MICs Of Aztreonam Research Articles

In vitro susceptibility of characterized β-lactamase-producing strains tested with avibactam combinations.

Avibactam, a broad-spectrum β-lactamase inhibitor, was tested with ceftazidime, ceftaroline, or aztreonam against 57 well-characterized Gram-negative strains producing β-lactamases from all molecular classes. Most strains were nonsusceptible to the β-lactams alone. Against AmpC-, extended-spectrum β-lactamase (ESBL)-, and KPC-producing Enterobacteriaceae or Pseudomonas aeruginosa, avibactam lowered ceftazidime, ceftaroline, or aztreonam MICs up to 2,048-fold, to ≤4 μg/ml. Aztreonam-avibactam MICs against a VIM-1 metallo-β-lactamase-producing Enterobacter cloacae and a VIM-1/KPC-3-producing Escherichia coli isolate were 0.12 and 8 μg/ml, respectively.

Human Simulated Studies of Aztreonam and Aztreonam-Avibactam To Evaluate Activity against Challenging Gram-Negative Organisms, Including Metallo-β-Lactamase Producers

Secondary to the stability of aztreonam against metallo-β-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum β-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-β-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14 Enterobacteriaceae and 13 Pseudomonas aeruginosa isolates, of which 25 produced metallo-β-lactamases. Additionally, six P. aeruginosa isolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT>MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of the Enterobacteriaceae bacterial isolates (aztreonam MIC, ≤ 32 μg/ml; fT>MIC, ≥ 38%) and minimal activity against the remaining isolates (aztreonam MIC, ≥ 128 μg/ml; fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14 Enterobacteriaceae isolates (aztreonam-avibactam MICs, ≤16 μg/ml; fT>MIC, ≥ 65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity against P. aeruginosa was noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were ≤ 16 μg/ml and variable efficacy noted when the MICs were ≥ 32 μg/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-β-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.

Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI)

Aztreonam for inhalation solution (AZLI) is an inhaled antibiotic for patients with cystic fibrosis (CF) and Pseudomonas aeruginosa airway infection. The risk of selecting for P. aeruginosa isolates with reduced susceptibility to antibiotics is inherent to their use, but is of particular concern following repeated exposure and when complete eradication of lung pathogens is difficult to obtain. We investigated whether repeated treatment courses of AZLI led to decreases in P. aeruginosa susceptibility to aztreonam or other antibiotics. Serial sputum specimens were collected and processed for isolation and quantification of all P. aeruginosa isolates in a Phase 3 open-label, 18 month study (NCT00128492) including 274 CF patients receiving up to nine courses of AZLI twice daily (AZLI2) or thrice daily (AZLI3) (28 days on/28 days off). P. aeruginosa antibiotic susceptibility testing was conducted. No changes were observed in the aztreonam MIC(50) for all P. aeruginosa isolates collected from AZLI3 patients, while intermittent increases were observed in the aztreonam MIC(90). Approximately 70% of the P. aeruginosa isolates with the highest aztreonam MIC from each patient receiving AZLI3 remained unchanged or decreased relative to that patient's equivalent isolate at baseline; 30% experienced an increase in MIC. Few decreases in P. aeruginosa susceptibility to other antibiotics were observed in AZLI3 patients, while increases in P. aeruginosa susceptibility to tobramycin were observed. Few decreases in aztreonam susceptibility were reported in patients receiving AZLI3. Increases in tobramycin susceptibility were observed, suggesting that novel treatment paradigms may be able to prolong antibiotic susceptibility in CF patients.

Quorum-sensing regulator sdiA and marA overexpression is involved in in vitro-selected multidrug resistance of Escherichia coli

The role of sdiA in the acquisition of low-level multidrug resistance (MDR) was analysed and compared with that of marA and soxS in two Escherichia coli clinical isolates and two in vitro-selected mutants. The mutants were developed by growth in lomefloxacin and ceftazidime. The sdiA, marA, soxS, ftsI, tolC and acrB gene transcript levels were determined by RT-PCR. Analyses of 2,4-dinitrophenol susceptibility, the effect of an active efflux inhibitor on antibiotic and mitomycin C susceptibility, beta-lactamase hydrolytic activity, outer and inner membrane proteins and acrR gene sequencing were also performed. Both mutants showed elevated marA and sdiA gene transcript levels, which were associated with increased susceptibility to 2,4-dinitrophenol; soxS overexpression was only seen in the mutant selected with ceftazidime. The two mutants showed MDR phenotypes in which ceftazidime, cefpirome and aztreonam MICs increased 4- to 128-fold, in addition to decreased susceptibility to quinolones, chloramphenicol and mitomycin C. The highest ceftazidime MIC in one of the mutants coincided with a frameshift mutation in acrR and the highest transcript level of ftsI (penicillin-binding protein 3), but not with a higher beta-lactamase activity. Likewise, active efflux associated with increased levels of acrB and tolC and decreased OmpF expression contributed to low-level MDR in both mutants. marA and sdiA overexpression was a common feature of multidrug-resistant mutants selected by growth in lomefloxacin and ceftazidime. To our knowledge, this report is the first to describe in vitro selection with a fluoroquinolone or ceftazidime triggering sdiA overexpression in E. coli isolates.

Gene cloning and characteristics of the RND-type multidrug efflux pump MuxABC-OpmB possessing two RND components in Pseudomonas aeruginosa

muxA-muxB-muxC-opmB (formerly PA2528-PA2527-PA2526-opmB), encoding a putative resistance nodulation cell division (RND)-type multidrug efflux pump system, was cloned from Pseudomonas aeruginosa PAO1. Introduction of muxABC-opmB into P. aeruginosa YM64, a drug-hypersusceptible strain, led to elevated MICs of aztreonam, macrolides, novobiocin and tetracycline. Since muxB and muxC, both of which encode RND components, were essential for function, MuxABC-OpmB is thought to be a drug efflux pump with four components. One novobiocin-resistant mutant, PMX725, isolated from P. aeruginosa PMX7 showed elevated resistance not only to novobiocin but also to aztreonam, macrolides and tetracycline. Increased mRNA expression of muxABC-opmB was observed in the mutant PMX725 compared with the parental strain. Sequencing analysis revealed that a single-nucleotide insertion had occurred in the deduced promoter region for muxABC-opmB in PMX725. In this study, we have characterized the last RND-type multidrug efflux pump predicted from the genome sequence in P. aeruginosa.

Pyrosequencing Using the Single-Nucleotide Polymorphism Protocol for Rapid Determination of TEM- and SHV-Type Extended-Spectrum β-Lactamases in Clinical Isolates and Identification of the Novel β-Lactamase Genes bla SHV-48 , bla SHV-105 , and bla TEM-155

TEM- and SHV-type extended-spectrum beta-lactamases (ESBLs) are the most common ESBLs found in the United States and are prevalent throughout the world. Amino acid substitutions at a number of positions in TEM-1 lead to the ESBL phenotype, although substitutions at residues 104 (E to K), 164 (R to S or H), 238 (G to S), and 240 (E to K) appear to be particularly important in modifying the spectrum of activity of the enzyme. The SHV-1-derived ESBLs are a less diverse collection of enzymes; however, the majority of amino acid substitutions resulting in an ESBL mirror those seen in the TEM-1-derived enzymes. Pyrosequencing by use of the single-nucleotide polymorphism (SNP) protocol was applied to provide sequence data at positions critical for the ESBL phenotype spanning the bla(TEM) and bla(SHV) genes. Three novel beta-lactamases are described: the ESBLs TEM-155 (Q39K, R164S, E240K) and SHV-105 (I8F, R43S, G156D, G238S, E240K) and a non-ESBL, SHV-48 (V119I). The ceftazidime, ceftriaxone, and aztreonam MICs for an Escherichia coli isolate expressing bla(SHV-105) were >128, 128, and >128 microg/ml, respectively. Likewise, the ceftazidime, ceftriaxone, and aztreonam MICs for an E. coli isolate expressing bla(TEM-155) were >128, 64, and > 128 microg/ml, respectively. Pyrosequence analysis determined the true identity of the beta-lactamase on plasmid R1010 to be SHV-11 rather than SHV-1, as previously reported. Pyrosequencing is a real-time sequencing-by-synthesis approach that was applied to SNP detection for TEM- and SHV-type ESBL identification and represents a robust tool for rapid sequence determination that may have a place in the clinical setting.

Contemporary in vitro synergy rates for aztreonam combined with newer fluoroquinolones and β-lactams tested against gram-negative bacilli

Aztreonam has been commonly used in various combinations to enhance antimicrobial spectrum of co-drugs and produce potential synergistic activity. Although well studied in vitro over 10 years ago, aztreonam combination testing has been poorly documented with newer or commonly used agents against contemporary isolates. All MIC tests (alone or in combination) used in this experiment were reference broth microdilution methods in checkerboard tray designs. Aztreonam was combined with ciprofloxacin, gatifloxacin, levofloxacin, cefepime, ceftazidime and imipenem at clinically relevant concentrations. Interaction categories were defined by established criteria. Forty strains each of Pseudomonas aeruginosa and Enterobacteriaceae (12 species; aztreonam MIC, 1-16 μg/ml) were tested for each antimicrobial combination (480 total determinations). No antagonism or indeterminate interactions were identified. The overall rates of synergy or partial synergy for aztreonam with fluoroquinolone combinations was 63.4% versus P. aeruginosa, greatest for aztreonam with gatifloxacin (67.5%). Interaction categories varied greatly among aztreonam with β-lactam combinations. Aztreonam with ceftazidime or cefepime versus P. aeruginosa had 75.0 - 85.0% partial or complete synergy rates, but aztreonam with imipenem showed dominant indifference (65.0%). In contrast, aztreonam with imipenem was more likely to exhibit synergy (32.5%) when tested against Enterobacteriaceae. Aztreonam, often used as an aminoglycoside substitute in antimicrobial combinations, continues to demonstrate enhanced, but variable drug activity interactions for contemporary antimicrobial combinations when tested against recent (2002) clinical isolates.

An approach for the evaluation of synergy between antimicrobials

Synergy can be assessed by a variety of microbiological techniques. Mathematical modelling of synergy data can accomplish similar results and may provide more information than currently available techniques. In this study a combination of 1/4 MIC of aztreonam (AZTR) and 1 MIC of ciprofloxacin (CIPX) showed synergy against Pseudomonas aeruginosa in killing curve studies (based on the two log different criteria) at the end of 24 h. However, re-growth was always observed even when bactericidal concentrations of antibiotics were present. The surviving organisms showed a two-fold increase of MIC to CIPX after the studies and this resistance was not reversible. A mathematical model to quantitatively describe this observation is proposed.

OXA-28, an extended-spectrum variant of OXA-10 beta-lactamase from Pseudomonas aeruginosa and its plasmid- and integron-located gene.

Pseudomonas aeruginosa ED-1, isolated from a pulmonary brush of a patient hospitalized in a suburb of Paris, France, was resistant to ceftazidime and of intermediate susceptibility to ureidopenicillins and to cefotaxime. Cloning and expression of the beta-lactamase gene content of this isolate in Escherichia coli DH10B identified a novel OXA-10 variant, OXA-28, with a pI value of 8.1 and a molecular mass of 29 kDa. It differed from OXA-10 by 10 amino acid changes and from OXA-13 and OXA-19 by 2 amino acid changes, including a glycine instead of tryptophan at position 164, which is likely involved in its resistance to ceftazidime. Like OXA-11, -14, -16, and -19 and as opposed to OXA-17, OXA-28 predominantly compromised ceftazidime and had only marginal effect on the MICs of aztreonam and cefotaxime in P. aeruginosa. Once expressed in E. coli, OXA-28 raised the MIC of ceftazidime to a much higher level than those of amoxicillin, cephalothin, and cefotaxime (128, 16, 8, and 4 microg/ml, respectively). OXA-28 beta-lactamase had a broad spectrum of activity, including ceftazidime. Its activity was partially antagonized by clavulanic acid (50% inhibitory concentration, 10 microM) and NaCl addition. The oxa28 gene cassette was inserted in the variable region of a class 1 integron, In57, immediately downstream of an amino 6'-N-acetyltransferase gene cassette, aac(6')Ib. The structures of the integrons carrying either oxa28, oxa13, or oxa19 gene cassettes were almost identical, suggesting that they may have derived from a common ancestor as a result of the common European origin of the P. aeruginosa isolates. In57 was located on a self-transferable plasmid of ca. 150 kb that was transferred from P. aeruginosa to P. aeruginosa.

Can results obtained with commercially available MicroScan microdilution panels serve as an indicator of beta-lactamase production among escherichia coli and Klebsiella isolates with hidden resistance to expanded-spectrum cephalosporins and aztreonam?

Among clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca, there is an ever-increasing prevalence of beta-lactamases that may confer resistance to newer beta-lactam antibiotics that is not detectable by conventional procedures. Therefore, 75 isolates of these species producing well-characterized beta-lactamases were studied using two MicroScan conventional microdilution panels, Gram Negative Urine MIC 7 (NU7) and Gram Negative MIC Plus 2 (N+2), to determine if results could be utilized to provide an accurate indication of beta-lactamase production in the absence of frank resistance to expanded-spectrum cephalosporins and aztreonam. The enzymes studied included Bush groups 1 (AmpC), 2b (TEM-1, TEM-2, and SHV-1), 2be (extended spectrum beta-lactamases [ESBLs] and K1), and 2br, alone and in various combinations. In tests with E. coli and K. pneumoniae and the NU7 panel, cefpodoxime MICs of >/=2 microg/ml were obtained only for isolates producing ESBLs or AmpC beta-lactamases. Cefoxitin MICs of >16 microg/ml were obtained for all strains producing AmpC beta-lactamase and only 1 of 33 strains producing ESBLs. For the N+2 panel, ceftazidime MICs of >/=4 microg/ml correctly identified 90% of ESBL producers and 100% of AmpC producers among isolates of E. coli and K. pneumoniae. Cefotetan MICs of >/= 8 microg/ml were obtained for seven of eight producers of AmpC beta-lactamase and no ESBL producers. For tests performed with either panel and isolates of K. oxytoca, MICs of ceftazidime, cefotaxime, and ceftizoxime were elevated for strains producing ESBLs, while ceftriaxone and aztreonam MICs separated low-level K1 from high-level K1 producers within this species. These results suggest that microdilution panels can be used by clinical laboratories as an indicator of certain beta-lactamases that may produce hidden but clinically significant resistance among isolates of E. coli, K. pneumoniae, and K. oxytoca. Although it may not always be possible to differentiate between strains that produce ESBLs and those that produce AmpC, this differentiation is not critical since therapeutic options for patients infected with such organisms are similarly limited.

Chromosomally encoded ampC-type beta-lactamase in a clinical isolate of Proteus mirabilis.

A clinical strain of Proteus mirabilis (CF09) isolated from urine specimens of a patient displayed resistance to amoxicillin (MIC >4,096 microg/ml), ticarcillin (4,096 microg/ml), cefoxitin (64 microg/ml), cefotaxime (256 microg/ml), and ceftazidime (128 microg/ml) and required an elevated MIC of aztreonam (4 microg/ml). Clavulanic acid did not act synergistically with cephalosporins. Two beta-lactamases with apparent pIs of 5.6 and 9.0 were identified by isoelectric focusing on a gel. Substrate and inhibition profiles were characteristic of an AmpC-type beta-lactamase with a pI of 9.0. Amplification by PCR with primers for ampC genes (Escherichia coli, Enterobacter cloacae, and Citrobacter freundii) of a 756-bp DNA fragment from strain CF09 was obtained only with C. freundii-specific primers. Hybridization results showed that the ampC gene is only chromosomally located while the TEM gene is plasmid located. After cloning of the gene, analysis of the complete nucleotide sequence (1,146 bp) showed that this ampC gene is close to blaCMY-2, from which it differs by three point mutations leading to amino acid substitutions Glu --> Gly at position 22, Trp --> Arg at position 201, and Ser --> Asn at position 343. AmpC beta-lactamases derived from that of C. freundii (LAT-1, LAT-2, BIL-1, and CMY-2) have been found in Klebsiella pneumoniae, E. coli, and Enterobacter aerogenes and have been reported to be plasmid borne. This is the first example of a chromosomally encoded AmpC-type beta-lactamase observed in P. mirabilis. We suggest that it be designated CMY-3.

A237T as a modulating mutation in naturally occurring extended-spectrum TEM-type beta-lactamases.

A TEM-1 beta-lactamase derivative containing the single amino acid substitution A237T slightly increased (from 24 to 32 microg/ml) the cephalothin MIC for Escherichia coli RYC1000 but did not influence the activities of cefotaxime, ceftazidime, and aztreonam (MICs of 0.03, 0.12, and 0.06 microg/ml, respectively). Despite its apparent neutrality, addition of the A237T mutation to the pair of mutations characterizing TEM-10 (R164S and E240K) had a strong effect on substrate preference. Ceftazidime and aztreonam MICs decreased from 128 and 16 microg/ml to 16 and 2 microg/ml, respectively. In contrast, the cefotaxime MIC increased from 0.5 to 4 microg/ml. The acquisition of apparently neutral or even deleterious mutations results in a very effective mechanism of resistance to different beta-lactams that may be simultaneously or subsequently present in the environment. We propose here that the mutation in position 237 is an example of a modulating mutation and that consideration of this type of mutation may be important for understanding the evolution of beta-lactamases.

Detection of extended-spectrum plasmid-mediated beta-lactamases by disk diffusion.

Detection of extended-spectrum plasmid-mediated beta-lactamases by disk diffusion.

Tumor necrosis factor alpha (TNF-alpha) production in mice immunized with Escherichia coli: correlation with mortality after lethal challenge and production of a native inhibitor of TNF-alpha activity.

The kinetics of tumor necrosis factor alpha (TNF-alpha) production, the correlation between cytokine levels and mortality rates after lethal challenge, and the production of a native inhibitor of TNF-alpha activity was investigated in mice immunized with formalin-killed Escherichia coli. Groups of mice were injected for 8 weeks with either untreated bacteria or bacteria treated with 0.5 MIC of aztreonam and subsequently challenged with 100 50% lethal doses of viable E. coli. Mice receiving saline only (controls) died within 24 h. The mortality of mice immunized with aztreonam-treated E. coli was significantly lower than that of mice immunized with untreated E. coli. There were no measurable levels of TNF-alpha in sera obtained from control mice during the entire period of immunization. TNF-alpha levels ranging from 90 to 306 U/ml were measured 90 min after each vaccination in sera obtained from mice immunized with untreated E. coli. Sera from mice immunized with antibiotic-treated E. coli showed lower TNF-alpha levels, ranging from 40 to 128 U/ml. TNF-alpha levels measured 90 min after lethal challenge correlated with the mortality rate observed in each group (r = 0.95). The cytotoxic activity of recombinant murine TNF-alpha was inhibited by the sera from immunized mice but not by the sera from controls. The inhibition was drastically reduced by preincubation of the sera with staphylococcal protein A. In immunoblot experiments, class G immunoglobulins reacting with recombinant murine TNF-alpha were observed in the sera of immunized mice. These data confirm the correlation existing between TNF-alpha levels and mortality and suggest that native inhibitors may play a role in the regulation of the biological function of the cytokine.

Antimicrobial effect of clindamycin in combination with aztreonam or aminoglycosides against Klebsiella spp.

The antimicrobial effect of clindamycin combined with aztreonam or an aminoglycoside (gentamicin, tobramycin or amikacin) was studied against 84 strains of Klebsiella pneumoniae and 18 strains of K. oxytoca with an agar dilution technique. Clindamycin concentrations of 1-20 mg/l and an inoculum of 10(4) cuf/spot were used. Anaerobic incubation of agar plates was associated with an increase in the MIC of aminoglycosides and no change or a decrease in the MIC of aztreonam. Lower concentrations of clindamycin (1-2 mg/l) were associated with a decrease in the MIC of aztreonam for 18% and an increase in the MIC of aminoglycosides for between 7% and 44% of the strains, depending upon the precise concentration used. However, higher concentrations of clindamycin (10-20 mg/l) were associated with a decrease in the MIC of aztreonam for between 36 and 87% and an increase in the MIC of aminoglycosides for between 13 and 64% of the isolates. These observations could be important when treatment plans for mixed aerobic/anaerobic infections including mixed Klebsiella spp. are considered.

Aztreonam

Aztreonam, the first commercially available monobactam, has a wide range of activity against aerobic gram-negative bacilli. It can be administered two to three hours daily because its half-life is 1.6 to 2 hours. Excellent blood and tissue concentrations are attained. The MIC of aztreonam against most Enterobacteriaceae is less than or equal to 2 micrograms/ml and against P aeruginosa less than or equal to 16 micrograms g/ml. Aztreonam has been used in a wide array of infections of the urinary tract and respiratory tract, blood, intra-abdominal and gynecologic infections and infections of the skin, bones and joints. As empiric therapy, aztreonam is usually combined with another antimicrobial agent active against anaerobes and/or aerobic gram-positive cocci until culture results are available. One exception is empiric therapy for gram-negative urinary tract infections in which aztreonam can be used initially as monotherapy against susceptible gram-negative pathogens. In general, the efficacy of aztreonam is equal or superior to that of the aminoglycosides. Adverse reactions to aztreonam are unusual, and it as been shown to be a poor hapten, permitting its administration to patients with proven allergy to the penicillins and cephalosporins. Aztreonam is a useful addition to the available antibiotics for treatment of gram-negative infections.

Characteristics of aztreonam as a substrate, inhibitor and inducer for .BETA.-lactamases.

Aztreonam was investigated as to its characteristics as a substrate, inhibitor and inducer for the well-defined beta-lactamases of Gram-negative bacteria, and its antibacterial efficacy as to bacterial cells producing eight types of beta-lactamases was also evaluated. Aztreonam was hydrolyzed at measurable rates by class A beta-lactamases, a TEM-2 type penicillinase and the Proteus vulgaris cephalosporinase with a broad substrate range. However, the affinity of aztreonam for the class A enzymes was low, this property being well reflected by its high antibacterial activity toward producers of class A beta-lactamases. Aztreonam was extremely stable as to the typical class C cephalosporinase of Citrobacter freundii, and acted as a competitive and progressive inhibitor for the beta-lactamase. While the MICs of aztreonam in the cases of the constitutive producers of class C beta-lactamases were evidently affected by enzyme production. An experiment involving aztreonam as a inhibitor in combination with a hydrolyzable beta-lactam gave ambiguous results, however, a strong synergistic effect was found in combination with mecillinam. Using Pseudomonas aeruginosa, aztreonam was confirmed to be a poor inducer of beta-lactamases.

臨床分離グラム陰性桿菌に見られるAztreonam (AZT) 耐性菌とAZT不活化酵素の型の推測

The MICs of Aztreonam (AZT) against 590 clinical isolates of Gram-negative bacilli were determined. About 13.4% (79 strains) of the isolates were AZT-resistant (MIC; 12.5 micrograms/ml less than or equal to). The resistance pattern against various beta-lactams and the effects on MICs of combination of Clavulanic acid (CVA) and AZT against AZT resistant strains suggested that AZT was inactivated by either type of IV (K1), Va (OXA1), or PSE2 beta-lactamases.

In-vitro activity of FCE 22101 and other β-lactam antibiotics against Enterobacteriaceae resistant to third, generation cephalosporins

The in-vitro activity of FCE 22101 was compared with those of imipenem, aztreonam, cefotaxime, ceftriaxone and latamoxef against 225 Enterobacteriaceae (209 clinical isolates and 16 derivatives of Escherichia coli K12) chosen for their resistance (MIC greater than or equal to 8 mg/l) to third-generation cephalosporins. The beta-lactamases produced by the strains of Enterobacter cloacae, Klebsiella pneumoniae and Esch. coli were identified. The mean MICs of FCE 22101 were 2-8 mg/l for Ent. cloacae, Citrobacter freundii and Morganella morganii. For Ent. cloacae, the MICs were slightly higher for the cephalosporinase non overproducing (5.5-8 mg/l) than for the cephalosporinase overproducing (4.5 mg/l) strains. The mean MIC was 9 mg/l for Serratia spp. but for half of the strains the MICs were greater than or equal to 16 mg/l. The MICs of FCE 22101 were 0.5-1 mg/l for the resistant clinical isolates or isogenic derivatives of K. pneumoniae and Esch. coli producing extended broad-spectrum beta-lactamases (SHV-2, SHV-3 or CTX-1), whether measured in the presence of clavulanate or not, and against the sensitive controls. This showed that the compound was not affected by these new beta-lactamases. The MICs of imipenem, on the average four to five times lower than those of FCE 22101, were found to be very similar for resistant and sensitive strains. The MICs of aztreonam were high (32-128 mg/l) for C. freundii, K. oxytoca and cephalosporinase overproducing strains of Ent. cloacae. There was cross-resistance between the third-generation cephalosporins, but the MICs of latamoxef remained low (1 mg/l) against M. morganii, Klebsiella spp. and Esch. coli.

Aztreonam in the Treatment of Gram-Negative Meningitis and Other Gram-Negative Infections

Ninety patients (41 males, 49 females) with a diagnosis of meningitis, urinary tract infection (UTI), gastroenteritis or other miscellaneous gram-negative infections were enrolled. Their ages ranged from 7 days to 10 years, with a mean age of 4 months. 58 (63%) patients had an etiology confirmed by either positive culture (52; 89%) or latex agglutination (6; 10%). 41 of these patients had meningitis diagnosed by positive CSE culture (38) or by positive CSF latex agglutination (3); 27/41 patients also had positive blood cultures. Aztreonam MIC100 for 27 isolates of Haemophilus influenzae, all ampicillin-sensitive, was 0.19 micrograms/ml; 4 Salmonella sp., 1 Neisseria meningitidis and 1 Serratia marcescens isolates were inhibited by 0.19 micrograms/ml, and the MIC100 for 2 Klebsiella pneumoniae, 1 Proteus vulgaris and 2 Pseudomonas aeruginosa isolates were 0.045 and 0.19, 0.022 and 12.5 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)