Dr. Shivkumar Chandrashekharan,
S07258, Dr. Shweta V. Sabnis, Dr. Sowmya Peri,
Dr. Rama Krishnan R
Chief Author: Shivkumar Chandrashekharan (S07258) , Co-authors: Ramakrishnan R, Shweta Sabnis, Sowmya Peri
Aravind Eye Hospital, Tirunelveli, Tamilnadu
ABSTRACT:
AIM: To study resistance of organisms causing endophthalmitis to routinely used Fluoroquinolones
METHOD: Organisms isolated from 729 cases of endophthalmitis presenting at a tertiary hospital from January 2007 to December 2013 were tested for sensitivity to antimicrobials as per protocol.
RESULTS: Postoperative (422, 97 isolates) and Traumatic (233, 51 isolates) endophthalmitis were the most common. Gram positive cocci (46% postoperative and 64% traumatic) and gram negative bacilli (41% postop and 17% traumatic) were the main organisms. Gram positive cocci from postoperative endophthalmitis showed a lower susceptibility as compared to traumatic (76 vs 83% to Ofloxacin, 85 vs 89% to Gatifloxacin, 76 vs 91% to Moxifloxacin). Gram negative bacilli showed even lower susceptibility (37 vs 100% to Ofloxacin, 39 vs 100% to gatifloxacin and 32 vs 87.5% to Moxifloxacin)
CONCLUSION: Emerging resistance of organisms to fluoroquinolones calls for judicious use in milder ocular infections
INTRODUCTION:
One of the most challenging, devastating and sight threatening ocular infections is Endophthalmitis. Accurate diagnosis, and timely and appropriate treatment are required for preventing irreversible visual loss. In acute cases the mainstay of treatment, especially in postoperative cases has been empiric intravitreal antibiotics against both Gram positive and Gram negative bacteria, usually Vancomycin and Ceftazidime.1
The Fluoroquinolones have gained popularity as they have been shown to be effective against Gram negative and anaerobic species and also against a variety of Gram positive organisms, thus being considered as broad-spectrum antibacterials. The fluoroquinolones act by inhibiting two enzymes involved in bacterial DNA synthesis : DNA gyrase and Topoisomerase IV. The Topoisomerases are essential for bacterial DNA replication and are not found in human cells. Thus the fluoroquinolones act as bactericidal.2 They have been found to be as effective as combination therapy2
Increasing resistance of ocular pathogens has been found to be parallel to that in systemic pathogens. The factors which may contribute are overuse of systemic as well as topical antibiotics, misuse of antibiotics for other ocular infections, globalization and migration.3 As fourth generation fluoroquinolones are used routinely in prophylaxis of many surgical procedures, the increasing trend of resistance of organisms to them is of concern.4 It is important to detect the trends by monitoring the causative organisms of endophthalmitis, and the resistance to routinely used antibiotics in order to guide the empiric management.3
AIM:
The aim of this study has been to study the resistance of organisms causing endophthalmitis to routinely used Fluoroquinolones
DESIGN:
Retrospective study of the laboratory reports of consecutive microbial isolates from cases diagnosed with endophthalmitis.
MATERIALS AND METHODS:
Vitreous aspirates and / or aqueous tap taken from patients presenting with clinically suspected or diagnosed endophthalmitis at a tertiary eye hospital in south India between January 2007 and December 2013 were subjected to culture for micro organisms. The obtained ocular specimens were inoculated directly onto 5% Blood agar (aerobic incubation), Chocolate agar (5% CO2), Sabouraud’s Dextrose agar (Emmons modification), Thioglycolate broth and Brain-heart infusion broth. Culture media were incubated overnight at 370C. On positive bacterial growth, the organisms were identified and subjected to sensitivity to antibiotics. In-vitro susceptibility testing was performed by Kirby-Bauer disc diffusion method and interpreted using Clinical and Laboratory Standards Institute’s serum standards. The antibacterial agents (Hi-media Laboratories Pvt. Ltd., Mumbai, India) used were amikacin, tobramycin, gentamicin, cefazolin, cephotaxime, ceftazidime, ciprofloxacin, norfloxacin, ofloxacin, gatifloxacin, moxifloxacin, and levofloxacin and were routinely tested as quality control for their efficacy against standard American Type Culture Collection (ATCC) bacteria (P. aeruginosa ATCC 27853, Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923).
Retrospectively these records were analyzed to note the causative organisms of various types of endophthalmitis and to note the difference in the susceptibility of these organisms causing postoperative and traumatic endophthalmitis to the commonly used Fluoroquinolones: Ciprofloxacin, Ofloxacin, Gatifloxacin and Moxifloxacin
RESULTS:
The most common cause for endophthalmitis was following surgery ( postoperative 58%) and following trauma ( 32%). The overall culture positivity for bacterial organisms was 22%. The number of cases in each category, the number and percentage of positive bacterial cultures are shown in the following table.
TABLE 1: Table showing the types of endophthalmitis ( and the percentage) the number of bacterial isolates from each type , and the rates of culture positivity for each type
| TYPE OF ENDOPHTHALMITIS | NUMBER OF CASES | NUMBER OF BACTERIAL ISOLATES | RATE OF CULTURE POSITIVITY |
| POST OPERATIVE | 422 (58%) | 97 | 23% |
| TRAUMATIC | 233 (32%) | 51 | 22% |
| OTHERS | 52 (7%) | 7 | 13% |
| ENDOGENOUS ENDOPHTHALMITIS | 22 (3%) | 4 | 18% |
| TOTAL | 729 | 159 | 22% |
The most common organisms causing postoperative endophthalmitis were Pseudomonas (28/97, 28.8%), Coagulase negative Staphylococci ( CONS: 20/97, 20.6% and Streptococcus pneumoniae 16/97,16.4% )
The most common organisms causing post traumatic endophthalmitis were Streptococcus viridians (21.5%) and CONS (19.6%)
TABLE 2: Table showing the causative organisms ( and percentage) for each type of endophthalmitis
| TYPE OF ENDOPHTHALMITIS (No Bact Isolates) | GRAM POSITIVE COCCI | GRAM NEGATIVE BACILLI | GRAM POSITIVE BACILLI | ACTINOMYCETES (NOCARDIA) |
| POSTOPERATIVE (97) | 45 (46.4%) | 40 (41.2%) | 5 (5.2%) | 7 (7.2%) |
| TRAUMATIC (51) |
33 (64.7%) | 9 (17.6%) | 8 (15.7%) | 1 (2%) |
| OTHERS (7) |
3 (43%) | 3 (43%) | 1 (14%) | 0 |
TABLE 3: GRAM POSITIVE COCCI: Percentage of susceptible organisms
| ANTIBIOTIC | POSTOPERATIVE | TRAUMATIC |
| CIPROFLOXACIN | 76% | 71% |
| OFLOXACIN | 76% | 83% |
| GATIFLOXACIN | 85% | 89% |
| MOXIFLOXACIN | 76% | 91% |
TABLE 3: Table comparing susceptibility pattern of Gram positive bacteria isolated from postoperative and traumatic endophthalmitis shows lower susceptibility of the organisms In the postoperative group
TABLE 4: GRAM NEGATIVE BACILLI : Percentage of susceptible organisms
| ANTIBIOTIC | POSTOPERATIVE | TRAUMATIC |
| CIPROFLOXACIN | 39% | 100% |
| OFLOXACIN | 37% | 100% |
| GATIFLOXACIN | 39% | 100% |
| MOXIFLOXACIN | 32% | 87.5% |
TABLE 4: Table comparing the susceptibility of Gram negative bacteria isolated from postoperative and traumatic endophthalmitis shows markedly low susceptibility patterns in the postoperative group
TABLE 5: ALL BACTERIA: Percentage of susceptible organisms
| ANTIBIOTIC | POSTOPERATIVE | TRAUMATIC |
| CIPROFLOXACIN | 58.5% | 80% |
| OFLOXACIN | 59.5% | 85% |
| GATIFLOXACIN | 62.5% | 91% |
| MOXIFLOXACIN | 54.5% | 93% |
TABLE 5: Table comparing the susceptibility of all organisms including Gram positive bacilli and Actinomycetes show lower susceptibility in the postoperative group
DISCUSSION:
Endophthalmitis is a severe sight threatening infection that needs to be treated at the earliest. While definitive identification of the microorganism causing the infection may take some time, empirical treatment is instituted to prevent irreversible visual loss, usually with antibacterials covering Gram positive and Gram negative bacteria.
The fluoroquinolones act by inhibiting the enzymes DNA gyrase and Topoisomerase IV, essential for DNA replication in the bacteria, and hence bactericidal. The fluoroquinolones being effective against Gram positive, negative and anaerobic organisms are considered to be broad spectrum antibacterials.2 Hence they are not only used in severe infections like endophthalmitis, but also in surgical prophylaxis and in treating various infections, even milder ones
Widespread use of antibiotics has been associated with growing resistance manifested by the organisms. The factors which contribute apart from globalization and migration of population are overuse or misuse of antibiotics, both systemic and topical. Studying the trends and changing patterns in the causative organisms of endopthtalmitis and the resistance patterns of these organisms to the antibiotics and antibacterials is essential for advocating changes in the empirical treatment. 3
In a study in Brazil462% cases of endophthalmitis presenting between January 2006 and October 2009 was secondary to surgery, and 12% following trauma, and 22% due to other reasons. Coagulase Negative Staphylococci were the most common cause, and sensitivity to Ciproflxacin was 62.5%, Gatifloxacin 79.5%, Moxifloxacin 89.5%,Ofloxacin 70.8%. The authors observed that the sensitivity to fourth generation Fluoroquinolones was lower than that cited in their previous publication. This increasing trend of CONS resistance according to the authorsis a matter of concern.4
Our present analysis too indicates that 58% cases of endophthalmitis were following surgery and 32% following trauma. The most common bacteria isolated were Pseudomonas aeruginosa (28.8%), Coagulase Negative Staphylococci ( CONS) (20.6%) and Streptococcus pneumoniae (16.4%) in the postoperative group and Streptococcus viridans ( 20.6%) and CONS ( ) in the traumatic group. Comparing the susceptibility patterns of all microorganisms isolated from postoperative endophthalmitis cases from a previous report published from our institute (Ramakrishnan R et al) covering the period from 1997 to 2006 and the present analysis covering from 2007-2013.we also find a decrease in susceptibility to the fluoroquinolones: Ciprofloxacin: 99% vs 58.5% Ofloxacin: 99% vs 59.5% Gatifloxacin : 96% vs 62.5% and Moxifloxacin 88% vs 54.5%.5
Moreover, we also see in the present analysis that there is a lower susceptibility of the Gram positive organisms ( Ofloxacin 76 vs 83%, Gatifloxacin 85 vs 89% and Moxifloxacin 76 vs 91%) and a markedly lower susceptibility of the Gram negative organisms (ciprofloxacin 39 vs 100%, Ofloxacin 37 vs 100%, Gatifloxacin 39 vs 100% and Moxifloxacin 32 vs 87.5%) causing postoperative endophthalmitis when compared to those causing traumatic endophthalmitis. The possible cause for this reduction in susceptibility in postoperative endophthalmitis cases may be explained by the fact that fluoroquinolones are used extensively for prophylaxis, and also later as a combination with steroids in the postoperative period . Resistance to fluoroquinolones develop as a result of mutations in the bacteria resulting in alterations in the drug target enzymes ( DNA gyrase and Topoisomerase) and alterations in access to the drug target enzymes .2 Though resistance of organisms causing eye infections to antibiotics is considered as an outcome of systemic antibiotic usage, there is growing evidence and reports that topical usage too could induce resistance among the bacteria.6 Our analysis too seems to support this possibility.
CONCLUSION:
Judicious use of the antibacterials, especially fluoroquinolones, may therefore help in limiting the growing resistance. It is therefore suggested that overuse and misuse of these drugs in topical forms especially for milder infections, prophylaxis and prolonged postoperative usage as a combination with steroids, needs to be avoided. A steroid antibiotic combination can be avoided and, it may be advisable to use steroids separately for a longer period , and the topical antibiotics separately ( fluoroquinolones ) for an appropriate period and in an appropriate dosage.
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- Joseph M. Blondeau, MSc, PhD, RSM (CCM), SM (AAM), FCCP. Fluoroquinolones: Mechanism of Action, Classification,and Development of Resistance. SurvOphthalmol2004;49 (Suppl2):S73–S78.
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- Fintelmann RE, Hoskins EN, Leitman TM, Keenan JD, Gaynor BD, Cevallos V, et al. Topical fluoroquinolone use as a risk factor for in vitro fluoroquinolone resistance in ocular cultures. ArchOphthalmol 2011; 129: 399 -402