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1.  Cefazolin high-inoculum effect in methicillin-susceptible Staphylococcus aureus from South American hospitals 
Journal of Antimicrobial Chemotherapy  2013;68(12):2773-2778.
Objectives
Clinical failures with cefazolin have been described in high-inoculum infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) producing type A β-lactamase. We investigated the prevalence of the cefazolin inoculum effect (InE) in MSSA from South American hospitals, since cefazolin is used routinely against MSSA due to concerns about the in vivo efficacy of isoxazolyl penicillins.
Methods
MSSA isolates were recovered from bloodstream (n = 296) and osteomyelitis (n = 68) infections in two different multicentre surveillance studies performed in 2001–02 and 2006–08 in South American hospitals. We determined standard-inoculum (105cfu/mL) and high-inoculum (107 cfu/mL) cefazolin MICs. PFGE was performed on all isolates that exhibited a cefazolin InE. Multilocus sequence typing (MLST) and sequencing of part of blaZ were performed on representative isolates.
Results
The overall prevalence of the cefazolin InE was 36% (131 isolates). A high proportion (50%) of MSSA isolates recovered from osteomyelitis infections exhibited the InE, whereas it was observed in 33% of MSSA recovered from bloodstream infections. Interestingly, Ecuador had the highest prevalence of the InE (45%). Strikingly, 63% of MSSA isolates recovered from osteomyelitis infections in Colombia exhibited the InE. MLST revealed that MSSA isolates exhibiting the InE belonged to diverse genetic backgrounds, including ST5, ST8, ST30 and ST45, which correlated with the prevalent methicillin-resistant S. aureus clones circulating in South America. Types A (66%) and C (31%) were the most prevalent β-lactamases.
Conclusions
Our results show a high prevalence of the cefazolin InE associated with type A β-lactamase in MSSA isolates from Colombia and Ecuador, suggesting that treatment of deep-seated infections with cefazolin in those countries may be compromised.
doi:10.1093/jac/dkt254
PMCID: PMC3820105  PMID: 23794599
inoculum effect; bloodstream infections; osteomyelitis
2.  In Vivo Effects of Cefazolin, Daptomycin, and Nafcillin in Experimental Endocarditis with a Methicillin-Susceptible Staphylococcus aureus Strain Showing an Inoculum Effect against Cefazolin 
Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P = 0.005; daptomycin versus nafcillin, P = 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log10 reduction of 1.4 versus 5.5, respectively; P = 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity.
doi:10.1128/AAC.00856-13
PMCID: PMC3754321  PMID: 23796934
3.  Is Cefazolin Inferior to Nafcillin for Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia?▿ 
Antimicrobial Agents and Chemotherapy  2011;55(11):5122-5126.
About 20% of methicillin-susceptible Staphylococcus aureus (MSSA) isolates have a substantial inoculum effect with cefazolin, suggesting that cefazolin treatment may be associated with clinical failure for serious MSSA infections. There are no well-matched controlled studies comparing cefazolin with nafcillin for the treatment of MSSA bacteremia. A retrospective propensity-score-matched case-control study was performed from 2004 to 2009 in a tertiary care hospital where nafcillin was unavailable from August 2004 to August 2006. The cefazolin group (n = 49) included MSSA-bacteremic patients treated with cefazolin during the period of nafcillin unavailability, while the nafcillin group (n = 84) comprised those treated with nafcillin. Treatment failure was defined as a composite outcome of a change of antibiotics due to clinical failure, relapse, and mortality. Of 133 patients, 41 patients from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment failure rates were not significantly different at 4 or 12 weeks (10% [4/41] versus 10% [4/41] at 4 weeks [P > 0.99] and 15% [6/41] versus 15% [6/41] at 12 weeks [P > 0.99]). Cefazolin treatment was interrupted less frequently than nafcillin treatment due to drug adverse events (0% versus 17%; P = 0.02). Cefazolin had clinical efficacy similar to that of nafcillin and was more tolerable than nafcillin for the treatment of MSSA bacteremia.
doi:10.1128/AAC.00485-11
PMCID: PMC3195033  PMID: 21825299
4.  Prevalence of blaZ Gene Types and the Inoculum Effect with Cefazolin among Bloodstream Isolates of Methicillin-Susceptible Staphylococcus aureus 
We sought to define the prevalence of blaZ gene types and the inoculum effect to cefazolin among methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections. The blaZ gene was present in 142/185 (77%) isolates. A total of 50 (27%) isolates had a ≥4-fold increase in the cefazolin MIC from a standard to a high inoculum, and 8 (4%) demonstrated a nonsusceptible cefazolin MIC, all type A blaZ strains. The efficacy of cefazolin in the presence of the inoculum effect requires further study.
doi:10.1128/AAC.00052-12
PMCID: PMC3421557  PMID: 22585225
5.  Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia 
BMC Infectious Diseases  2011;11:279.
Background
The high prevalence of methicillin-resistant S. aureus (MRSA) has led clinicians to select antibiotics that have coverage against MRSA, usually vancomycin, for empiric therapy for suspected staphylococcal infections. Clinicians often continue vancomycin started empirically even when methicillin-susceptible S. aureus (MSSA) strains are identified by culture. However, vancomycin has been associated with poor outcomes such as nephrotoxicity, persistent bacteremia and treatment failure. The objective of this study was to compare the effectiveness of vancomycin versus the beta-lactam antibiotics nafcillin and cefazolin among patients with MSSA bacteremia. The outcome of interest for this study was 30-day in-hospital mortality.
Methods
This retrospective cohort study included all adult in-patients admitted to a tertiary-care facility between January 1, 2003 and June 30, 2007 who had a positive blood culture for MSSA and received nafcillin, cefazolin or vancomycin. Cox proportional hazard models were used to assess independent mortality hazards comparing nafcillin or cefazolin versus vancomycin. Similar methods were used to estimate the survival benefits of switching from vancomycin to nafcillin or cefazolin versus leaving patients on vancomycin. Each model included statistical adjustment using propensity scores which contained variables associated with an increased propensity to receive vancomycin.
Results
267 patients were included; 14% (38/267) received nafcillin or cefazolin, 51% (135/267) received both vancomycin and either nafcillin or cefazolin, and 35% (94/267) received vancomycin. Thirty (11%) died within 30 days. Those receiving nafcillin or cefazolin had 79% lower mortality hazards compared with those who received vancomycin alone (adjusted hazard ratio (HR): 0.21; 95% confidence interval (CI): 0.09, 0.47). Among the 122 patients who initially received vancomycin empirically, those who were switched to nafcillin or cefazolin (66/122) had 69% lower mortality hazards (adjusted HR: 0.31; 95% CI: 0.10, 0.95) compared to those who remained on vancomycin.
Conclusions
Receipt of nafcillin or cefazolin was protective against mortality compared to vancomycin even when therapy was altered after culture results identified MSSA. Convenience of vancomycin dosing may not outweigh the potential benefits of nafcillin or cefazolin in the treatment of MSSA bacteremia.
doi:10.1186/1471-2334-11-279
PMCID: PMC3206863  PMID: 22011388
6.  beta-Lactamase-mediated inactivation and efficacy of cefazolin and cefmetazole in Staphylococcus aureus abscesses. 
12694668 Clinical reports and animal models have demonstrated that cefazolin may have decreased efficacy against some strains of Staphylococcus aureus because of type A beta-lactamase-mediated hydrolysis. We sought to measure biologically active cefazolin concentrations within abscesses with high concentrations of S. aureus and compare the concentrations with those of cefmetazole, a beta-lactamase-stable cephamycin. A type A beta-lactamase-producing strain of S. aureus with a demonstrated inoculum effect against cefazolin (MIC at an inoculum of 5 x 10(5) CFU/ml, 1.0 micrograms/ml; MIC at an inoculum of 5 x 10(7) CFU/ml, 32.0 micrograms/ml) but not cefmetazole (MICs at inocula of 5 x 10(5) and 5 x 10(7) CFU/ml, 2.0 micrograms/ml) was used. Cefazolin or cefmetazole (100 mg/kg of body weight every 8 h for 8 days) was administered to rabbits with infected tissue cages. No differences in the concentrations of the two drugs in the uninfected tissue cages were observed. Higher concentrations of cefmetazole than cefazolin were found in infected tissue cages at day 3 (5.9 +/- 0.7 versus 2.2 +/- 0.3 micrograms/ml; P < 0.01), day 5 (9.1 +/- 2.6 versus 3.6 +/- 0.7 micrograms/ml; P = 0.02), and day 8 (9.4 +/- 1.4 versus 4.8 +/- 0.9 micrograms/ml; P = 0.01) after infection. Cefazolin and cefmetazole were equally effective in reducing the bacterial concentration in the abscess. In vitro experiments demonstrated greater cefazolin than cefmetazole degradation by S. aureus, but the differences were greater in serum than in abscess fluid supernatants. We conclude that abscess cefazolin concentrations are diminished by type A beta-lactamase-producing S. aureus, but this did not affect drug efficacy in this model.
PMCID: PMC187639  PMID: 8452349
7.  Relative Inactivation by Staphylococcus aureus of Eight Cephalosporin Antibiotics 
These studies extend the recent observation that cefazolin is inactivated to a greater extent than cephaloridine by some strains of penicillinase-producing Staphylococcus aureus, whereas cephalothin undergoes little if any inactivation. In Mueller-Hinton broth (inoculum, 3 × 106) 100 recently isolated strains had minimal inhibitory concentrations (MICs) ≤ 2 μg/ml for cephalothin and cephaloridine, whereas in Trypticase soy broth (TSB) 50% had MICs > 2 μg/ml and 10% (designated “resistant” strains) were >8 μg/ml for cephaloridine but remained ≤2 μg/ml for cephalothin. A large inoculum (3 × 107) of strains with high MICs in TSB almost completely inactivated 50 μg of cefazolin per ml in 6 h, with progressively less inactivation, in the following order, of cephaloridine, cephalexin, cephradine, cephapirin, and cefamandole; cefoxitin and cephalothin underwent little if any inactivation. The greater inactivation in TSB than in Mueller-Hinton broth appeared to be due to a greater production of β-lactamases by each colony-forming unit, since the inoculum size in the two broths was not significantly different. In contrast, “susceptible” strains (MICs ≤ 2 μg/ml in both broths) inactivated cephaloridine more than cefazolin, and equal amounts of powdered bacterial extracts confirmed the fact that qualitatively different β-lactamases were produced by the susceptible and resistant strains. Disk diffusion tests were unreliable in separating the two groups of staphylococci. The clinical significance of inactivation by strains with high MICs is not known but, unless susceptibility can be clearly established, cephalothin appears preferable for severe staphylococcal infections, since it undergoes little if any inactivation by any strains of staphylococci.
PMCID: PMC429654  PMID: 938023
8.  Evaluation of Cefazolin, a New Cephalosporin Antibiotic 
Cefazolin sodium was tested in vitro against 308 isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus, and enterococcus. Broth and agar dilution and disk diffusion techniques were used with at least two sizes of inocula of organisms. Cefazolin was also studied in the treatment of 85 hospitalized patients with a variety of serious infections. In concentations of 5 μg or less/ml, cefazolin inhibited and killed more than 90% of isolates of Enterobacteriaceae with the exception of indole-positive Proteus and Enterobacter species. No isolate of P. aeruginosa and only a few of Enterobacter and enterococci were killed by 25 μg of cefazolin/ml, a concentration readily attainable in serum with a 500-mg dose given intramuscularly. Penicillin-susceptible as well as penicillin-resistant isolates of S. aureus were killed by 1 μg or less of cefazolin per ml; however, 25 μg/ml was required to kill 100% of the strains when the inoculum size was increased 100-fold. Cefazolin treatment appeared effective in 82 of 85 patients, including four with endocarditis. Pain was minimal after intramuscular injection, and thrombophlebitis was not observed in those treated intravenously. No patient developed a positive Coombs test, and no evidence of renal toxicity was apparent in clinical studies.
PMCID: PMC444440  PMID: 4790605
9.  Prospective Comparison of Cefoxitin and Cefazolin in Infections Caused by Aerobic Bacteria 
Intravenous cefazolin and cefoxitin were compared in a prospective randomized trial in infections where the suspected pathogen was expected to be susceptible to both antibiotics. In the cefazolin group (12 patients) the diagnosis was pneumonia in 4, including 2 with pneumococcal bacteremia, soft tissue infection in 5, Staphylococcus aureus bacteremia in 1, acute pyelonephritis in 1, and disseminated gonococcal infection in 1. In the cefoxitin group (10 patients) the diagnosis was pneumonia in 4, including 2 with pneumococcal bacteremia, soft tissue infection in 4, acute pyelonephritis in 1, and disseminated gonococcal infection in 1. In the cefazolin group receiving an evaluable course of therapy, a good clinical response was seen in 10 of 11 patients, and a bacteriological response was seen in 5 of 7. Cefazolin failed to eradicate S. aureus bacteremia in 1 patient and S. aureus in a skin ulcer of another patient. All 10 cefoxitin patients had good clinical and bacteriological responses, but in 1 patient S. aureus colonization of a postoperative wound recurred after discontinuation of the drug. Side effects in both groups included skin rash, phlebitis, and elevation of the serum alkaline phosphatase. Both cefoxitin and cefazolin appeared effective in infections caused by susceptible aerobic pathogens with the possible exception of S. aureus, although all 11 strains of S. aureus isolated in this study were susceptible in vitro to both antibiotics. Cefoxitin appeared to be equivalent to cefazolin in efficacy and occurrence of side effects.
PMCID: PMC352223  PMID: 348096
10.  In Vivo Activity of Ceftobiprole in Murine Skin Infections Due to Staphylococcus aureus and Pseudomonas aeruginosa▿  
Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (methicillin-susceptible S. aureus [MSSA]), S. aureus OC 8525 (MRSA), Pseudomonas aeruginosa OC 4351 (having an inducible AmpC β-lactamase), and P. aeruginosa OC 4354 (overproducing AmpC β-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC β-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.
doi:10.1128/AAC.00642-09
PMCID: PMC2798551  PMID: 19884364
11.  In Vitro Synergistic Effects of Double and Triple Combinations of β-Lactams, Vancomycin, and Netilmicin against Methicillin-Resistant Staphylococcus aureus Strains 
Antimicrobial Agents and Chemotherapy  2000;44(11):3055-3060.
Several studies have previously reported synergistic effects between vancomycin and a given β-lactam or a given aminoglycoside against methicillin-resistant Staphylococcus aureus (MRSA) strains. The aim of our study was to exhaustively compare the effects of different combinations of a β-lactam, vancomycin, and/or an aminoglycoside against 32 clinical MRSA strains with different aminoglycoside susceptibility patterns. The effects of 26 different β-lactam–vancomycin and 8 different aminoglycoside-vancomycin combinations were first studied using a disk diffusion screening method. The best interactions with vancomycin were observed with either imipenem, cefazolin, or netilmicin. By checkerboard studies, imipenem-vancomycin and cefazolin-vancomycin each provided a synergistic bacteriostatic effect against 22 strains; the mean fractional inhibitory concentration (FIC) indexes were 0.35 and 0.46 for imipenem-vancomycin and cefazolin-vancomycin, respectively. The vancomycin-netilmicin combination provided an indifferent effect against all of the 32 strains tested; the mean of FIC index was 1.096. The mean concentrations of imipenem, cefazolin, netilmicin, and vancomycin at which FIC indexes were calculated were clinically achievable. Killing experiments were then performed using imipenem, cefazolin, netilmicin, and vancomycin at one-half of the MIC, alone and in different combinations, against 10 strains. The vancomycin-netilmicin regimen was rarely bactericidal, even against strains susceptible to netilmicin. The imipenem-vancomycin and cefazolin-vancomycin combinations were strongly bactericidal against six and five strains, respectively. The addition of netilmicin markedly enhanced the killing activity of the combination of cefazolin or imipenem plus vancomycin, but only for the MRSA strains against which the β-lactam–vancomycin combinations had no bactericidal effect. It is noteworthy that the latter strains were both susceptible to netilmicin and heterogeneously resistant to methicillin.
PMCID: PMC101602  PMID: 11036022
12.  Antimicrobial-Resistant Pathogens in Intensive Care Units in Canada: Results of the Canadian National Intensive Care Unit (CAN-ICU) Study, 2005-2006▿  
Between 1 September 2005 and 30 June 2006, 19 medical centers collected 4,180 isolates recovered from clinical specimens from patients in intensive care units (ICUs) in Canada. The 4,180 isolates were collected from 2,292 respiratory specimens (54.8%), 738 blood specimens (17.7%), 581 wound/tissue specimens (13.9%), and 569 urinary specimens (13.6%). The 10 most common organisms isolated from 79.5% of all clinical specimens were methicillin-susceptible Staphylococcus aureus (MSSA) (16.4%), Escherichia coli (12.8%), Pseudomonas aeruginosa (10.0%), Haemophilus influenzae (7.9%), coagulase-negative staphylococci/Staphylococcus epidermidis (6.5%), Enterococcus spp. (6.1%), Streptococcus pneumoniae (5.8%), Klebsiella pneumoniae (5.8%), methicillin-resistant Staphylococcus aureus (MRSA) (4.7%), and Enterobacter cloacae (3.9%). MRSA made up 22.3% (197/884) of all S. aureus isolates (90.9% of MRSA were health care-associated MRSA, and 9.1% were community-associated MRSA), while vancomycin-resistant enterococci (VRE) made up 6.7% (11/255) of all enterococcal isolates (88.2% of VRE had the vanA genotype). Extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae occurred in 3.5% (19/536) and 1.8% (4/224) of isolates, respectively. All 19 ESBL-producing E. coli isolates were PCR positive for CTX-M, with blaCTX-M-15 occurring in 74% (14/19) of isolates. For MRSA, no resistance against daptomycin, linezolid, tigecycline, and vancomycin was observed, while the resistance rates to other agents were as follows: clarithromycin, 89.9%; clindamycin, 76.1%; fluoroquinolones, 90.1 to 91.8%; and trimethoprim-sulfamethoxazole, 11.7%. For E. coli, no resistance to amikacin, meropenem, and tigecycline was observed, while resistance rates to other agents were as follows: cefazolin, 20.1%; cefepime, 0.7%; ceftriaxone, 3.7%; gentamicin, 3.0%; fluoroquinolones, 21.1%; piperacillin-tazobactam, 1.9%; and trimethoprim-sulfamethoxazole, 24.8%. Resistance rates for P. aeruginosa were as follows: amikacin, 2.6%; cefepime, 10.2%; gentamicin, 15.2%; fluoroquinolones, 23.8 to 25.5%; meropenem, 13.6%; and piperacillin-tazobactam, 9.3%. A multidrug-resistant (MDR) phenotype (resistance to three or more of the following drugs: cefepime, piperacillin-tazobactam, meropenem, amikacin or gentamicin, and ciprofloxacin) occurred frequently in P. aeruginosa (12.6%) but uncommonly in E. coli (0.2%), E. cloacae (0.6%), or K. pneumoniae (0%). In conclusion, S. aureus (MSSA and MRSA), E. coli, P. aeruginosa, H. influenzae, Enterococcus spp., S. pneumoniae, and K. pneumoniae are the most common isolates recovered from clinical specimens in Canadian ICUs. A MDR phenotype is common for P. aeruginosa isolates in Canadian ICUs.
doi:10.1128/AAC.01538-07
PMCID: PMC2292546  PMID: 18285482
13.  Staphylococcus aureus nasal carriage and patterns of antibiotic resistance in bacterial isolates from patients and staff in a dialysis center of southeast Iran 
Background and Objectives
Staphylococcus aureus is an important infection in hemodialysis patients. We studied the prevalence of nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) and its antibiotic resistance pattern in patients receiving hemodialysis as well as in dialysis unit staff.
Materials and Methods
From June to September 2012, we evaluated 74 cases including 61 patients on hemodialysis and 13 dialysis unit staff. Nasal swabs were taken from all cases and were cultured on a blood medium agar. We identified S. aureus based on conventional laboratory methods. For antimicrobial resistance patterns, we used disk diffusion method. Oxacillin MIC, oxacillin and cefoxcitin disk diffusion methods were used for detection of MRSA. Disk approximation test (D-test) was applied for the frequency of erythromycin induced clindamycin resistance.
Results
S. aureus carrier state was determined in 12 of the 61 patients on hemodialysis (19.67%) and 5 of the 13 dialysis unit staffs (38.46%). In hemodialyzed patients, MRSA and MSSA carrier of S. aureus were 6.56% and 13.11%, respectively. All nasal carriage states in studied staffs were MSSA. All isolated S. aureus were found to be sensitive to vancomycin, teicoplanin, and rifampin. However, reduced sensitivity of MRSA isolates to other antibiotics was noted. Resistance frequencies to tested antibiotic was as follows: cefteriaxone and penicillin (100%), tetracycline and doxycilin (75%), gentamicin, cloxacillin, and cefazolin (50%), ciprofloxacin, trimethoprim-sulfamethoxazol, erythromycin, and clindamycin (25%). The resistance rate of isolated MSSA against tested antibiotics was lower than isolated MRSA. Inducible clindamycin resistance was shown in 25% of identified MRSA strains.
Conclusion
S. aureus nasal carrier state was lower than former reports from other parts of Iran. The antibiotic resistance patterns also differed, perhaps due to different pattern of administering antibiotics at our hospital. Screening of these patients should be noted as a health priority and microbial sensitivity tests should be considered in order to optimize treatment options.
PMCID: PMC4281664
Nasal carriers; MRSA; Staphylococcus aureus; Hemodialyzed patients; Iran
14.  Fusidic Acid Resistance Determinants in Staphylococcus aureus Clinical Isolates▿ †  
Antimicrobial Agents and Chemotherapy  2010;54(12):4985-4991.
A total of 71 fusidic acid-resistant Staphylococcus aureus (45 methicillin-resistant and 26 methicillin-susceptible) isolates were examined for the presence of resistance determinants. Among 45 fusidic acid-resistant methicillin-resistant S. aureus (MRSA), isolates, 38 (84%) had fusA mutations conferring high-level resistance to fusidic acid (the MIC was ≥128 μg/ml for 22/38), none had fusB, and 7 (16%) had fusC. For 26 fusidic acid-resistant methicillin-susceptible S. aureus (MSSA), only 3 possessed fusA mutations, but 15 (58%) had fusB and 8 (31%) had fusC. Low-level resistance to fusidic acid (MICs ≤ 32 μg/ml) was found in most fusB- or fusC-positive isolates. For 41 isolates (38 MRSA and 3 MSSA), with fusA mutations, a total of 21 amino acid substitutions in EF-G (fusA gene) were detected, of which R76C, E444K, E444V, C473S, P478S, and M651I were identified for the first time. The nucleotide sequencing of fusB and flanking regions in an MSSA isolate revealed the structure of partial IS257-aj1-LP-fusB-aj2-aj3-IS257-partial blaZ, which is identical to the corresponding region in pUB101, and the rest of fusB-carrying MSSA isolates also show similar structures. On the basis of spa and staphylococcal cassette chromosome mec element (SCCmec) typing, two major genotypes, spa type t037-SCCmec type III (t037-III; 28/45; 62%) and t002-II (13/45; 29%), were predominant among 45 MRSA isolates. By pulsed-field gel electrophoresis analysis, 45 MRSA isolates were divided into 12 clusters, while 26 MSSA isolates were divided into 15 clusters. Taken together, the distribution of fusidic acid resistance determinants (fusA mutations, fusB, and fusC) was quite different between MRSA and MSSA groups.
doi:10.1128/AAC.00523-10
PMCID: PMC2981276  PMID: 20855746
15.  Laboratory Evaluation of FR10024, a New Cephalosporin Derivative 
FR10024 is a broad-spectrum antibiotic. The in vitro antibacterial activity of FR10024 against clinical isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis is greater than that of any of the cephalosporins developed to date. Indole-positive Proteus, Enterobacter, and Citrobacter are resistant to FR10024, as is true for the other cephalosporins. However, more than half of the strains of Enterobacter and Citrobacter tested were susceptible to FR10024 at an inoculum of 106 cells/ml. A single subcutaneous injection of FR10024 to mice with peritoneal infections due to S. aureus and several species of gram-negative bacilli gave a protective effect inferior to that of cefazolin but appeared to be superior to that of cephalothin. When given in two divided doses, however, the protective effect of FR10024 was enhanced and almost equaled that of cefazolin. The serum levels and rates of urinary recovery of FR10024 varied in different animal species. The mean peak serum level of FR10024 in humans after a single intramuscular injection of 500 mg was two times higher than that of cephalothin. The serum half-life after intramuscular injections of 250 and 500 mg was slightly shorter than that of cephalothin. After receiving 250 mg of FR10024 intramuscularly the urinary recovery rate was 87.7% in healthy volunteers. The biliary excretion rate of FR10024 was particularly high. The 24-h excretion of FR10024 in rats was 63.3%, this being six to seven times higher than that for cefazolin, which has the highest biliary excretion of the other known cephalosporins. When FR10024 was injected intramuscularly (20 mg/kg), it was found that the hepatic levels of FR10024 in rats were the highest of all the cephalosporins, including cefazolin, but the levels of FR10024 in other tissues were not as high as those of cefazolin.
PMCID: PMC351918  PMID: 836014
16.  Evidence for a purifying selection acting on the β-lactamase locus in epidemic clones of methicillin-resistant Staphylococcus aureus 
BMC Microbiology  2011;11:76.
Background
The β-lactamase (bla) locus, which confers resistance to penicillins only, may control the transcription of mecA, the central element of methicillin resistance, which is embedded in a polymorphic heterelogous chromosomal cassette (the SCCmec element). In order to assess the eventual correlation between bla allotypes and genetic lineages, SCCmec types and/or β-lactam resistance phenotypes, the allelic variation on the bla locus was evaluated in a representative collection of 54 international epidemic methicillin-resistant Staphylococcus aureus (MRSA) clinical strains and, for comparative purposes, also in 24 diverse methicillin-susceptible S. aureus (MSSA) strains.
Results
Internal fragments of blaZ (the β-lactamase structural gene) were sequenced for all strains. A subset of strains, representative of blaZ allotypes, was further characterized by sequencing of internal fragments of the blaZ transcriptional regulators, blaI and blaR1. Thirteen allotypes for blaZ, nine for blaI and 12 for blaR1 were found. In a total of 121 unique single-nucleotide polymorphisms (SNP) detected, no frameshift mutations were identified and only one nonsense mutation within blaZ was found in a MRSA strain. On average, blaZ alleles were more polymorphic among MSSA than in MRSA (14.7 vs 11.4 SNP/allele). Overall, blaR1 was the most polymorphic gene with an average of 24.8 SNP/allele. No correlation could be established between bla allotypes and genetic lineages, SCCmec types and/or β-lactam resistance phenotypes. In order to estimate the selection pressure acting on the bla locus, the average dN/dS values were computed. In the three genes and in both collections dN/dS ratios were significantly below 1.
Conclusions
The data strongly suggests the existence of a purifying selection to maintain the bla locus fully functional even on MRSA strains. Although, this is in agreement with the notion that in most clinical MRSA strains mecA gene is under the control of the bla regulatory genes, these findings also suggest that the apparently redundant function of blaZ gene for the MRSA resistant phenotype is still important for these strains. In addition, the data shows that the sensor-inducer blaR1 is the primary target for the accumulation of mutations in the bla locus, presumably to modulate the response to the presence of β-lactam antibiotic.
doi:10.1186/1471-2180-11-76
PMCID: PMC3102608  PMID: 21496235
β-lactamase; β-lactam resistance; allelic variation; MSSA; MRSA; mecA stabilization
17.  Methicillin-Susceptible Staphylococcus aureus as a Predominantly Healthcare-Associated Pathogen: A Possible Reversal of Roles? 
PLoS ONE  2011;6(4):e18217.
Background
Methicillin-resistant Staphylococcus aureus (MRSA) strains have become common causes of skin and soft tissue infections (SSTI) among previously healthy people, a role of methicillin-susceptible (MSSA) isolates before the mid-1990s. We hypothesized that, as MRSA infections became more common among S. aureus infections in the community, perhaps MSSA infections had become more important as a cause of healthcare-associated infection.
Methods
We compared patients, including children and adults, with MRSA and MSSA infections at the University of Chicago Medical Center (UCMC) from all clinical units from July 1, 2004-June 30, 2005; we also compared the genotypes of the MRSA and MSSA infecting bacterial strains.
Results
Compared with MRSA patients, MSSA patients were more likely on bivariate analysis to have bacteremia, endocarditis, or sepsis (p = 0.03), to be an adult (p = 0.005), to be in the intensive care unit (21.9% vs. 15.6%) or another inpatient unit (45.6% vs. 40.7%) at the time of culture. MRSA (346/545) and MSSA (76/114) patients did not differ significantly in the proportion classified as HA-S. aureus by the CDC CA-MRSA definition (p = 0.5). The genetic backgrounds of MRSA and MSSA multilocus sequence type (ST) 1, ST5, ST8, ST30, and ST59 comprised in combination 94.5% of MRSA isolates and 50.9% of MSSA isolates. By logistic regression, being cared for in the Emergency Department (OR 4.6, CI 1.5-14.0, p = 0.008) was associated with MRSA infection.
Conclusion
Patients with MSSA at UCMC have characteristics consistent with a health-care-associated infection more often than do patients with MRSA; a possible role reversal has occurred for MSSA and MRSA strains. Clinical MSSA and MRSA strains shared genotype backgrounds.
doi:10.1371/journal.pone.0018217
PMCID: PMC3076382  PMID: 21533238
18.  Population Pharmacokinetics of Cefazolin in Serum and Tissue for Patients with Complicated Skin and Soft Tissue Infections (cSSTI) 
Infectious Diseases and Therapy  2014;3(2):269-279.
Introduction
Cefazolin is commonly used to treat complicated skin and soft tissue infections (cSSTI) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacteriaceae. We aimed to determine the variability of cefazolin exposure in interstitial fluid (ISF) of tissue and evaluate its dosing recommendations.
Methods
Population pharmacokinetics were performed to co-model serum and ISF concentration data from six patients enrolled in a previous in vivo microdialysis study. A 5,000 patient Monte Carlo simulation was then conducted for 1 and 2 g every 8 h (q8h) regimens to calculate the penetration ratio and probability of target attainment (PTA) at 30% and 50% of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT > MIC) in ISF of tissue.
Results
A three-compartment model, with one of the compartments representing ISF concentrations, fits the data best. The final model resulted in the mean ± SD parameter values: Clearance = 3.8 ± 2.1 L/h, volume of distribution in central compartment = 8.6 ± 6.4 L and volume of distribution in ISF = 36.6 ± 17.9 L. The mean ± SD and median penetration ratios were 1.36 ± 4.57 and 0.80, respectively. At the MIC90 for MSSA of 1 mg/L, PTAs for the 1 g q8h dose in ISF were 96% and 91% for 30% and 50% fT > MIC targets, respectively, which decreased to 87% and 71% at 2 mg/L. For the same respective targets, a 2 g q8h dosing regimen increased PTA to 96% and 91% at 2 mg/L.
Conclusion
Cefazolin penetration into the ISF of a lower limb infection varied across this simulated patient population. Based on these data, a 1 g q8h regimen should be sufficient to obtain 30% fT > MIC exposure against most MSSA causing cSSTI. However, a 2 g q8h dose is required to obtain 50% fT > MIC pharmacodynamic targets at the current breakpoint for Enterobacteriaceae (2 mg/L).
Electronic supplementary material
The online version of this article (doi:10.1007/s40121-014-0049-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s40121-014-0049-3
PMCID: PMC4269627  PMID: 25410773
Cefazolin; cSSTI; Diabetic wound; Microdialysis; Tissue pharmacokinetics
19.  Determination of an Inoculum Effect with Various Cephalosporins among Clinical Isolates of Methicillin-Susceptible Staphylococcus aureus▿  
Using 98 clinical methicillin-susceptible Staphylococcus aureus isolates of known β-lactamase (Bla) type, we found a pronounced inoculum effect for cephalexin (mostly Bla type A and C strains), a mild inoculum effect for cephalothin (especially types B and C), and no inoculum effects for ceftriaxone and cefuroxime. Ceftobiprole showed the lowest MICs at a high inoculum but with a slight increase for Bla-positive versus Bla-negative strains. Since a potential therapeutic effect associated with a cephalosporin inoculum effect has been described, further studies are warranted.
doi:10.1128/AAC.01325-09
PMCID: PMC2863656  PMID: 20211890
20.  Activities of Ceftobiprole and Other Cephalosporins against Extracellular and Intracellular (THP-1 Macrophages and Keratinocytes) Forms of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus▿ †  
Staphylococcus aureus is an opportunistic intracellular organism. Although they poorly accumulate in eukaryotic cells, β-lactams show activity against intracellular methicillin (meticillin)-susceptible S. aureus (MSSA) if the exposure times and the drug concentrations are sufficient. Intraphagocytic methicillin-resistant S. aureus (MRSA) strains are susceptible to penicillins and carbapenems because the acidic pH favors the acylation of PBP 2a by these β-lactams through pH-induced conformational changes. The intracellular activity (THP-1 macrophages and keratinocytes) of ceftobiprole, which shows almost similar in vitro activities against MRSA and MSSA in broth, was examined against a panel of hospital-acquired and community-acquired MRSA strains (MICs, 0.5 to 2.0 mg/liter at pH 7.4 and 0.25 to 1.0 mg/liter at pH 5.5) and was compared with its activity against MSSA isolates. The key pharmacological descriptors {relative maximal efficacy (Emax), relative potency (the concentration causing a reduction of the inoculum halfway between E0 and Emax [EC50]), and static concentration (Cs)} were measured. All strains showed sigmoidal dose-responses, with Emax being about a 1 log10 CFU decrease from the postphagocytosis inoculum, and EC50 and Cs being 0.2 to 0.3× and 0.6 to 0.9× the MIC, respectively. Ceftobiprole effectively competed with Bocillin FL (a fluorescent derivative of penicillin V) for binding to PBP 2a at both pH 5.5 and pH 7.4. In contrast, cephalexin, cefuroxime, cefoxitin, or ceftriaxone (i) were less potent in PBP 2a competitive binding assays, (ii) showed only partial restoration of the activity against MRSA in broth at acidic pH, and (iii) were collectively less effective against MRSA in THP-1 macrophages and were ineffective in keratinocytes. The improved activity of ceftobiprole toward intracellular MRSA compared with the activities of conventional cephalosporins can be explained, at least in part, by its greater ability to bind to PBP 2a not only at neutral but also at acidic pH.
doi:10.1128/AAC.01135-08
PMCID: PMC2687181  PMID: 19289525
21.  Association of Borderline Oxacillin-Susceptible Strains of Staphylococcus aureus with Surgical Wound Infections 
Journal of Clinical Microbiology  1998;36(1):219-222.
Staphylococcus aureus isolates which produce type A staphylococcal β-lactamase have been associated with wound infections complicating the use of cefazolin prophylaxis in surgery. To further evaluate this finding, 215 wound isolates from 14 cities in the United States were characterized by antimicrobial susceptibility and β-lactamase type and correlated with the preoperative prophylactic regimen. Borderline-susceptible S. aureus isolates of phage group 5 (BSSA-5), which produce large amounts of type A β-lactamase and exhibit borderline susceptibility to oxacillin, comprised a greater percentage of the 120 wound isolates associated with cefazolin prophylaxis than they did of the 95 isolates associated with other prophylactic regimens (25% versus 12.6%, respectively; P < 0.05). In contrast, methicillin-resistant S. aureus isolates were distributed evenly between the two groups (8.3% versus 11.6%, respectively). In vitro assays demonstrated that cefazolin was hydrolyzed faster by BSSA-5 strains than by other β-lactamase-producing, methicillin-susceptible strains (1.54 versus 0.50 μg/min/108 CFU, respectively; P < 0.0001). These data demonstrate that BSSA-5 strains are a distinct subpopulation of methicillin-susceptible S. aureus which frequently cause deep surgical wound infections. Cefazolin use in prophylaxis is a risk factor for BSSA-5 infection.
PMCID: PMC124838  PMID: 9431951
22.  Increased Killing of Staphylococci and Streptococci by Daptomycin Compared with Cefazolin and Vancomycin in an In Vitro Peritoneal Dialysate Model 
Antimicrobial Agents and Chemotherapy  2003;47(12):3764-3767.
Peritoneal dialysate fluid (PDF) is a bacteriostatic medium that compromises the antibacterial activity of cell wall-active agents. By use of an in vitro static model, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), and Streptococcus sanguis were exposed to daptomycin at concentrations of 10, 30, and 100 mg/liter, cefazolin at 125 mg/liter, and vancomycin at 25 mg/liter in cation-adjusted Mueller-Hinton Broth or Todd Hewitt Broth (for S. sanguis) and PDF at pHs of 5.5 and 7.4. The pH had no effect on antibacterial activity. Neither cefazolin nor vancomycin produced a bactericidal or a bacteriostatic effect versus MRSA, MSSA, MSSE, or S. sanguis in PDF, while all concentrations of daptomycin were bactericidal against all organisms in PDF. Daptomycin did not exhibit concentration-dependent activity in PDF. Daptomycin appears to be a promising agent for use in peritoneal dialysis-associated peritonitis, producing bacterial kill to a greater extent and at a higher rate than cefazolin or vancomycin in PDF.
doi:10.1128/AAC.47.12.3764-3767.2003
PMCID: PMC296225  PMID: 14638479
23.  In Vitro Comparison of Combination- and Mono-therapy for the Empiric and Optimal Coverage of Bacterial Keratitis Based on Incidence of Infection 
Cornea  2013;32(6):830-834.
Purpose
Cefazolin/tobramycin, Cefuroxime/gentamicin, and moxifloxacin were compared using bacterial keratitis isolates to determine whether empiric therapy constituted optimal anti-bacterial treatment.
Methods
Based on percent incidence of corneal infection, 27 Staphylococcus aureus, 16 Pseudomonas aeruginosa, 10 Serratia marcescens, 4 Moraxella lacunata, 3 Haemophilus influenzae, 9 coagulase-negative Staphylococci, 7 Streptococcus viridans, 6 Streptococcus pneumoniae, 7 assorted Gram-positive isolates, and 11 assorted Gram-negative isolates were tested for MICs to cefazolin, tobramycin, cefuroxime, gentamicin, and moxifloxacin using E-tests to determine susceptibility and potency.
Results
The in vitro coverage (susceptible to at least one antibiotic) of cefuroxime/gentamicin (97%) was statistically equal to cefazolin/tobramycin (93%) and moxifloxacin (92%) (p=0.29). Double coverage (susceptible to both antibiotics) was equivalent (p=0.77) for cefuroxime/ gentamicin (42%) and cefazolin/tobramycin (40%). The susceptibilities of individual coverage were moxifloxacin (92%), gentamicin (89%), tobramycin (74%), cefazolin (58%), and cefuroxime (52%). Methicillin-resistant Staphylococcus aureus was best covered by gentamicin 100% (9 of 9). Tobramycin was more potent (p=0.00001) than gentamicin for Pseudomonas aeruginosa, while cefazolin was more potent (p=0.0004) than cefuroxime for Staphylococcus aureus.
Conclusions
Although there appears to be no in vitro empiric coverage advantage between cefazolin/tobramycin, cefuroxime/gentamicin, and moxifloxacin monotherapy, potency differences may occur, and optimal treatment can best be determined with laboratory studies.
doi:10.1097/ICO.0b013e318268d6f4
PMCID: PMC3568252  PMID: 23132444
keratitis; antibiotics; empiric topical therapy
24.  In Vitro Activity and Pharmacokinetics in Patients of Cefamandole, a New Cephalosporin Antibiotic 
Cefamandole nafate, a new cephalosporin for parenteral use, was evaluated in vitro against 231 recent clinical isolates and in 12 patients. Cefamandole had activity equivalent to cefazolin against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. Cefamandole was more active than cephalothin or cefazolin against Proteus mirabilis. Both cefamandole and cefazolin were as active as cephalothin against S. aureus, were slightly more active against K. pneumoniae, and were considerably more active against E. coli. All strains of indole-positive Proteus sp. were inhibited by 6.3 μg of cefamandole per ml but only 20% were inhibited by 25 μg of cefazolin or cephalothin per ml. Eighty-eight percent of Enterobacter sp. was inhibited by 25 μg of cefamandole per ml, but only 20 and 5% were inhibited by the same concentration of cefazolin and cephalothin, respectively. Peak levels of cefamandole ranged from 6.0 to 110 μg/ml in serum and levels ranged from 440 to 16,800 μg/ml in a 4- to 6-h collection of urine after a 500-mg or 1-g intramuscular dose (6.1 to 17.3 mg/kg) in patients with endogenous creatinine clearances of ≥31 ml/min. These levels were done after the first dose, at mid-therapy, and at the end of therapy. There was no evidence of accumulation with the 500-mg or 1-g dose given every 4 to 6 h. The percentage of the dose excreted in the urine within the first 4 to 6 h after administration of cefamandole was ≥43%. The half-life of cefamandole in serum was 49 to 126 min.
PMCID: PMC429447  PMID: 1211920
25.  Epidemiology and Outcomes of Community-Associated Methicillin-Resistant Staphylococcus aureus Infection▿  
Journal of Clinical Microbiology  2007;45(6):1705-1711.
Over a 2-year period (2003 to 2005) patients with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and community-acquired methicillin-susceptible Staphylococcus aureus (CA-MSSA) infections were prospectively identified. Patients infected with CA-MRSA (n = 102 patients) and CA-MSSA (n = 102 patients) had median ages of 46 and 53 years, respectively; the most common sites of infection in the two groups were skin/soft tissue (80 and 93%, respectively), respiratory tract (13 and 6%, respectively), and blood (4 and 1%, respectively). Fourteen percent of patients with CA-MRSA infections and 3% of patients with CA-MSSA infections had household contacts with similar infections (P < 0.01). Among the CA-MRSA isolates, the pulsed-field gel electrophoresis (PFGE) groups detected were USA300 (49%) and USA100 (13%), with 27 PFGE groups overall; 71% of the isolates were staphylococcal chromosome cassette mec (SCCmec) type IV, 29% were SCCmec type II, and 54% had the Panton-Valentine leucocidin (PVL) gene. Among the CA-MSSA isolates there were 33 PFGE groups, with isolates of the USA200 group comprising 11%, isolates of the USA600 group comprising 11%, isolates of the USA100 group comprising 10%, and isolates of the PVL type comprising 10%. Forty-six and 18% of the patients infected with CA-MRSA and CA-MSSA, respectively, were hospitalized (P < 0.001). Fifty percent of the patients received antibiotic therapy alone, 5% received surgery alone, 30% received antibiotics and surgery, 3% received other therapy, and 12% received no treatment. The median durations of antibiotic therapy were 12 and 10 days in the CA-MRSA- and CA-MSSA-infected patients, respectively; 48 and 56% of the patients in the two groups received adequate antimicrobial therapy, respectively (P < 0.001). The clinical success rates of the initial therapy in the two groups were 61 and 84%, respectively (P < 0.001); recurrences were more common in the CA-MRSA group (recurrences were detected in 18 and 6% of the patients in the two groups, respectively [P < 0.001]). CA-MRSA was an independent predictor of clinical failure in multivariate analysis (odds ratio, 3.4; 95% confidence interval, 1.7 to 6.9). In the community setting, the molecular characteristics of the S. aureus strains were heterogeneous. CA-MRSA infections were associated with a more adverse impact on outcome than CA-MSSA infections.
doi:10.1128/JCM.02311-06
PMCID: PMC1933099  PMID: 17392441

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