the evolutionary potential of those genes. Intuition suggests that current biochemical activity of gene products should be a good predictor of the potential to evolve related activities; however, we have little evidence to support that intuition. Here we use our in vitro evolution method to evaluate biochemical activity as a predictor of future evolutionary potential. Neither the class C Citrobacter freundii CMY-2 AmpC beta-lactamase nor the class A TEM-1 beta-lactamase confer resistance to the beta-lactam antibiotic cefepime, nor do any of the naturally occurring alleles descended from them. However, the CMY-2 AmpC enzyme and some alleles descended from TEM-1 confer high-level resistance to the structurally similar ceftazidime. On the basis of the comparison of TEM-1 and CMY-2, we asked whether biochemical activity is a good predictor of the evolutionary potential of an enzyme. If it is, then CMY-2 should be more able than the TEMs to evolve the ability to confer higher levels of cefepime resistance. Although we generated CMY-2 evolvants that conferred increased cefepime resistance, we did not recover any CMY-2 evolvants that conferred resistance levels as high as the best cefepime-resistant TEM alleles.

Bacterial Proteins↗

PubMed1976

Amikacin in obstetric, gynecologic, and neonatal infections: laboratory and clinical studies.

Based on the proportion of resistant, moderately sensitive, and sensitive strains, the descending order of activity of amikacin against clinical isolates of urinary pathogens was Salmonella, Klebsiella, Enterobacter, Escherichia coli, Staphylococcus aureus, Citrobacter, Proteus species, and Pseudomonas aeruginosa. However, amikacin was the most active of the antibiotics tested (including gentamicin and tobramycin) against 100 strains of P. aeruginosa. The calculated half-life of amikacin was substantially longer in patients with compromised renal function than in normal subjects. Immaturity of renal function, characteristic of the newborn, similarly slowed the rate of excretion of amikacin. The cure rate (complete clinical remission and eradication of the pathogen) was 91% in 22 patients with urinary tract infection (including 16 with chronic pyelonephritis) treated with 500 mg of amikacin every 8 or 12 hr for eight to 17 days. After single injections of 7.5 mg/kg 2-3 hr before delivery, appreciable amounts of the drug were recovered from the cord blood. No local or systemic intolerance or laboratory abnormalities were observed in a total of 42 patients (including eight infants) treated for a maximum of two weeks. No ototoxicity was demonstrable in any of the 12 patients subjected to audiometry; nystagmography revealed slight vestibular dysfunction in two elderly patients.

Amikacin↗

PubMed1985

An outbreak of antibiotic-resistant Salmonella enteritidis in Liberia, West Africa.

Between October 1980 and August 1982, 100 patients in the pediatric population at Curran Lutheran Hospital, Zorzor, Liberia were identified as having multiple drug-resistant Salmonella enteritidis serotype enteritidis. The illness usually presented as an enteric fever but also as meningitis, gastroenteritis, empyema, subcutaneous abscesses, chronic otitis media, or a combination of these conditions. Predisposing factors were young age and debilitation from malnutrition or measles. The mortality of infected patients was 27.8%. The organism was originally misidentified as a Citrobacter species because of a delayed reaction on lysine decarboxylase medium. Incubation of the medium for five days resulted in a positive reaction that identified the organism as a Salmonella species. The isolates were resistant to multiple antibiotics. Genes mediating resistance were located on a 120-megadalton conjugative plasmid. A cryptic nonconjugative 40-megadalton plasmid was also present in several isolates.

Adolescent↗

PubMed1988

Failure of antisera to J5 and R595 rough mutants to reduce endotoxemic lethality.

Rabbit antisera to J5 (Rc) Escherichia coli and R595 (Re) Salmonella minnesota rough mutants were selected for the highest content of hemagglutinating antibodies to their respective core glycolipids. Despite titers of 1:2560 vs. J5 and 1:640 vs. R595 core glycolipids, the antisera failed to passively protect ICR or CF-1 mice against lethality induced by endotoxins from a variety of wild-type, smooth enterobacteria: E. coli O111:B4, E. coli O127:B8, Salmonella typhimurium, S. minnesota, and Citrobacter freundii. J5 antisera, however, reduced lethality from J5 core glycolipid. In contrast, O-specific rabbit antisera were consistently protective against the lethal activity of wild-type, smooth enterobacterial endotoxins, but such protection was limited to the homologous endotoxin. These findings are consistent with in vitro demonstrations of a highly restricted ability of antibodies to J5 and R595 core glycolipids to bind to endotoxins from wild-type, smooth enterobacteria.

Animals↗

PubMed1991

Antibacterial activity of crotalid venoms against oral snake flora and other clinical bacteria.

Despite heavy oral and fang contamination of crotalid species with a wide variety of potentially pathogenic bacteria, crotalid envenomation is associated with a low incidence of bacterial infection. Minimal inhibitory and bactericidal concentrations of venoms from three crotalid species were determined against six aerobic and eight anaerobic reference and oral crotalid microorganisms. All anaerobic isolates were resistant to greater than 20,480 micrograms/ml, whereas variable activity (range, 5-20,480 micrograms/ml) was observed for aerobic strains. Further studies against other aerobic clinical isolates demonstrated that venom had the greatest activity (MIC, less than or equal to 80 micrograms/ml) against staphylococci, Pseudomonas aeruginosa, and Enterobacter, Citrobacter, Proteus, and Morganella species. Inhibitory activity was lost with prolonged incubation for many gram-negative species. Crotalid venoms are broadly active against aerobic gram-negative and -positive bacteria. This activity may play a role in the low incidence of infection after envenomation injuries.

Animals↗

PubMed1993

A multidrug resistance regulatory chromosomal locus is widespread among enteric bacteria.

Constitutive expression of the mar operon (marRAB) in Escherichia coli produces a multiple antibiotic resistance phenotype mediated by the expression of multiple genetic loci in response to regulatory proteins in the operon. A mar-specific DNA probe was used to search for the operon in bacterial strains representing 53 species and 27 genera. Among these, 6 other Enterobacteriaceae, Salmonella, Shigella, Klebsiella, Citrobacter, Hafnia, and Enterobacter species, contained DNA sequences that hybridized to the probe under high-stringency conditions. By use of a selection protocol developed to obtain multiple antibiotic resistant mutants of E. coli, multiply resistant mutants that showed increased expression of mar-specific RNA were obtained from Enterobacter agglomerans and Salmonella species.

Blotting, Northern↗

PubMed1983

The in-vitro activity of O-demethylfortimicin.

The activity of O-demethylfortimicin against ampicillin, cefazolin and carbenicillin resistant bacteria was determined. O-Demethylfortimicin showed excellent in-vitro activity against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Ent. agglomerans, Ent. aerogenes, Citrobacter freundii, Proteus vulgaris, Morganella, and Providencia inhibiting these organisms at less than or equal to 3.1 mg/l. It was particularly effective against Ent. cloacae and Serratia marcescens that were resistant to cefotaxime, cefoperazone and moxalactam. O-Demethylfortimicin did not show particularly good activity against Pseudomonas aeruginosa. Acinetobacter or other Pseudomonas species, MIC90 values were 100 mg/l. Combination of O-demethylfortimicin and ticarcillin or cefsulodin tested against Ps. aeruginosa were primarily indifferent. Combination of O-demethylfortimicin and ticarcillin showed partial synergy for 65% of Enterobacter isolates.

Amikacin↗

PubMed1983

Cefotetan: profile of in-vitro activity.

Cefotetan, a novel 7 alpha-methoxy cephalosporin, was shown to be comparable to other third-generation cephalosporins when tested in vitro against 1063 Gram-negative clinical isolates of 11 species. Ninety per cent of all isolates of Escherichia coli, Klebsiella, Proteus mirabilis, Proteus vulgaris, Proteus rettgeri, Providencia stuartii, Serratia marcescens and Citrobacter freundii were inhibited by concentrations of cefotetan between 0.07 and 3.2 mg/l. Activity against Gram-positive cocci was about equal to that of moxalactam. Pseudomonas aeruginosa and Acinetobacter were resistant. Cefotetan inhibited about two-thirds of Enterobacter strains at 16 mg/l. beta-Lactamases of Enterobacter cloacae highly resistant to cefotetan inactivated this cephamycin. These strains were resistant to most other beta-lactams as well. Synergism between cefotetan and aminoglycosides was found in 8 out of 16 Gram-negatives.

Aminoglycosides↗

PubMed1983

Cefotetan: comparative study in vitro against 226 Gram-negative clinical isolates.

The activity in vitro of the new cephamycin, cefotetan, was compared with that of cephalothin, cefoxitin, cefuroxime and cefotaxime against 226 recently isolated Gram-negative pathogens (207 Enterobacteriaceae and 19 Acinetobacter). Cefotetan was consistently more potent than cephalothin, cefoxitin and cefuroxime. Cefotaxime and cefotetan were essentially similar in activity against the Enterobacteriaceae with the singular exception of Enterobacter spp. which were markedly more susceptible to the former drug. None of the five agents was especially active against acinetobacter but cefotaxime was the best. Limited tests of bactericidal activity showed that the MBC differed from the MIC by a factor of 4 at most. Increasing the inoculum tested from 10(2) to 10(8) per ml had little adverse effect on the MIC of cefotetan. If the recommendations of the National Committee for Clinical Laboratory Standards for susceptibility to cephalosporins are applicable to cefotetan and the breakpoint criteria of less than or equal to 10 mg/l (sensitive) and greater than or equal to 32 mg/l (resistant) are acceptable, then only a few of the Enterobacteriaceae in this study were resistant. These resistant organisms were amongst Enterobacter spp. and Citrobacter spp.

Anti-Bacterial Agents↗

PubMed1983

In-vitro activity of cefotetan, other beta-lactams and netilmicin.

In-vitro activity of cefotetan was compared to that of other cephalosporins netilmicin. Cefotetan at very low concentrations inhibited Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Serratia marcescens. Poor activity was seen for all beta-lactams against Enterobacter and Citrobacter spp. Activity of cefotetan against Staphylococcus aureus was comparable to that of ceftazidime and moxalactam. Netilmicin was the only agent equally active against all Gram-negative bacilli and Staph. aureus tested. Under conditions simulating serum levels cefotetan demonstrated rapid and long-acting bactericidal activity and bacteria exposed to these concentrations required up to 10.2 h to recover from the effect of the antibiotic. Six out of 15 strains did not recover fully.

Anti-Bacterial Agents↗

PubMed1983

Susceptibilities of gentamicin-resistant Gram-negative aerobic bacilli to cefotetan and other beta-lactams.

The activity of the 7 alpha-methoxycephalosporin, cefotetan was determined against 365 infecting isolates of gentamicin- and multiply-resistant Gram-negative aerobic bacilli, and compared with those of cefuroxime, cefoxitin, cephradine, cefotaxime, ceftriaxone and ceftazidime. All proteus (4), providencia (6) salmonella (3) and serratia (2) were susceptible to 8 mg/l of cefotetan, as were respectively 90 and 81% of 42 Escherichia coli and 16 citrobacter isolates. The intrinsic activity of cefotetan was high against 237 klebsiellae (38 different serotypes), only 4 being relatively insusceptible (MICs 16- greater than 32 mg/l). Activity against pseudomonas (10 isolates) acinetobacter (15 isolates) and enterobacter (30 isolates) was poor. Overall, the activities of cefotetan were similar to those of cefotaxime, ceftriaxone and ceftazidime but ceftazidime was also active against the majority of pseudomonas, acinetobacter and enterobacter. Cefotaxime was less active than cefotetan against some cefuroxime-resistant klebsiellae. Much greater numbers of isolates were insusceptible to either cefuroxime or cefoxitin. Cephradine was the least active.

Anti-Bacterial Agents↗

PubMed1983

Early results of a comparative trial of ceftazidime versus cephalothin, carbenicillin and gentamicin in the treatment of febrile granulocytopenic patients.

Ceftazidime was compared with a combination of cephalothin, carbenicillin and gentamicin as empirical therapy for fever in granulocytopenic patients. Forty-eight patients were studied in this randomized trial. In the 44 evaluable cases, favourable clinical responses were seen in 9/21 ceftazidime-treated cases and 13/23 patients treated with the combination. Four of 5 bacteraemias were cured with ceftazidime and 3 of 4 with triple therapy. Comparable numbers of patients developed new fevers while on therapy. Five ceftazidime-treated patients developed documented superinfection compared to 6 patients in the other group. Five patients treated with ceftazidime died from the initial infection or a superinfection compared with 3 on the combination. The overall results appear to be similar at this time. However, remarkable differences were observed between the types of superinfecting organisms with the two regimens. If all 48 patients are considered the isolates were as follows: ceftazidime treatment--5 clostridia, 3 enterococci, 1 Staphylococcus epidermidis and 1 Citrobacter; cephalothin-carbenicillin-gentamicin treatment--4 Pseudomonas, 1 Escherichia coli, 1 Bacteroides fragilis and 2 Candida spp. These results suggest that Gram-positive coverage should be added to ceftazidime in the empirical treatment of febrile granulocytopenic patients.

Adult↗

PubMed1984

Do we need the third-generation cephalosporins?

Third-generation cephalosporins have been available for the past 5 years. The continued increase in resistance of bacteria to older antimicrobial agents and the safety profile of a number of the third-generation agents have established situations in which these compounds are useful. Upper respiratory infections such as epiglottitis, lower respiratory tract infections due to Enterobacteriaceae are examples of illnesses in which third-generation cephalosporins would be preferred to older drug programmes. Bone and joint infections due to Enterobacteriaceae can be treated with third-generation cephalosporins with less risk of toxicity than that associated with aminoglycoside use. But this is an area in which resistance may develop. Meningitis in the elderly due to Escherichia coli or Klebsiella pneumoniae are best treated with cefotaxime and the third-generation cephalosporins are alternative therapy for neonatal and the other forms of meningitis except Listeria or Pseudomonas. These drugs have proved extremely useful in treatment of penicillinase-producing Neisseria gonorrhoeae. Hospital-acquired urinary tract infections in the elderly can be treated with these agents since they provide excellent urinary levels and have a low risk of nephrotoxicity. The need for third-generation cephalosporins in gynaecological and intra-abdomonal infections is less clear. Selected patients will benefit from their use. Closer attention to the excellent in vitro activity and pharmacological activity of third-generation cephalosporins should establish other areas of need for these compounds, but it will be necessary to follow closely the development of resistance to these compounds since species such as Enterobacter, Serratia and Citrobacter can become resistant.

Abdomen↗

PubMed1984

Treatment of 160 cases of acute bacterial meningitis with cefotaxime.

One hundred and sixty cases of acute bacterial meningitis were treated with cefotaxime. Patients were between 9 days and 79 years old: 7 new borns, 37 infants, 43 children, 19 adolescents and 54 adults. Fifty-eight patients (36%) were in coma when admitted. Aetiology was determined in 110 patients (68.8%): Neisseria meningitidis in 42, Streptococcus pneumoniae in 36, Haemophilus influenzae in 16, Salmonella spp. in 7, Staphylococcus aureus in 2, Enterobacter spp. in 2 and Haemophilus parainfluenzae, pseudomonas aeruginosa, Escherichia coli, Citrobacter freundii and Klebsiella pneumoniae in one patient each. All isolates were sensitive to cefotaxime, with MIC's for 26 strains ranging from 0.01 to 0.50 mg/l. One hundred and fifty-six of the 160 patients were treated with cefotaxime alone and the four others with cefotaxime in association with an aminoglycoside in three and rifampicin in one. Cefotaxime was administered by intravenous infusion, in a daily dose 100 to 300 mg/kg. Duration of treatment ranged from 8 days to 6 weeks, with a mean of 15 days. One hundred and forty-nine patients (93.1%) were cured, two after a relapse. Three patients had sequelae. Most (88.5%) had sterile CSF within 72 h after starting treatment. Eleven patients (6.9%) died, eight within the first 48 h. The only side-effects observed were mild transient eosinophilia in some patients and rash and leukopenia in 2 each. The study demonstrates that cefotaxime is effective in the treatment of acute bacterial meningitis.

Acute Disease↗

PubMed1984

Single-dose cefotaxime in the treatment of urinary tract infections in children: a randomized clinical trial.

Thirty-seven patients with a median age of 5 years with symptomatic lower or upper urinary tract infection, documented by a clean-catch midstream urine culture and sediment examination, completed a randomized study comparing the effectiveness of a single dose of cefotaxime with 10-day treatment with an antibiotic chosen by in-vitro sensitivities. Eighteen patients were randomly assigned to the cefotaxime group (50 mg/kg/im route) and 19 patients were placed in the 10-day therapy group. In the cefotaxime group 4/18 patients had an upper urinary tract infection and 11/18 had a history of recurrences. The causal organisms were Escherichia coli (16 cases) and Klebsiella pneumoniae (two cases). All patients had sterile urine 48 hours after therapy, and 2/18 cases had recurred 28 days later. In the 10-day treatment group, 7/19 patients had an upper urinary tract infection, 6/19 had a history of recurrences, 17 cases were caused by E. coli, one case by Citrobacter freundii and one case by K. pneumoniae. Eighteen of 19 patients had sterile urine 48 hours after therapy and 1 case remained symptomatic with positive culture. The other 18 patients had no recurrences. Rates of cures and recurrence in the compared groups were not statistically different (P greater than 0.05).

Adolescent↗