Abstract
Objectives
The purpose of this study is to compare the antimicrobial activity of linezolid and tigecycline with other commonly used antibiotics against a variety of clinical isolates at Royal Hospital, Muscat.
Methods
Clinically-significant bacterial isolates in Royal hospital during the period from 1st of March to 30th of June 2007 were collected, stored and finally tested to determine their susceptibility to different antibiotics by broth microdilution (microscan panels).
Results
Two hundred ten bacterial strains were collected and tested including Staphylococcus aureus (29), Group B ß-haemolytic Streptococcus (10), Streptococcus pneumoniae (15), Enterococcus spp. (16), Haemophilus spp. (15), Escherichia coli (26), Klebsiella spp. (26), Enterobacter spp. (25), Serratia spp. (10), Acinetobacter baumannii (17) and Pseudomonas aeruginosa (21). All strains except P. aeuginosa were susceptible to tigecycline. All gram-positive strains were susceptible to linezolid. Meropenem and piperacillin-tazobactam showed good activity against most organisms tested including P. aeruginosa and Acinetobacter baumannii. Levofloxacin showed 100% activity against K. pneumoniae and 61% activity against E. coli. The activity of 3rd generation cephalosporins against E.coli and K.pneumoniae ranged from 76% to 100%.
Conclusion
Tigecycline and linezolid showed excellent activity against microorganisms in their relevant spectrum of activity. However, they should be used wisely and judiciously.
Introduction
Microorganisms have virtually unlimited capacity to develop resistance to all antimicrobial agents. Hospitals provide the ideal environment for the evolution and dissemination of antibiotic resistant bacteria as a result of selective pressure caused by antibiotic overuse and spread of resistant bacteria.1 In our hospitals and particularly intensive care units, there is a steady increase in multi-resistant bacteria.2,3 This ever developing antimicrobial resistance among hospital as well as community bacterial strains presents a serious therapeutic problem.4 Therefore development of novel antimicrobial agents effective against such multi-resistant bacteria has been sought. Several novel antimicrobial agents such as oxazolidinones and glycylcyclines have been developed and introduced to clinical practice.
The purpose of this study was to test and compare the antimicrobial activity of the newly introduced linezolid and tigecycline with other commonly used antibiotics against a wide variety of clinical isolates from patients in the Royal Hospital, Muscat.
Bacterial strains
Clinically significant bacterial strains isolated from different body sites during the period 1st March to 30th June 2007 were collected. They were then stored in trypticase soya broth with glycerol at -80o C until tested. Duplicate microorganisms were excluded from the study.
Isolation and identification of microorganisms
Clinical specimens were inoculated onto blood agar, chocolate agar and MacConkey agar and incubated at 37o C for 24 hours. Significant isolates were then picked and identified according to standard microbiological procedures,5 and further identified to the species level by Phoenix system (Becton Dickenson).
Antibiotic Susciptibility Testing
Antibiotic susceptibility testing was performed by broth microdilution using MicroScan (Siemens) either Gram-positive or Gram-negative panel. Gram-positive panel consisted of penicillin (0.06-8µg/ml), ampicillin (0.06-16µg/ml), augmentin (0.03-8µg/ml), Piperacillin-tazobactam (0.25-16µg/ml), cefotaxime (0.03-64µg/ml), levofloxacin (0.06-32µg/ml), linezolid (0.5-8µg/ml), minocycline (0.25-8µg/ml), vancomycin (0.12-32µg/ml), tigecycline (0.008-16µg/ml) and meropenem (0.12-16µg/ml). Gram-negative panel consisted of ampicillin (0.0.5-32µg/ml), augmentin (0.12-32µg/ml), piperacillin/tazobactam (0.06-128µg/ml), cefotaxime (0.06-64µg/ml), cefepime (0.5-32µg/ml), ceftazidime (8-32µg/ml), levofloxacin (0.008-8µg/ml), amikacin (0.5-64µg/ml), minocycline (0.5-16µg/ml), tigecycline (0.008-16µg/ml) and meropenem (0.06-16µg/ml). Using an inoculum loop, 5-10 morphologically similar colonies were picked from the agar plate and emulsified in 3 ml of inoculum water. The final turbidity was adjusted to 0.5 McFarland Standard. 0.1 (100 µg) of the standardized suspension were added to 25 ml of broth. H. influenzae strains were inoculated into Haemophilus test medium broth, while S. pneumoniae and S. agalctiae were inoculated into Mueller-Hinton broth with 5% lysed horse blood. The remaining microorganisms were inoculated into cation adjusted Mueller-Hinton broth. Rehydration and inoculation were performed using the Renok system for MicroScan panels (Siemens). The following control bacterial strains were also tested: E. coli ATCC25922, P. aeruginosa ATCC27853, S. aureus ATCC29213, E. faecalis ATCC29212, S. pneumoniae ATCC49619 and H. influenzae ATCC49766. The panels were then incubated at 35oC without CO2 for 20-24 hours. The panels were read manually using the microdilution viewer. Minimum inhibitory concentration (MIC) for each antibiotic was recorded as the lowest antibiotic concentration showing inhibition of growth. CLSI criteria were used to interpret MIC values except for tigecycline where FDA susceptible breakpoint of ≤ 0.5mg/L was used.
Results
Bacterial strains
Bacterial strains isolated from different clinical specimens are shown in Table 1. A total of Two hundred and ten bacterial strains were collected including Staphylococcus aureus (29), Group B ß-haemolytic Streptococcus (10), Streptococcus pneumoniae (15), Enterococcus spp. (16), Haemophilus species (15), Escherichia coli (26), Klebsiella spp. (26), Enterobacter species. (25), Serratia species. (10), Acinetobacter baumannii (17) and Pseudomonas aeruginosa (21).
Table 1. Counts of bacterial isolates by clinical specimen.
| Organisms | Blood | Sputum | Abscess | IV catheter | Urine | Wound and skin | GU | Other* | Total |
|---|---|---|---|---|---|---|---|---|---|
| S. aureus | 5 | 1 | 5 | - | 2 | 9 | - | 7 | 29 |
| S. pneumoniae | 5 | 8 | - | - | - | - | - | 2 | 15 |
| S. agalactiae | - | - | - | - | 3 | - | 7 | - | 10 |
| Enterococcus spp. | 5 | - | 1 | 2 | 3 | 4 | - | 1 | 16 |
| E.coli | 2 | 2 | 1 | - | 12 | 6 | - | 3 | 26 |
| Klebsiella spp | 1 | 5 | 2 | 1 | 7 | 7 | - | 3 | 26 |
| Haemophilus spp | 1 | 12 | - | - | - | - | - | 2 | 15 |
| P. aeruginosa | 1 | 3 | 2 | 3 | 4 | 7 | - | 1 | 21 |
| Serratiaspp | 5 | 1 | 1 | - | 1 | 2 | - | - | 10 |
| Acinetobacter baumannii | 2 | 4 | - | - | 2 | 6 | - | 3 | 17 |
| Enterobacter spp | 1 | 5 | 1 | - | 6 | 10 | - | 2 | 25 |
| Total | 28 | 41 | 13 | 6 | 40 | 51 | 7 | 24 | 210 |
*Others: Ear, Eye, unspecified
GU: Genitourinary, S: Streptococcus, spp: species, P: Psuedomonas
S. aureus, P. aeruginosa, Enterobacter spp. and Acinetobacter spp. were mostly isolated from skin infections, while S. pneumoniae and Haemophilus specises were recovered from sputum. Group B β-haemolytic Streptococcus was isolated only from genital specimens and E. coli and Klebsiella spp. mostly from urine. S. aureus, S. pneumoniae, Enterococcus spp. and Serratia spp. were the most frequent blood isolates.
Antibiotic susceptibilities
Antibiotic susceptibilities of tested organisms are shown in tables 2 and 3. All strains, except P. aeruginosa were susceptible to tigecycline with MIC range of 0.12 to 1 mg/L. and susceptibilities to amikacin ranged from 90% to 100%. All Gram positive bacteria were susceptible to linezolid with MIC90 (MIC required to inhibit the growth of 90% of organisms) ranging from 1 to 2 mg/L. Enterococcus spp except one E. faecium strain were susceptible to ampicillin and vancomycin.
Table 2. Antibiotic susceptibilities of Gram-positive bacterial isolates.
| Antimicrobial | MIC90* (mg/L) |
Susceptible (%) |
Intermediate (%) | Resistant (%) |
|---|---|---|---|---|
| S. pneumoniae | ||||
| Penicillin | 2 | 50 | 20 | 30 |
| Ceftriaxone | 1 | 80 | 20 | - |
| Levofloxacin | 1 | 100 | - | - |
| Linezolid | 1 | 100 | - | - |
| Meropenem | 0.5 | 60 | - | 40 |
| Minocycline | 2 | 90 | 10 | - |
| Tigecycline | 0.03 | 100 | - | - |
| Vancomycin | 0.25 | 100 | - | - |
| S.agalactiae | ||||
| Penicillin | 0.12 | 100 | - | - |
| Ampicillin | 0.12 | 100 | - | - |
| Ceftriaxone | 0.12 | 100 | - | - |
| Levofloxacin | 1 | 100 | - | - |
| Linezolid | 1 | 100 | - | - |
| Meropenem | ≤ 0.12 | 100 | - | - |
| Minocycline | > 8 | - | - | - |
| Tigecycline | 0.12 | 100 | - | - |
| Vancomycin | 0.5 | 100 | - | - |
| Enterococcus spp | ||||
| Ampicillin | 1 | 93.75 | - | 6.25 |
| Levofloxacin | 32 | 62.5 | - | 37.5 |
| Linezolid | 2 | 100 | - | - |
| Minocycline | 8 | 43.75 | 56.25 | - |
| Tigecycline | 0.12 | 100 | - | - |
| Vancomycin | 2 | 93.75 | - | 6.25 |
| S. aureus** | ||||
| Penicillin | 32 | 10.3 | - | 89.7 |
| Amoxicillin Clavulanic Acid | 1 | 93.1 | - | 6.9 |
| Levofloxacin | o.5 | 100 | - | - |
| Linezolid | 2 | 100 | - | - |
| Minocycline | ≤ 0.25 | 100 | - | - |
| Tigecycline | 0.12 | 100 | - | - |
| Vancomycin | 1 | 100 | - | - |
*MIC90: Minimum Inhibitory Concentration required to inhibit the growth of 90% of organisms.
** 29 isolates including 4 methicillin resistant S. aureus (MRSA)
Table 3. Antibiotic susceptibilities of Gram-negative bacterial isolates.
| Antimicrobial | MIC90* (mg/L) |
Susceptible (%) | Intermediate (%) | Resistant (%) |
|---|---|---|---|---|
| E. coli | ||||
| Amikacin | 4 | 100 | - | - |
| Amoxicillin Clavulanic Acid | 16 | 65.38 | 26.92 | 7.69 |
| Ampicillin | > 32 | 30.77 | 3.85 | 65.38 |
| Cefepime | 16 | 84.62 | 7.69 | 7.69 |
| Ceftazidime | ≤ 8 | 96.15 | 3.85 | - |
| Ceftriaxone | > 64 | 76.92 | - | 23.08 |
| Levofloxacin | 8 | 61.54 | - | 38.46 |
| Meropenem | ≤ 0.06 | 100 | - | - |
| Minocycline | 16 | 73.08 | 15.38 | 11.54 |
| Piperacillin Tazobactam | 8 | 92.31 | - | 7.69 |
| Tigecycline | 0.25 | 100 | - | - |
| Klebsiella spp | ||||
| Amikacin | 2 | 100 | - | - |
| Amoxicillin Clavulanic Acid | 8 | 92.3 | 3.85 | 3.85 |
| Ampicillin | > 32 | 3.85 | 96.15 | |
| Cefepime | ≤ 0.5 | 100 | - | - |
| Ceftazidime | ≤ 8 | 100 | - | - |
| Ceftriaxone | ≤ 0.06 | 96.15 | - | 3.85 |
| Levofloxacin | 0.06 | 100 | - | - |
| Meropenem | ≤ 0.06 | 100 | - | - |
| Minocycline | 4 | 92.3 | 3.85 | 3.85 |
| Piperacillin Tazobactam | 2 | 100 | - | - |
| Tigecycline | 0.5 | 100 | - | - |
| Enterobacter spp | ||||
| Amikacin | 2 | 100 | - | - |
| Amoxicillin Clavulanic Acid | > 32 | 4.35 | 4.35 | 91.3 |
| Ampicillin | > 32 | - | - | 100 |
| Cefepime | 16 | 86.96 | 4.35 | 8.7 |
| Ceftazidime | 16 | 82.61 | 8.7 | 8.7 |
| Ceftriaxone | 64 | 78.26 | 4.35 | 17.39 |
| Levofloxacin | 8 | 86.96 | - | 13.04 |
| Meropenem | 0.12 | 95.65 | 4.35 | - |
| Minocycline | 4 | 91.30 | 8.7 | - |
| Piperacillin Tazobactam | 4 | 86.96 | 8.7 | 4.35 |
| Tigecycline | 1 | 100 | - | - |
| Serratia spp | ||||
| Amikacin | 2 | 100 | - | - |
| Amoxicillin Clavulanic Acid | > 32 | 10 | - | 90 |
| Ampicillin | > 32 | 10 | - | 90 |
| Cefepime | ≤ 0.5 | 100 | - | - |
| Ceftazidime | ≤ 8 | 100 | - | - |
| Ceftriaxone | 1 | 100 | - | - |
| Levofloxacin | 0.12 | 100 | - | - |
| Meropenem | 0.06 | 100 | - | - |
| Minocycline | 4 | 100 | - | - |
| Piperacillin Tazobactam | 4 | 100 | - | - |
| Tigecycline | 1 | 100 | - | - |
| Haemophilus spp. | ||||
| Amoxicillin Clavulanic Acid | 1 | 100 | - | - |
| Ampicillin | 1 | 90.9 | - | 9.1 |
| Cefepime | ≤ 0.5 | 100 | - | - |
| Ceftazidime | ≤ 8 | 100 | - | - |
| Ceftriaxone | ≤ 0.06 | 100 | - | - |
| Levofloxacin | 0.015 | 100 | - | - |
| Meropenem | 0.12 | 100 | - | - |
| Minocycline | ≤ 0.5 | 100 | - | - |
| Piperacillin Tazobactam | ≤ 0.06 | 100 | - | - |
| Tigecycline | 0.25 | 100 | - | - |
| Acinetobater baumannii | ||||
| Amikacin | 8 | 94.12 | - | 5.88 |
| Cefepime | 32 | 82.35 | 5.88 | 11.76 |
| Ceftazidime | > 32 | 82.35 | - | 17.65 |
| Ceftriaxone | > 64 | 41.18 | 41.18 | 17.65 |
| Levofloxacin | 4 | 70.59 | 23.53 | 5.88 |
| Meropenem | 2 | 100 | - | - |
| Minocycline | 4 | 100 | - | - |
| Piperacillin Tazobactam | 128 | 82.35 | - | 17.65 |
| Tigecycline | 0.5 | 100 | - | - |
| P. aeruginosa | ||||
| Amikacin | 4 | 90.48 | 9.52 | - |
| Cefepime | 16 | 85.71 | 14.29 | - |
| Ceftazidime | 16 | 95.00 | 5.00 | - |
| Ceftriaxone | > 64 | 9.52 | 47.62 | 42.86 |
| Levofloxacin | > 8 | 80.00 | 5.00 | 15.00 |
| Meropenem | 16 | 80.00 | 5.00 | 15.00 |
| Minocycline | > 16 | - | - | 100 |
| Piperacillin Tazobactam | 32 | 95.00 | - | 5.00 |
| Tigecycline | > 16 | - | - | 100 |
*MIC90: Minimum Inhibitory Concentration required to inhibit the growth of 90% of organisms. spp: species
Only 30% of E. coli isolates were susceptible to ampicillin, 96.15% to ceftazidime, 76.9% to each of ceftriaxone and cefepime and 61% to levofloxacin. On the other hand 100% of Klebsiella spp. were susceptible to levofloxacin, while susceptibilities to other antibiotics ranged from 92% to 100%. 95.65% and 86.96% of Enterobacter spp. were susceptible to meropenem and piperacillin-tazobactam respectively. 82.6% of them were susceptible to ceftazidime, but only 78.26% were susceptible to ceftriaxone. All tested A. baumannii strains were susceptible to meropenem, minocycline and tigecycline. 82.75% of them were susceptible to ceftazidime and cefepime, but only 41.18% were susceptible to ceftriaxone. All Serratia spp. were susceptible to all tested antibiotics except augmentin, where only 10% were susceptible. P. aeruginosa was universally resistant to tigecycline with MIC range 8-16 mg/L. Over 90% of P. aeruginosa were susceptible to amikacin and piperacillin-tazobactam and 80% were susceptible to meropenem and levofloxacin. Haemophilus species were susceptible to all tested antimicrobial agents except ampicillin where 9.1% were resistant.
Four strains (12.12%) of S. aureus were found to be oxacillin resistant (MRSA). The remaining strains were susceptible to all other antibiotics except penicillin, to which 10% were susceptible. All strains of S. agalactiae were susceptible to all antibiotics. 50% of S. pneumoniae were resistant to penicillin 20% of which were intermediately sensitive and 30% were fully resistant. 80% were fully susceptible to ceftriaxone and 20% showed intermediate susceptibility.
Discussion
We tested a wide variety of commonly encountered microorganisms in clinical practice. This selection represents the types of bacteria isolated from patients in Oman, since the Royal hospital is the main tertiary referral hospital, where patients from different parts of Oman are treated. All tested strains were susceptible to tigecycline, except P. aeruginosa, which is known to be resistant to glycylcycline due to efflux pump (MexXY-OprM) mediated resistance mechanism.6-8 Similarly all Gram positive organisms were universally susceptible to linezolid. This oxazolidinone antibiotic is known to be effective against all Gram positive bacteria. It binds to the 50S subunit of the bacterial ribosome via interaction with the 23S rRNA, thereby blocking protein synthesis.9 Tigecycline and Linezolid should however be kept as reserve antibiotics and used only when other antibiotics are not effective. Their use should be restricted and only permitted when approved by the hospital microbiologist or infectious disease physician as unrestricted use will lead to development of resistance to these valuable antibiotics. Hence, establishing antimicrobial stewardship program in each hospital is highly desirable and would ensure judicious use of antibiotics as well as evidence-based, safe and effective antimicrobial therapy. On the other hand all E. coli strains were susceptible to meropenem and amikacin. Susceptibilities to 3rd generation cephalosporins varied. While only 4% were resistant to ceftazidime, 24% were resistant to ceftriaxone. This is most probably due to the prevalence of CTX-M type extended spectrum β-lactamase (ESBL) producing strains, known to mostly hydrolyze cefotaxime and ceftriaxone, but to a less extent ceftazidime.10,11 Indeed most of our recent ESBL producing E. coli isolates have been shown to belong to type CTX-M (unpublished data). CTX-M type ESBL producing strains are spreading rapidly worldwide and are increasingly dominant.12 Because of the increasing significance of multi-resistant ESBL producing E. coli in the community, clinicians should be aware of the possibility of treatment failure associated with infections caused by such organisms.13 We also found wide prevalence of levofloxacin resistance among E. coli stains. Quinolone resistance among E. coli has been reported worldwide and believed to be due to acquisition of qnr gene that protects DNA from binding to gyrase and topoisomerase.14 This has been reported to occur more frequently among ESBL producing strains.15 Indeed this correlates with the high prevalence of ESBL producers among our isolates.
Although A. baummanni is known as one of the most resistant Gram negative bacteria that can acquire resistance by multiple mechanisms, all strains isolated during the study period were highly susceptible to antimicrobial agents.16,17 On the other hand, about 4% and 13% of Enterobacter spp. were resistant to meropenem and piperacillin-tazobactam respectively. This could be due to production of a carbapenemase or efflux pump.18,19 Similarly 20% of P. aeruginosa were resistant to meropenem, which can also be explained by the above mechanisms. However, since the same meropenem resistant strains were also resistant to levofloxacin, it is more likely that this was an efflux mechanism. Overproduction of the efflux system Mex AB-OprM confers resistance to meropenem as well as quinolones and may result in treatment failure.20 Piperacillin-tazobactam, however showed high activity against P. aeruginosa. This may be considered as the drug of choice for treating infections with P. aeruginosa in our setting.
Only four S. aureus strains (12.12%) were methicillin resistant. Although this is consistent with previous findings (unpublished data), it appears much lower than that reported in other GCC countries and in some European countries.21-23 On the other hand all strains were susceptible to linezolid and tigecycline, a finding consistent with other studies.24 Although all S. pneumoniae strains were also susceptible to linezolid and tigecycline, 50% of them were not susceptible to penicillin and 20% were intermediately resistant to ceftriaxone. This represents a significant increase in the rate of resistance to penicillin and ceftriaxone as compared to a previous report from Oman.25 A similar trend has also been reported in other neighboring countries.26 It is imperative, therefore, to consider adding vancomycin in empirical treatment of serious pneumococcal infections. The only isolate of E. faecium was resistant to vancomycin. Although we rarely encounter vancomycin resistant Enterococcus (VRE) in our region, it is often reported from some parts of North America and Europ.27 However, E. faecalis, the dominant strain remained to be susceptible to commonly used anti-enterococcus agents.
In our hospital we have been experiencing mechanisms of resistance as these reported worldwide, as a result of increasing antibiotic pressure. However new antimicrobial agents, linezolid and tigecycline, seem to be effective agents against all clinical isolates in the Royal Hospital, only they need to be restricted and used judiciously and only when approved by microbiologist or infectious diseases physicians so that these valuable drugs continue to be effective in the future.
Funding
The study was funded by Wyeth Pharmaceuticals as part of an international study.
Transparency Declarations
None to declare.
Acknowledgements
We thank Royal Hospital Microbiology staff for their technical support.
References
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