Novel resistance selected by the new expanded-spectrum cephalosporins: a concern.
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Bacterial Infections↗
Biomedical subjects
C C Sanders
Publications and source records attributed to C C Sanders.
Azlocillin: a new broad spectrum penicillin.
Azlocillin is a new semisynthetic penicillin with a broad spectrum of antibacterial activity. Azlocillin is highly active against Pseudomonas aeruginosa including many strains that are resistant to carbenicillin and ticarcillin. Unlike many other penicillins with activity against Enterobacteriaceae and Pseudomonas, azlocillin retains a high degree of potency against Gram-positive organisms, fastidious Gram-negative organisms, and many obligate anaerobes. Because azlocillin is susceptible to certain beta-lactamases it is not highly active against bacteria that are resistant to other penicillins and/or cephalosporins due to the production of such enzymes. Like other penicillins, azlocillin is bactericidal for susceptible strains. It also interacts synergistically with aminoglycosides against enterococci, certain Enterobacteriaceae, and Ps. aeruginosa.
Azlocillin↗
Effects of clindamycin on derepression of beta-lactamases in gram-negative bacteria.
Depression of beta-lactamases in certain non-fastidious Gram-negative bacilli has been responsible for (i) the rapid development of resistance to a variety of beta-lactam antibiotics and (ii) antagonism between beta-lactam antibiotics. Therefore, the effects of a variety of inhibitors of macro-molecular synthesis on derepression of beta-lactamase were investigated with four strains each of enterobacter and Pseudomonas aeruginosa. When tested at concentrations that were not inhibitory to growth, clindamycin was the most effective inhibitor of derepression of beta-lactamases in some of the strains examined. In one enterobacter isolate, clindamycin completely prevented derepression of beta-lactamases. This effect was highly specific as clindamycin did not influence constitutive beta-lactamase or depression of other inducible enzymes in this same strain. These results suggest that clindamycin may selectively inhibit synthesis of beta-lactamase under repressor control in some bacteria without affecting synthesis of other proteins or replication. Such selective inhibition may provide a new approach for the enhancement of the antibacterial activity of certain beta-lactam antibiotics.
Cefamandole↗
Characterization of beta-lactamase induction in Enterobacter cloacae.
The induction of beta-lactamase was studied in a strain of Enterobacter cloacae. A wide variety of beta-lactam compounds were found to induce beta-lactamase in this organism, and the degree of induction was directly related to the stability of the inducer to degradation by the enzyme. The kinetics of the induction process were consistent with a system normally under repressor control, suggesting a direct interaction of the beta-lactam compound with a repressor protein in the E. cloacae cells. Although these characteristics are common to many inducible systems in gram-negative organisms, the induction of beta-lactamase in this strain was not subject to catabolite repression with glucose and remained unaffected by exogenous cyclic AMP in the culture medium. This suggests that the organization and function of the beta-lactamase regulatory genes in E. cloacae are unlike those of other inducible gene systems, such as those composing the well-characterized lactose operon in Escherichia coli.
Cefoxitin↗
Influence of clindamycin on derepression of beta-lactamases in Enterobacter spp. and Pseudomonas aeruginosa.
Previous studies in this and other laboratories have shown that derepression of beta-lactamases in strains of Enterobacter and Pseudomonas spp. is responsible for the rapid development of resistance to a variety of beta-lactam antibiotics. The purpose of the current study was to evaluate the effects of clindamycin on derepression of beta-lactamases in these two genera. In tests with four strains of each genus, clindamycin diminished derepression in one isolate of each genus and completely prevented derepression in a second Enterobacter isolate (strain 55). Additional tests with strain 55 revealed that other inhibitors of macromolecular synthesis did not completely prevent derepression of beta-lactamase when tested at concentrations that did not inhibit replication. However, clindamycin did not affect synthesis of beta-lactamase that was constitutively produced in a mutant of this strain (55M). It also did not inhibit derepression of beta-galactosidase in either strain 55 or 55M. Clindamycin did not diminish the bactericidal effects of beta-lactam antibiotics against Enterobacter or Pseudomonas spp. However, it enhanced the bactericidal activity of cefamandole against strain 55. These in vitro effects of clindamycin on strain 55 that were related to prevention of derepression of beta-lactamase were confirmed in vivo with an animal model of infection. These results indicate that in some strains, clindamycin can specifically prevent derepression of beta-lactamases without inhibiting growth. Such a selective effect may provide a new approach for the enhancement of the antibacterial activity of certain beta-lactam antibiotics.
Cefamandole↗
Comparison of moxalactam and gentamicin in the treatment of complicated urinary tract infections.
Moxalactam and gentamicin were compared in a prospective, randomized study of 49 hospitalized patients with complicated urinary tract infections. Patients received parenteral moxalactam, 250 mg every 12 h, or gentamicin, 1 mg/kg every 8 h. The average duration of therapy (moxalactam, 7.5 days; gentamicin, 8.6 days) was similar for both groups. Sixty-two percent of patients treated with moxalactam and 57% of those receiving gentamicin were cured of their infection, as defined by a negative culture after therapy. No side effects required discontinuation of either drug. An enterococcus caused two superinfections and three reinfections in patients treated with moxalactam. Moxalactam resistance developed in Pseudomonas aeruginosa isolates from three patients treated with moxalactam. Moreover, two of these isolates showed decreased susceptibility to gentamicin, tobramycin, and amikacin. An additional 10 patients with gentamicin-resistant but moxalactam-susceptible isolates were treated with moxalactam. Forty percent of these patients were cured of their infections. Moxalactam appears to be a safe, effective drug for complicated urinary tract infections caused by susceptible bacteria, including those resistant to gentamicin. However, patients receiving moxalactam should be carefully monitored to detect enterococcal superinfections or development of resistance to moxalactam in isolates of P. aeruginosa.
Adult↗
Toxic shock syndrome: an ecologic imbalance within the genital microflora of women?
Epidemiologic data suggested that toxic shock syndrome (TSS) may be caused by an imbalance among the flora of the female genital tract. Since natural defense mechanisms often involve antagonistic interactions between the flora and potential pathogens, the ability of genital lactobacilli to inhibit Staphylococcus aureus was determined in agar overlay assays. Lactobacilli were chosen for study because previous investigations had suggested an important role for this genus in maintenance of health of the female genital tract. Fourteen of 50 strains of lactobacilli and Lactinex inhibited the growth of certain staphylococci, including strains from cases of TSS. The inhibitory activity of some lactobacilli was variable and could be enhanced by exogenously supplied substrates. Growth of one consistently inhibitory lactobacillus was inhibited by Staphylococcus aureus. A model for the etiology of toxic shock syndrome in menstruating women is proposed. The model includes antagonistic interactions between lactobacilli and staphylococci and the influence of tampons on these interactions to favor the staphylococcus.
Ecology↗
Resistance to cefamandole: a collaborative study of emerging clinical problems.
Cefamandole resistance in five patients was studied. Microorganisms emerged resistant to cefamandole during therapy with the drug in three patients with complicated infections. This resistance was associated with an enhanced production of beta-lactamase and/or with a change in the substrates and the isoelectric focusing patterns of the enzymes. Cross-resistance to other beta-lactam antibiotics developed concurrently in isolates from these patients. Disk diffusion tests did not detect resistance to cefamandole in the pretreatment isolate from the fourth patient; this isolate produced inactivating enzymes, and resistance was detected only in broth dilution tests. In the fifth patient, infection with a cefamandole-resistant Enterobacter developed during postoperative therapy with the drug. Resistance to cefamandole in the isolate from this patient was unstable and was associated with inducible beta-lactamase activity. These examples emphasize the need for close monitoring of patients who are given cefamandole and for thorough in vitro evaluation of isolates from the patients both before and after treatment.
Adult↗
Resistance to cefamandole: derepression of beta-lactamases by cefoxitin and mutation in Enterobacter cloacae.
Studies were performed to characterize resistance to cefamandole in two strains of Enterobacter cloacae. Susceptible wild-type cells were exposed either to cefamandole to select stably resistant mutants or to cefoxitin to induce unstable resistance. The two types of resistant cells inactivated cefamandole, and their beta-lactamases had identical isoelectric focusing patterns and substrate profiles. Studies of the beta-lactamases of these resistant cells indicated that the enzymes belonged to the Richmond and Sykes Group I and suggested that their production in wild-type cells is under repressor control. The resistant mutants appeared to be stably derepressed at the locus for beta-lactamase expression, whereas cefoxitin-induced cells were reversibly derepressed wild-type cells. Transfer of plasmids from one mutant colony to recipient Escherichia coli cells did not transfer resistance. These two types of resistance to cefamandole may explain the widely discrepant results obtained during in vitro and in vivo studies, as well as the rapid emergence of resistance that has been observed during clinical use.
Cefamandole↗
Enocin: an antibiotic produced by Streptococcus salivarius that may contribute to protection against infections due to group A streptococci.
Clinical studies have indicated that certain constituents of the normal throat flora may play a role in resistance to group A streptococcal infections. Strains of Streptococcus salivarius were among the most active components of this protective flora. The present studies were designed to determine the mechanism responsible for the antagonism of group A streptococci by S. Salivarius. Cell-free filtrates made at the end of the logarithmic growth phase of S. salivarius inhibited the growth of group A streptococci. The only other organisms susceptible to inhibition by these filtrates were those that require exogenous pantothenate, as group A streptococci do. The activity of filtrates was primarily bacteriostatic and could be specifically reversed by pantothenate. Activity was not due to a simple depletion of the vitamin but rather to the presence of a substance that interfered with the utilization of pantothenate. This substance, given the name enocin, was heat labile but was unaffected by proteolytic enzymes. Thus, strains of S. salivarius that appear to enhance the resistance of certain individuals to streptococcal infection may exert their protective effect through in situ production of the antibiotic enocin.
Bacteriocins↗
Mezlocillin: a broad spectrum penicillin highly active against gram-positive organisms and Haemophilus influenzae.
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Anti-Bacterial Agents↗
Sch 29482: comparative activity against Enterobacteriaceae multiply-resistant to beta-lactam antibiotics and mycobacteria.
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Anti-Bacterial Agents↗
Antagonism of carbenicillin and cefamandole by cefoxitin in treatment of experimental infections in mice.
The ability of cefoxitin to antagonize the in vivo efficacy of cefamandole and carbenicillin as predicted by in vitro assays was analyzed in experimental infections in mice. Cefoxitin was administered in a nonprotective dose either at the time of challenge or simultaneously with the protective drug, 1 and 3.5 h postchallenge. In mice infected with Enterobacter cloacae, median 50% protective doses of cefamandole and carbenicillin were markedly increased by cefoxitin, especially when the latter was given at the time of challenge. The antagonistic effect was also associated with increased numbers of challenge bacteria present in animal heart blood within a 6.5-h period after infection. In infections with Pseudomonas aeruginosa, cefoxitin antagonized carbenicillin; however, the effect was less dramatic than that seen with E. cloacae. Antagonism in this model was pronounced with simultaneous administration of antagonizing and protective drugs. The antagonistic effects observed in all in vivo tests were not due to the selection of stable resistance to the protective drugs, but appeared to be due to a reversible induction of beta-lactamases by cefoxitin.
Animals↗
In vitro antagonism of beta-lactam antibiotics by cefoxitin.
We assessed the extent and mechanisms of antagonism of beta-lactam antibiotics by cefoxitin. In tests with 41 gram-negative isolates, cefoxitin antagonized cephalothin, cefamandole, cefsulodin, cefotaxime, moxalactam, ampicillin, carbenicillin, piperacillin, mezlocillin, and azlocillin, but not cephalexin, mecillinam, or N-formimidoyl thienamycin. The extent of antagonism varied with the beta-lactam and genus studied. However, antagonism occurred most often with strains possessing inducible cephalosporinases. Antagonism of cephalothin and cefamandole correlated closely with the induction of beta-lactamases capable of inactivating these drugs. Although antagonism of the remaining drugs occurred more often with strains possessing inducible beta-lactamases, these enzymes did not inactivate the drugs. Morphological studies revealed that cefoxitin inhibited filamentation and lysis produced by various beta-lactam drugs. Results of this investigation suggest that cefoxitin antagonizes beta-lactams via (i) induction of drug-inactivating beta-lactamases, and (ii) the induction of beta-lactamases that cannot inactivate the drug but serve as barriers against access to target proteins. This barrier appears most efficient for drugs that bind to penicillin-binding proteins 1 and 3.
Anti-Bacterial Agents↗
Emergence of resistance to beta-lactam and aminoglycoside antibiotics during moxalactam therapy of Pseudomonas aeruginosa infections.
In four patients with Pseudomonas aeruginosa infections, the infecting strain developed resistance to moxalactam during therapy with this drug. In addition, P. aeruginosa isolates from two of these four patients showed increased resistance to aminoglycosides. Isolates from a third patient acquired cross-resistance to other antipseudomonal beta-lactams. In three of the cases, disk susceptibility tests failed to detect the resistance that was demonstrated in broth dilution assays. Isolate identities were confirmed by serotyping. No new plasmids were found by agarose gel electrophoresis. The mechanisms for this resistance did not involve enzymatic antibiotic degradation. These findings suggest that currently available expanded-spectrum cephalosporin derivatives should probably not be used alone for most serious infections due to P. aeruginosa. They also suggest that strains with multiple antibiotic resistance may become more prevalent in hospitals if these drugs are used extensively.
Aminoglycosides↗
Development and evaluation of a biochemical scheme for identification of endocervical lactobacilli.
A biochemical scheme for the species identification of endocervical lactobacilli was developed and evaluated with 10 isolates obtained from the American Type Culture Collection (ATCC) and 106 endocervical isolates obtained from women reporting to a local venereal disease clinic and a local hospital clinic. The scheme consisted of two stages. Stage I included six tests and was tested and modified with results obtained with ATCC strains. From the modified stage I, stage II was developed. Tests to be performed in this stage were determined from expected characteristics of lactobacilli. Stage II was also tested with the ATCC strains. Of the 106 endocervical isolates, 78 (74%) were identified with the two-stage scheme as developed with the ATCC strains. Unexpected results were obtained in one or both stages with the other 28 isolates. For 10 isolates, the final species identified were not previously expected to be recovered. A "best-fit" method was used to determine the most likely identification of the remaining 18 isolates. In a few instances, the use of a third stage was necessary to reach an identification. The final identification scheme, although complicated in appearance, generated a species identification with a total of 12 tests with a range of 7 to 10 tests per isolate.
Cervix Uteri↗
In vitro studies with Win 42122-2: comparison with gentamicin, netilmicin, and amikacin.
The in vitro activity of Win 42122-2 against gram-negative clinical isolates was compared in serial twofold broth dilution tests with gentamicin, netilmicin, and amikacin. Against 173 gentamicin-susceptible Enterobacteriaceae, the activity of Win 42122-2 was generally twofold less than those of gentamicin or netilmicin and similar to that of amikacin. Against 60 gentamicin-susceptible nonfermentative gram-negative bacilli, including P. aeruginosa, the activity of Win 42122-2 was four- to eightfold less than that of gentamicin or netilmicin and two- to fourfold less than that of amikacin. Minimal bacterial concentrations for Win 42122-2 were usually similar to minimal inhibitory concentrations. Win 42122-2 was not highly active against gentamicin-resistant bacteria. Win 42122-2 was as active as gentamicin against Mycobacterium tuberculosis but was less active than gentamicin or amikacin against atypical mycobacteria. Win 42122-2 interacted synergistically with penicillin G against enterococci, including strains highly resistant to streptomycin.
Amikacin↗
Comparative activity of mezlocillin, penicillin, ampicillin, carbenicillin, and ticarcillin against gram-positive bacteria and Haemophilus influenzae.
The in vitro activity of mezlocillin was compared to penicillin G, ampicillin, carbenicillin, and ticarcillin in tests with 195 gram-positive bacteria and 20 Haemophilus influenzae. Against gram-positive isolates excluding enterococci, penicillin was the most active drug, followed by ampicillin, mezlocillin, carbenicillin, and ticarcillin. Ampicillin was the most active of the five drugs against enterococci, whereas mezlocillin was the most active drug against 14 strains of ampicillin-susceptible H. influenzae.
Ampicillin↗