Antipseudomonal Drugs Research Articles

Prevalence of metallo-beta-lactamase-producing Pseudomonas aeruginosa isolated from diabetic foot ulcer patients

Metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa strains have been reported to be an important cause of nosocomial infections. There is not enough information from India regarding their prevalence in diabetic foot ulcer (DFU) patients. The present study was undertaken over a period of two year from December 2008 to March 2011 to study the incidence of MBL producing P. aeruginosa isolated from 162 DFU patients with various grades of ulcer (Texas classification). Forty isolates of P. aeruginosa were obtained from patients. These isolates were subjected to susceptibility testing to anti-pseudomonal drugs as per Clinical Laboratory and Standards Institute (CLSI) guidelines, and were further screened for the production of MBL by disc potentiation testing using ethylenediaminetetraacetic acid (EDTA)-impregnated imipenem and meropenem discs. Of the 40 isolates of P. aeruginosa, 22 (55%) isolates were found resistant to carbapenems (imipenem) and 18 (81.1%) were found to be MBL producers using imipenem+(EDTA) and 15(68.1%) by meropenem+EDTA. This rapid dissemination of MBL producers is worrisome and necessitates the implementation of not just surveillance studies but also proper and judicious selection of antibiotics, especially carbapenems.

Efficacy and Safety of Colistin in the Treatment of Infections Caused by Multidrug-resistant Pseudomonas aeruginosa in Patients with Hematologic Malignancy: A Matched Pair Analysis

A rise in infections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is a significant contributor to increased morbidity and mortality of patients with hematologic malignancies. The aim of this study was to determine the efficacy and safety of colistin (colistimethate sodium) in the treatment of serious infections caused by MDR-PA in these patients. A matched pair analysis of renal function, toxicities, and outcome of 26 patients receiving colistin and control subjects was done. All patients had clinical signs of sepsis; P. aeruginosa was isolated from blood in 69% of patients in colistin group and 84% in control group. Patients treated with colistin received 3 million units every 8 hours for a median duration of 13 days. Additionally, patients received at least two additional antimicrobial or antifungal drugs. Resolution of infection was achieved in twenty patients (76.9%) receiving colistin and in 17 (65.4%) control subjects. Mortality rate was 11% in both groups. There was no statistically significant difference in the level of serum creatinine, creatinine clearance, or potassium levels before and after treatment between groups. Only one patient receiving colistin developed de novo renal failure and one displayed transient neurologic toxicity. Our results suggest that in patients with hematologic malignancies, colistin is effective in treating severe infections caused by MDR-PA while maintaining an acceptable toxicity profile. Prospective randomized studies comparing efficacy and safety of colistin with those of other antipseudomonal drugs are needed.

Antimicrobial use and incidence of multidrug-resistant Pseudomonas aeruginosa in a teaching hospital: an ecological approach

Multidrug-resistant Pseudomonas aeruginosa is a major threat in healthcare settings. The use of antimicrobials can influence the incidence of resistant strains by direct and indirect mechanisms. The latter can be addressed by ecological studies. Our group attempted to analyze the relation between the use of antipseudomonal drugs and the incidence of MDR-PA among 18 units from a 400-bed teaching hospital. The study had a retrospective, ecological design, comprising data from 2004 and 2005. Data on the use of four antimicrobials (amikacin, ciprofloxacin, ceftazidime and imipenem) were tested for correlation with the incidence of MDR-PA (defined as isolates resistant to the four antimicrobials of interest) in clinical cultures. Univariate and multivariate linear regression analyses were performed. Significant correlations were determined between use and resistance for all antimicrobials in the univariate analysis: amikacin (standardized correlation coefficient = 0.73, p = 0.001); ciprofloxacin (0.71, p = 0.001); ceftazidime (0.61, p = 0.007) and imipenem (0.87, p < 0.001). In multivariate analysis, only imipenem (0.67, p = 0.01) was independently related to the incidence of multidrug-resistant strains. These findings share similarities with those reported in individual-based observational studies, with possible implications for infection control.

Insights into antifolate activity of phytochemicals against Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic drug resistant pathogen. Drug interaction studies for phytochemicals (protocatechuic acid (PA), gallic acid (GA), quercetin (QUER), and myricetin (MYR)) in combination with antifolates (sulfamethoxazole (SMX) and trimethoprim (TMP)) are presented. Our results show that the combinations of SMX and phytochemicals are synergistic, whereas TMP in combination with phytochemicals results in additive mode of interaction. Molecular docking of phytochemicals in the active site of modeled P. aeruginosa dihydrofolate reductase (DHFR), an important enzyme in the folic acid biosynthesis pathway, shows that the phytochemicals QUER and MYR dock in the active site of P. aeruginosa DHFR with promoted binding at the NADP site, PA, and GA dock in the active site of P. aeruginosa DHFR with promoted binding at the folate binding site. Possible mode of action of these phytochemicals as anti-DHFR compounds in this bacterium is suggested. Taken together, the above findings provide novel insights to mode of interactions of these phytochemicals with antibiotics and may have significance as prospective leads in the development of antipseudomonal drug developments.

Pseudomonas aeruginosa bacteraemia in an academic hospital in South Africa.

The aim of the study was to determine the clinical manifestations, outcome of and prognostic factors associated with Pseudomonas aeruginosa bacteraemia at Chris Hani Baragwanath Hospital, Johannesburg, during the period 1998 - 1999, to describe and quantify resistance to antipseudomonal drugs, to characterise bacteraemic isolates, and to investigate the clustering and genotype distribution of drug-susceptible and multiply-resistant strains in the hospital. Clinical and laboratory investigations, culture and antimicrobial susceptibility testing were performed. Bacteraemic isolates were typed by endonuclease macrorestriction. Those with > or = 97% band pattern similarity were assigned genotype status. Of 91 P. aeruginosa blood isolates, 52 (57.1%) were nosocomially acquired. Underlying conditions associated with episodes were burns in 24 (28%) and HIV infection in 21 (24%). Multidrug resistance was present in 14 (15.4%) of isolates from 91 episodes. In 79 episodes where the outcome was known, 37 (46.8%) of the patients died. Case fatality rates were 75% in adults and 25% in children. Being a child, receiving appropriate antimicrobial treatment and admission to a specialised care unit were significantly associated with improved prognosis. P. aeruginosa bacteraemia was associated with outbreaks caused by two multiply-resistant genotypes. Eighteen antimicrobial-susceptible isolates from bacteraemic episodes in paediatric wards, 9 in HIV-seropositive children, could be linked to small outbreaks in both hospitalised and community-based children.

INCIDENCE OF CARBAPENEM-RESISTANT PSEUDOMONAS AERUGINOSA IN DIABETES AND CANCER PATIENTS

Two hundred and thirty isolates of Pseudomonas aeruginosa were obtained from samples of patients having diabetes (75%), cancer (20%), and both diabetes and cancer (5%) who were admitted to a tertiary care hospital in Western India from January to December 2006. These isolates were tested for susceptibility to antipseudomonal drugs and considered to be resistant to carbapenem when the zone of inhibition around imipenem and meropenem discs was ≤13 mm. Of these 230 isolates, 26% were found to be carbapenem resistant. The rapid dissemination of carbapenem resistance is worrisome and calls for the implementation of surveillance studies as well as judicious use of antibiotics.

Antimicrobial Effects of Drugs against Multidrug-Resistant Pseudomonas aeruginosa

We evaluated the effects of antimicrobial drugs on four strains of Pseudomonas aeruginosa that are resistant to eight widely used antipseudomonal drugs (piperacillin, piperacillin-tazobactam, imipenem, meropenem, ceftazidime, aztreonam, amikacin, ciprofloxacin) and colistin. In the killing test, colistin (2 microg/ml) was the most effective, followed by aztreonam (48 microg/ml), piperacillin-tazobactam (192-4 microg/ml), piperacillin (192 microg/ml), and a three drug combination of azetreonam (16 microg/ml), ceftazidime (16 microg/ml), and amikacin (4 microg/ml). Six hours after drug addition, colistin (2 microg/ml), aztreonam (48 microg/ml), piperacillin-tazobactam (192-4 microg/ml), piperacillin (192 microg/ml), and the above three drug combination had bacteriostatic effects on all four strains. Colistin, three time breakpoint of aztreonam, piperacillin, or piperacillin-tazobactam, and the three drug combination of aztreonam, ceftazidime, and amikacin were effective in vitro.

Incidence of metallo-beta-lactamase-producing Pseudomonas aeruginosa in diabetes and cancer patients

Metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa strains have been reported to be an important cause of nosocomial infections. There is not enough information from India regarding their prevalence in diabetic and cancer patients. The present study was undertaken over a period of one year from January to December 2006 to study the incidence of MBL P. aeruginosa and the clinical outcome in diabetes and cancer patients admitted to S.L. Raheja Hospital, Mumbai. Two hundred and thirty isolates of P. aeruginosa were obtained from different samples of patients. These isolates were subjected to susceptibility testing to anti-pseudomonal drugs as per CLSI guidelines. They were further screened for the production of MBL by disc potentiation testing using EDTA-impregnated imipenem and meropenem discs. Of the 230 isolates of P. aeruginosa, 60 (26%) isolates were found resistant to carbapenems (both imipenem and meropenem) and 33 (14.3%) were found to be MBL producers. Of the 33 MBL-producing isolates, 24 (72.7%) were diabetic patients, six (18.1%) were cancer patients and three (9%) patients had both diabetes and cancer. Five (15.1%) patients responded to the combination therapy of colistin, piperacillin with tazobactam and amikacin, while 28 (84.8%) patients responded to the combination therapy of amikacin, piperacillin with tazobactam and gatifloxacin. Thus, the rapid dissemination of MBL producers is worrisome and necessitates the implementation of not just surveillance studies but also proper and judicious selection of antibiotics, especially carbapenems.

Incidence of carbapenem-resistant &lt;i&gt; Pseudomonas aeruginosa&lt;/i&gt; in diabetes and cancer patients

Two hundred and thirty isolates of Pseudomonas aeruginosa were obtained from samples of patients having diabetes (75%), cancer (20%), and both diabetes and cancer (5%) who were admitted to a tertiary care hospital in Western India from January to December 2006. These isolates were tested for susceptibility to antipseudomonal drugs and considered to be resistant to carbapenem when the zone of inhibition around imipenem and meropenem discs was < or =13 mm. Of these 230 isolates, 26% were found to be carbapenem resistant. The rapid dissemination of carbapenem resistance is worrisome and calls for the implementation of surveillance studies as well as judicious use of antibiotics.

Correlation between antibiotic use and changes in susceptibility patterns of Pseudomonas aeruginosa in a medical-surgical intensive care unit

Context:Multiple surveillance programmes have reported a decline in antibiotic susceptibility of P. aeruginosa.Aim:Our study aimed to study the relationship between the use of antipseudomonal drugs and the development of resistance of P. aerogenosa to these drugs.Setting and Design:Our study is retrospective. It was conducted in a medical surgical intensive care unit during a five-year period (January 1st, 1999 to December 31, 2003), which was divided into 20 quarters. We had monitored the use of antipseudomonal agents and the resistance rates of P. aeruginosa to these drugs.Statistical Methods:The associations between use and resistance were quantified using non-partial and partial correlation coefficients according to Pearson and Spearman.Results:Over the study period, the most frequently used antipseudomonal agent was Imipenem (152 ± 46 DDD/1000 patients-day) and the resistance rate of P. aeruginosa to Imipenem was 44.3 ± 9.5% (range, 30 and 60%). In addition, Imipenem use correlated significantly with development of resistance to Imipenem in the same (P < 0.05) and in the following quarter (P < 0.05); and Ciprofloxacin use correlated significantly with resistance to Ciprofloxacin in the following quarter (P < 0.05). However, use of Ceftazidime or Amikacine had no apparent association with development of resistance.Conclusion:We conclude that the extensive use of imipenem or ciprofloxacin in intensive care units may lead to the emergence of imipenem- and ciprofloxacin-resistant strains of P. aeruginosa and that antibiotic prescription policy has a significant impact on P. aeruginosa resistance rates in an intensive care unit.

Coexistence of Epidemic Colistin-Only-Sensitive Clones ofPseudomonas aeruginosa, Including theblaSPMClone, Spread in Hospitals in a Brazilian Amazon City

Nosocomial outbreaks caused by multidrug-resistant (MDR) Pseudomonas aeruginosa have been associated to fibrocystic patients and isolates harboring metallo-beta-lactamase (MBL) genes. Genotyping is an important tool for interpreting bacterial nosocomial outbreaks and implementing adequate control strategies. The aim of this study was to evaluate whether an outbreak of MDR P. aeruginosa occurring in different hospitals was due to a unique clone or independent isolates. From 2000 to 2003, 108 P. aeruginosa were recovered from colonized/infected inpatients in hospitals of São Luís, Maranhão, Brazil. The susceptibility test was performed with antipseudomonal drugs, and the presence of MBL genes were verified by PCR. Isolates were genotyped by pulsed-field gel electrophoresis (PFGE). The majority of strains was multiresistant including a great number presenting the colistin-only-sensitive (COS) profile. PFGE analysis revealed 54 genotypes, with predominance of three major COS clones (A, C, and E) coexisting at different moments and hospitals. Clone A harbored the bla(SPM) gene. Eight unique genotypes also had the COS profile. Other eight MDR genotypes presented isolates with differences in resistance profiles. Here we detected, for the first time, the coexistence of COS P.aeruginosa genotypes disseminated in several hospitals during long periods, attacking patients under various clinical conditions.

Characterization of acquired -lactamases and their genetic support in multidrug-resistant Pseudomonas aeruginosa isolates in Taiwan: the prevalence of unusual integrons

The present study was conducted to investigate acquired beta-lactamases and their genetic support in 26 Pseudomonas aeruginosa isolates that were resistant to nearly all antipseudomonal drugs from six medical centres in Taiwan. Acquired beta-lactamases and their genetic support were determined by PCR-based strategies. Four and 16 of the 26 isolates were found to produce VIM-2 and VIM-3 metallo-beta-lactamases (MBLs), respectively, and 1, 1 and 2 isolates produced OXA-17, OXA-10 and PSE-1, respectively. These bla genes are all in class 1 integrons that are probably chromosomally located. The bla(VIM-3)-containing integron, with a deletion between int1 and the bla(VIM-3) structural gene, has six gene cassettes, bla(VIM-3), a probable fosfomycin resistance determinant, aacA4, aacA4, aadB and aacA4. The bla(VIM-2)-containing integron, without detectable 5'-conserved segment, contains four genes cassettes (aacA7-bla(VIM-2)-dhfr-aacA5) and is ended by tniC. The bla(OXA-10)-containing integron includes a catB3 cassette and a fused gene cassette, which is made up of bla(OXA-17) and a novel streptomycin-spectinomycin gene, designated aadA15. The bla(OXA-17)-containing integron has three gene cassettes (aacA4-catB2-bla(OXA-17)) but the 59-base element of the bla(OXA-17) cassette is interrupted by a putative transposase gene. The bla(PSE-1)-containing integron has three gene cassettes, aacA4, an aadA3-related gene designated aadA3b and bla(PSE-1). PFGE revealed genetic diversity among the multidrug-resistant isolates from different hospitals. This study demonstrated the high prevalence of VIM-type MBLs and the presence of unusual bla-encoding integrons in multidrug-resistant P. aeruginosa isolates in Taiwan. The spread of bla(VIM-2)-related genes by horizontal transfer might have occurred.

Pseudomonas aeruginosa bloodstream infections: risk factors and treatment outcome related to expression of the PER-1 extended-spectrum beta-lactamase.

BackgroundBloodstream infection (BSI) due to Pseudomonas aeruginosa (Pa) has relevant clinical impact especially in relation to drug resistance determinants. The PER-1 extended-spectrum beta-lactamase (ESBL) is a common enzyme conferring high-level resistance to anti-pseudomonal cephalosporins. Risk factors and treatment outcome of BSI episodes caused by PER-1-positive Pa (PER-1-Pa) strains were compared to those caused by ESBL-negative Pa isolates (ESBL-N-Pa).MethodsTwenty-six BSI cases due to ceftazidime-resistant Pa strains have been investigated. MIC values of anti-pseudomonal drugs were determined by the Etest method (AB Biodisk, Solna, Sweden). The double-disk synergy test was used to detect ESBL production. PCR amplification and DNA sequencing were used to characterize ESBL types. Clinical records of BSI-patients were examined retrospectively. Demographic data, underlying diseases (McCabe-Jackson classification and Charlson weighted index), risk factors, antimicrobial therapy, and treatment outcome were evaluated in cases due to ESBL-positive and cases due to ESBL-N-Pa isolates. Unpaired Student's t-test, Mann-Whitney U-test, Fisher's exact test and the χ2 test were used for statistical analysis.ResultsNine Pa isolates expressed the PER-1 ESBL; the remaining 17 isolates did not produce ESBLs. Severe sepsis (P = 0.03), bladder and intravascular catheters (both P = 0.01), immunosuppressive therapy (P = 0.04), and mechanical ventilation (P = 0.03) were significantly associated with BSI due to PER-1-Pa. Empirical treatment (P = 0.02) and treatment after ID/AST (P < 0.01) were rarely adequate in PER-1-Pa cases. With regard to treatment outcome, 77.8% BSI cases due to PER-1-Pa vs. 28.6% cases due to ESBL-N-Pa isolates failed to respond (P < 0.03). All cases due to PER-1-Pa that were treated with carbapenems (alone or in combination with amikacin) failed to respond. In contrast, 7/8 cases due to ESBL-N-Pa given carbapenems were responders.ConclusionTherapeutic failure and increased hospital costs are associated with BSI episodes caused by PER-1-Pa strains. Thus, recognition and prompt reporting of ESBL-production appears a critical factor for the management of patients with serious P. aeruginosa infections.

Antibacterial activity of liposomal gentamicin against Pseudomonas aeruginosa: a time–kill study

Cystic fibrosis (CF) is a common and lethal genetic disorder with a carrier frequency of 1 in 29 Caucasians. Chronic respiratory infections with Pseudomonas aeruginosa are the leading cause of morbidity and mortality in individuals with CF. Aminoglycoside antibiotics, including gentamicin, are highly effective against P. aeruginosa, but severe toxicity limits their use. One potential strategy for avoiding this problem is to encapsulate aminoglycosides in liposomes. In this study, we compared the bactericidal capacity of liposome-encapsulated gentamicin with that of free antibiotic against clinical isolates of P. aeruginosa. Liposome size, encapsulation efficiency and minimal inhibitory concentrations (MICs) of the free and liposomal gentamicin against gentamicin-sensitive and -resistant strains of P. aeruginosa were determined. In vitro time–kill studies were performed using free and liposomal gentamicin at 1, 2 or 4 times the MICs. The average liposomal size was 426.25 ± 13.56 nm, with a gentamicin encapsulation efficiency of 4.51 ± 0.54%. The MICs for liposomal gentamicin were significantly lower than those of corresponding free gentamicin. In addition, the time–kill values for liposomal gentamicin were either equivalent to or better than those of the free antibiotic. In conclusion, our liposomal gentamicin formulation is a more potent antipseudomonal drug with an improved killing time and prolonged antimicrobial activity.

Microbiological rationale for the utilisation of prulifloxacin, a new fluoroquinolone, in the eradication of serious infections caused by Pseudomonas aeruginosa

Minimal inhibitory concentrations (MICs) of prulifloxacin were evaluated in comparison with ciprofloxacin, levofloxacin and moxifloxacin against a large collection ( N = 300) of Pseudomonas aeruginosa strains characterised according to the CLSI/NCCLS microdilution method. Additional in vitro tests (time–kill curves and mutant prevention concentration (MPC) determinations) were carried out. Assuming a susceptibility breakpoint for prulifloxacin identical to that of ciprofloxacin, the new fluoroquinolone emerged as the most potent antibiotic (72% of susceptible strains versus 65%, 61% and 23% for ciprofloxacin, levofloxacin and moxifloxacin, respectively). Time–kill tests at 4× MIC confirmed the pronounced bactericidal potency of the drug against P. aeruginosa. Amongst the members of the fluoroquinolone class assessed, prulifloxacin produced the lowest MPC values (≤4 mg/L). Our in vitro results indicate that prulifloxacin represents the most powerful antipseudomonal drug available today.

Nosocomial Infections Due to Multidrug-ResistantPseudomonas aeruginosa: Epidemiology and Treatment Options

Pseudomonas aeruginosa is one of the leading gram-negative organisms associated with nosocomial infections. The increasing frequency of multi-drug-resistant Pseudomonas aeruginosa (MDRPA) strains is concerning as efficacious antimicrobial options are severely limited. By searching MEDLINE from January 1966-February 2005 and relevant journals for abstracts, we reviewed the frequency, risk factors, and patient outcomes of MDRPA nosocomial infections in critically ill patients, determined the available antimicrobial therapies, and then provided recommendations for clinicians. The definition of MDRPA was established as isolates intermediate or resistant to at least three drugs in the following classes: beta-lactams, carbapenems, aminoglycosides, and fluoroquinolones. Reported rates of MDRPA varied from 0.6-32% according to geographic location and type of surveillance study. Risk factors for MDRPA infection included prolonged hospitalization, exposure to antimicrobial therapy, and immunocompromised states such as human immunodeficiency virus infection. Emergence of MDRPA isolates during therapy was reported in 27-72% of patients with initially susceptible P. aeruginosa isolates. Patients with severe MDRPA infections should be treated with combination therapy, consisting of an antipseudomonal beta-lactam with an aminoglycoside or fluoroquinolone rather than aminoglycoside and fluoroquinolone combinations, to provide adequate therapy and improve patient outcomes. Synergy has been observed when resistant antipseudomonal drugs were combined in vitro against MDRPA with successful clinical application reported in two centers. Colistin with adjunctive therapy, such as a beta-lactam or rifampin, may be a useful agent in MDRPA when antimicrobial options are limited, but patients should be monitored closely for toxicities associated with this agent. Standardization of terminology for MDRPA isolates is needed for consistency and comparability of surveillance and institutional reports. Clinical studies are needed to identify risk factors for MDRPA development and to determine the economic impact of these infections, as well as to determine the most efficacious antimicrobial regimens and duration of therapy to maximize outcomes in the treatment of MDRPA infections.

Hypermutation and the preexistence of antibiotic-resistant Pseudomonas aeruginosa mutants: implications for susceptibility testing and treatment of chronic infections.

Whether or not resistant mutants will be present before the start of antibiotic treatment of an initially susceptible population of bacteria depends on the size of the infecting population, the rate of mutation to resistance, and the amount of time that the population has been maintained. In the present investigation, we argue that for the treatment of chronic infections caused by hypermutable Pseudomonas aeruginosa of the sort frequently found in cystic fibrosis patients, mutants resistant to all single antipseudomonal drugs will almost invariably be present in a high proportion at the onset of treatment, and consequently, these strains should be considered resistant to all agents when they are used as monotherapy. Using a construct of P. aeruginosa strain PAO1 with a mutS deletion (strain PAODeltamutS), we show that when in vitro populations of less than 5 x 10(4) seemingly susceptible hypermutable bacteria are confronted with any of 11 antipseudomonal agents, mutants for which the MICs and the minimum bactericidal concentrations are in the range of clinical resistance will almost invariably ascend to dominance within 24 to 36 h. This does not occur for PAO1 without the mutS deletion. The results of our detailed analysis of this evolution of acquired resistance to two of these antibiotics, imipenem and ciprofloxacin, indicate that although the rates of mutation to resistance in PAODeltamutS are on the order of 1 x 10(-6) per generation, resistant mutants are very likely to either be present in cultures of between 2 x 10(4) and 4 x 10(4) bacteria or arise after the bacterial populations are confronted with antibiotics. We also demonstrate with in vitro experiments that the problem of acquired resistance to treatment with single antibiotics can be thwarted by combination therapy with pairs of antibiotics of different classes with synergistic activities. We discuss the clinical implications of our analysis of these observations.

In vitro effects of combinations of antipseudomonal agents against seven strains of multidrug-resistant Pseudomonas aeruginosa.

The aim of this study was to evaluate the combined effects of antibiotic combinations by agar incorporation inhibitory tests and by time-kill tests on seven geographically and epidemiologically distinct isolates of multidrug-resistant Pseudomonas aeruginosa. All seven strains were resistant to piperacillin, meropenem, ceftazidime, cefoperazone-sulbactam, aztreonam, amikacin and ciprofloxacin. Strains were distinguished by pulsed-field gel electrophoresis after DNA extraction and restriction with SpeI. MICs of the seven antibiotics listed above were determined by agar dilution. The effect of combinations of these agents was determined by agar incorporation tests and by time-kill studies. Among the two-drug combinations, the combination aztreonam and amikacin was the most effective, inhibiting proliferation in five of the seven strains. Among the three-drug combinations, the combinations of piperacillin, ceftazidime and amikacin, and that of ceftazidime, aztreonam and amikacin were the most effective, inhibiting proliferation in all seven strains. In the killing tests, the three-drug combination of ceftazidime, aztreonam and amikacin was the most effective. This three-drug combination had bacteriostatic effects on all seven strains 2, 4, 6 and 24 h after drug addition, synergic effects on 2-3 strains and bactericidal effects on 1-2 strains after 4, 6 and 24 h. The three-drug combination of ceftazidime, aztreonam and amikacin may be effective against P. aeruginosa resistant to all commonly used antipseudomonal drugs, and deserves further study.

Consultation with the specialist: Chronic suppurative otitis media.

1. Charles D. Bluestone, MD* 2. Jerome O. Klein, MD† 1. 2. *Eberly Professor of Pediatric Otalaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA. 3. 4. †Professor of Pediatrics, Boston Univerisity School of Medicine, Boston MA. Dr Klein is a consultant to Eli Lily Company; is a consultant to and lecturer for Bristol Myers Squibb and SmithKline Beecham; is a consultan to and has grant support from Abott Laboratories abd Pfizer Pharmaceuticals; and is a consultant to a, lecturer for, and has grant support from Roche Laboratories. Chronic suppurative otitis media (CSOM) is a chronic infection of the middle ear cleft (including eustachian tube, middle ear, and mastoid) that is defined by three elements: 1) perforation of the tympanic membrane due to acute infection or tympanotomy tube, 2) discharge from the middle ear (otorrhea), and 3) prolonged duration (;gt;2 wk). The initial therapy of most cases is use of appropriate topical and systemic antibiotics, which can be managed by the pediatrician. Otolaryngologic referral is necessary in four circumstances: 1) if otomicroscopy is required for initial or subsequent examination, 2) if the patient fails to respond to initial therapy, 3) if a cholesteatoma or other mass is present, and 4) if a suppurative complication occurs. CSOM affects diverse racial and cultural groups living not only in temperate climates but in climate extremes ranging from the Arctic Circle to the equator. Among the groups affected most are the Inuits of Alaska (30% to 46%), Australian aborigines (12% to 25%), and certain Native Americans (eg, Apache and Navajo tribes) (4% to 8%). Studies from industrialized nations have reported low rates of CSOM due to acute infection with perforation, but many cases of CSOM are associated with use of tympanotomy tubes. No population-based data are available regarding the incidence of CSOM associated with tympanotomy tubes. Risk factors attributed to high rates of CSOM are similar to factors associated with recurrent acute otitis media (AOM): lack of breastfeeding, overcrowding, poor hygiene, poor nutrition, passive smoking, high rates of nasopharyngeal colonization with potentially pathogenic bacteria, and inadequate and unavailable health care. Data from Thailand and Kenya indicate that public health measures and appropriate medical care are effective in decreasing the rate of CSOM. When hearing is assessed in children who have otitis media with effusion (OME), the median level is 25 dB (equivalent …

In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics

OBJECTIVE: To study the interactions of colistin (MIC 2 mg/L) at concentrations of 0.5 and 5 mg/L with ceftazidime (1 and 75 mg/L, MIC 0.5 mg/L), aztreonam (1 and 30 mg/L, MIC 0.12 mg/L), meropenem (1 and 25 mg/L, MIC 0.03 mg/L), gentamicin (1 and 10 mg/L, MIC 2 mg/L), piperacillin (5 and 100 mg/L, MIC 4 mg/L) and ciprofloxacin (0.25 and 4 mg/L, MIC 1 mg/L) using a representative strain of Pseudomonas aeruginosa isolated from a cystic fibrosis patient. METHODS: The method used was a bacterial time kill curve with single agents and combinations. Using inocula of 106 CFU/mL, multiple sampling was performed over 6 h and in triplicate. The AUBKC of the time versus viable count curve, with single agents and combinations of agents, was taken as the endpoint for comparison. RESULTS: For colistin plus ceftazidime, colistin plus aztreonam, colistin plus meropenem and colistin plus ciprofloxacin, the pattern was for all the combinations (high or low concentrations) to produce smaller AUBKCs than single agents. In experiments using a bacteriostatic agent such as ceftazidime, the AUBKCs (log CFU/µL per h) for colistin 0.5 mg/L or 5 mg/L alone were 32.3±0.8 or 12.7±0.5, and for ceftazidime 1 mg/L or 75 mg/L alone they were 24.3±1.5 or 20.9±2.7. Combinations of colistin 0.5 mg/L plus either ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 23.8±1.8 or 16.1 mg/L. Combinations of colistin 5 mg/L plus ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 12.2±0.8 or 8.7±1.0. The AUBKCs for colistin 5 mg/L plus 75 mg/L are significantly smaller than those for the single agents, indicating synergy. In experiments using the bactericidal agent ciprofloxacin, the AUBKCs (log CFU/mL per h) for colistin 0.5 mg/L or 5 mg/L alone were 33.6±1.9 or 11.2±2.4, and for ciprofloxacin 0.25 mg/L or 4 mg/L alone they were 32.8±1.3 or 5.0±0.7. Combinations of colistin 0.5 mg/L plus either ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 32.2±0.9 or 4.3±1.4. Combinations of colistin 5 mg/L plus ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 10.7±1.5 or 4.2±0.6. Although combination AUBKCs were smaller than those for single agents, in no case did this reach statistical significance (p<0.05). CONCLUSIONS: These studies indicate that addition of colistin to other antipseudomonal drugs tends to produce smaller AUBKCs and hence greater killing of Pseudomonas aeruginosa than monotherapy.