Thea Supplement Nov 14

Supplement november 2014

Use of Intracameral Cefuroxime

Sunday 14 September 2014 XXXII Congress of the ESCRS London, uk

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n 2007, results from the ESCRS Endophthalmitis Prophylaxis Study showed that intracameral cefuroxime significantly reduced the risk of endophthalmitis after cataract surgery [ESCRS Endophthalmitis Study Group. J Cataract Refract. Surg. 2007;33:978988]. Then in 2012, a major obstacle to systematic intracameral use was eliminated when Aprokam® (cefuroxime 50mg powder for injection; Laboratoires Théa) was approved across Europe as the first and only product indicated for intracameral administration to prevent endophthalmitis after cataract surgery.

As of September, 2014, this single-use agent is available in 23 European countries, with approval being sought elsewhere around the world.

At a symposium held during the XXXII ESCRS Congress in London, a faculty of experts in cataract surgery and ocular anti-infective treatments reviewed scientific principles of endophthalmitis prophylaxis, reported on current practices in Europe, and addressed common questions regarding intracameral cefuroxime and topical antibiotic regimens for endophthalmitis prophylaxis.

The information in this supplement summarising the proceedings should be valuable for cataract surgeons as they strive to optimise patient outcomes.

– Peter S Barry FRCS, Programme Chair Consultant Ophthalmic Surgeon at St Vincent’s Private Hospital, Dublin 4, Ireland; Chairman, ESCRS Endophthalmitis Study Group

Antimicrobial Treatment Tailored to the Eye Susanne Gardner D Pharm, Specialist in Ocular Infections and Pharmacokinetics

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urrent scientific rationale lends strong support to the intracameral injection as the preferred route of antibiotic administration for prophylaxis of postcataract surgery endophthalmitis, with cefuroxime the only antibiotic with an official indication for such use, said Susanne Gardner D Pharm.

“Direct injection of antibiotic into the anterior chamber assures consistent and immediate delivery of the highest possible, safe dose to this target site. Thereby, peak aqueous humor levels are maximised along with the applicable pharmacokinetic/pharmacodynamic parameters associated with bacterial eradication,” said Dr Gardner, specialist in ocular pharmacology and pharmacokinetics.

“Regarding antibiotic selection, cefuroxime is the best option and the most frequently used agent, because it is the only antibiotic with clinical evidence proving efficacy and safety, and is the only commercially available product with a licensed indication for prophylaxis of endophthalmitis after cataract surgery.”

“Direct injection of antibiotic into the anterior chamber assures consistent and immediate delivery of the highest possible, safe dose...”

TREATMENT FUNDAMENTALS Dr Gardner discussed principles of antibiotic treatment as they pertain to the eye and drug delivery into the anterior chamber by various administration routes. She noted that, because of unique features of the eye, data from the general infectious disease literature relating to antibiotic efficacy may not translate directly to treatment or prophylaxis of intraocular infection.

One issue to consider is that barriers to drug diffusion into the eye limit achievable antibiotic concentrations

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after systemic or topical administration. In addition, drug elimination routes in the eye are unique, including washout through the nasolacrimal ducts after topical administration, and aqueous humor turnover, which affect drug concentrations achieved and maintained in aqueous humor over time.

Other factors to consider include an altered host immune response in the anterior chamber due to its relatively avascular nature, and restricted direct access to the anterior chamber, which emphasizes the need to develop single dose versus multiple dose approaches to attaining meaningful antibiotic levels inside the eye.

“Information on minimum inhibitory concentration (MIC) values established with standard laboratory methods, which describe the concentration of antibiotic inhibiting microbial growth, may need to be reinterpreted as they apply to the eye,” Dr Gardner said.

She explained that MIC and minimum bactericidal concentration (MBC) are values used to measure antibiotic potency and provide breakpoints at which microorganisms are considered susceptible or resistant. Notably, MBC values for cefuroxime are close to its MIC for many bacteria, and it may also have the benefit of a bactericidal mechanism of action against certain organisms due to the high concentration achieved with intracameral administration.

However, the MIC and MBC values are determined in the laboratory where bacteria in test tubes are exposed to drug for approximately18 to 24 hours. This in vitro scenario is not necessarily representative of drug residence time in the eye, Dr. Gardner said.

Furthermore, the laboratory-defined MIC and MBC values are intended to relate to antibiotic concentrations that are safe and anticipated in the blood after systemic administration. Although the concentration of antibiotic in topical formulations may far exceed the MIC and MBC values of relevant pathogens, the concentrations achieved in target tissues and fluids of the internal eye are limited by the corneal barrier and by routes of elimination.

Pharmacokinetics parameters used to predict antibiotic efficacy include peak concentration achieved (Cmax) and area under the concentration-time curve (AUC) which represents total drug exposure over time. Integrating the PK parameters with the MIC presents additional

Use of Intracameral Cefuroxime

pharmacokinetic/pharmacodynamic parameters that help quantify antibiotic effects. These include Cmax/MIC, AUC/ MIC, area under the inhibitory curve (AUIC)/MIC, and time of exposure above the MIC (T>MIC).

Explaining their relevance to antibiotics used for endophthalmitis prophylaxis, Dr Gardner said that generalised guidelines from the infectious disease literature categorise cephalosporins as time-dependent antibiotics for which T>MIC is important, as is the AUC. Fluoroquinolones are characterised as concentrationdependent antibiotics with AUC/MIC or AUIC/MIC being important parameters. However, the concept that fluoroquinolones are only “concentration-dependent” is misleading, she said.

“For all antibiotics, time is an important parameter in antimicrobial effects.”

Dr Gardner illustrated this point by presenting findings from a study investigating the time needed for two commercially available, topical fourth-generation fluoroquinolones (gatifloxacin 0.3% and moxifloxacin 0.5%) to eradicate common ocular pathogens in vitro [Callegan MC et al, Adv Ther. 2009;26:447-454]. Results showed that, for the antibiotic without added benzalkonium chloride (moxifloxacin), the time to eradication exceeded 60 minutes for many of the bacterial strains tested.

“The difference between these two fluoroquinolones in time to kill bacteria was attributed to the presence of benzalkonium chloride (BAK) in the gatifloxacin formulation. BAK has a strong bactericidal effect in itself, but because of toxicity cannot be used inside the eye,” Dr Gardner said.

TOPICAL VERSUS INTRACAMERAL TREATMENT Results of numerous studies investigating different topical antibiotics with various administration regimens show that, even with multiple, frequent dosing, the aqueous humor Cmax achieved remained low, from below 1 mcg/ ml to about 4 mcg/ml. In addition, there is large interpatient variability in the levels achieved. Furthermore, results from several studies investigating various antibiotic regimens show there is little or no benefit from adding antibiotic drops preoperatively to povidone-iodine antisepsis in terms of reducing endophthalmitis rates or conjunctival bacterial flora load, Dr Gardner said.

She also cautioned against assuming that achieving an antibiotic concentration in internal ocular structures and fluids that is merely equivalent to the MIC is adequate for efficacy.

“For many years we have been targeting aqueous humor levels, content to reach between 1 and 2 mcg/ml after topical administration. However, the time of bacteria exposure to that level is limited because the antibiotic concentration diminishes parallel with aqueous humor turnover,” Dr Gardner explained.

A very important point, but often overlooked, is that antibiotic levels in aqueous humor, present in the anterior chamber from preoperatively administered topical drops, is expelled at the time of the surgical incision.

With that issue in mind, Dr Gardner and colleagues investigated aqueous humor concentrations achieved with postoperative drop dosing, and she compared those results with antibiotic levels reported in association with preoperative topical dosing and intracameral cefuroxime.

In the study of postoperative drop dosing [Sundelin K et al, Acta Ophthalmol. 2009;87:160-165], patients undergoing phacoemulsification were administered levofloxacin 0.5% using a regimen duplicating that in the perioperative topical treatment group in the ESCRS Study (two doses 30 minutes apart preoperatively + three doses at five-minute intervals at the close of surgery).

Use of Intracameral Cefuroxime

Mean AH (mcg/ml) fluoroquinolone levels after topical drops Moxifloxacin Gatifloxacin 0.5% 0.3%

Levofloxacin 0.5% 1.5%

4.430

Sundelin 2009

1.619 Bucci 2004

0.0523

0.976 Holland 2007

1.31 0.63 Solomon 2005 1.18 0.48 Kim 2005 1.74

Katz 2005

Price 2005

1.26

2.28

Hariprasad 2005

1.86

McCulley 2006

2.16 0.82 Ong-Tone 2007 0.9 0.3 Holland 2008 Figure 1

When measured one hour after the last dose, the mean levofloxacin aqueous humor concentration reached 4.4 mcg/ml.

“This level is higher than that reported for any preoperatively administered antibiotic using any dosing regimen (Figure 1). Yet, in the ESCRS Study, the endophthalmitis rate in the perioperative topical treatment group was significantly higher than in the intracameral cefuroxime arm,” Dr Gardner said.

“Compared with topical drops, direct intracameral injection of 1mg/0.1ml cefuroxime results in a nearly 1000fold higher aqueous humor concentration of 4000 mcg/ml.

This difference is important because starting with a higher Cmax then increases all of the other pharmacokinetics/ pharmacodynamics parameters associated with antibiotic activity, and the concentration achieved with intracameral cefuroxime far surpasses the MIC levels of most clinically isolated endophthalmitis pathogens (Figure 2).”

Comparing AH PK/PD Parameters

Figure 2

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Figure 3

Dr Gardner also presented data showing that with a cefuroxime Cmax of 4000 mcg/ml (using 0.25ml aqueous humour volume), and conservatively estimating its aqueous humor half-life as one hour, the cefuroxime aqueous humor concentration should exceed the MIC for important endophthalmitis pathogens for at least 10 hours postinjection (Figure 3).

ALTERNATIVE ROUTES OF ANTIBIOTIC ADMINISTRATION A small percentage of cataract surgeons use a subconjunctival injection route to deliver antibiotic for endophthalmitis prophylaxis. In a study evaluating aqueous humor concentration achieved

using this technique, Jenkins et al. administered a cefuroxime dose of 125 mg and found a mean aqueous humor concentration of 20.23 mcg/ ml, measured 12 to 24 minutes postinjection [Jenkins CDG et al, Br J Ophthalmol. 1996;80:685-688]. As a comparison, Dr Gardner said that even when utilizing a larger aqueous humor volume of 0.3ml, the aqueous humor concentration achieved with direct intracameral administration of cefuroxime 1mg is expected to be 3300 mcg/ml, a level that is more than 100-fold higher than described after subconjunctival cefuroxime 125mg.

Addition of antibiotic to a surgical irrigating solution also delivers antibiotic directly into the anterior

Changes Highlighted by the EurObsCat After One Year

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Béatrice Cochener MD, PhD, Professor and Chair, Department of Ophthalmology, University of Brest, France

nformation obtained from the second wave of participants in the European Observatory of Cataract Surgery (EurObsCat) point to growing uptake of intracameral cefuroxime for endophthalmitis prophylaxis and in the use of the only product licensed for this indication (Aprokam).

Corresponding with this trend, the data also show increasing influence of the ESCRS Endophthalmitis Guidelines as well as diminishing use of pre- and postoperative topical antibiotics.

However, the results also indicate a need for more education about the ESCRS guidelines and appropriate regimens for medication use, said

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Dr Béatrice Cochener, Professor and Chair, Department of Ophthalmology, University of Brest, France.

Dr Cochener commented: “We have to thank the ESCRS for conducting the only randomised, placebo-controlled study on endophthalmitis prophylaxis and for providing cataract surgeons with evidence to support a new way of thinking about prevention. Now, through the EurObsCat survey, we are encouraged by the increase in Aprokam use. Still, next year, we hope to see more surgeons are following the ESCRS guidelines and using the only antibiotic product labeled for intracameral endophthalmitis prophylaxis.”

chamber. However, the concentrations utilised commonly, ranging from about 8 to 20 mcg/ml, are much lower than the concentration achieved with direct intracameral injection.

“There are conflicting reports in the literature about the efficacy of this approach, but there is evidence that aqueous humor contamination can persist, even after irrigation with vancomycin and gentamicin. In addition, the irrigation may dislodge local bacteria, and it is very difficult to quantitate total drug exposure,” Dr Gardner said.

“Furthermore the US Centers for Disease Control and the American Academy of Ophthalmology discourage the use of vancomycin in irrigation fluids.” (Joint Statement of the American Academy of Ophthalmology and the Centres for Disease Control and Prevention)

PUTTING IT ALL TOGETHER Dr Gardner concluded her talk by saying that, collectively, the information she presented currently provides mathematical and scientific support for intracameral injection of cefuroxime as the preferred method for cataract surgery endophthalmitis prophylaxis.

She also reiterated there are practical reasons for using Aprokam.

“Aprokam is the only dosage form of an antibiotic with regulatory approval for intracameral injection. Use of any other agent opens the door to medicolegal risks, and the errors and complications associated with extemporaneous compounding,” Dr Gardner said.

The EurObsCat project was undertaken under the sponsorship of Thea and was developed by the European Team for the propHylaxis of Infection in Cataract Surgery (ETHICS), a group of 10 cataract surgery opinion leaders representing nine European countries (Belgium, France, Italy, Germany, The Netherlands, Poland, Spain, Sweden and the UK).

The questionnaire was designed to gather data on key practice performance indicators and will be administered annually to a cohort of surgeons.

Participants are randomly selected to provide a realistic and representative sample within their country if they satisfy the requirement of performing at least 150 cataract operations a year.

The first survey conducted in 2013 included 479 surgeons, and its results were presented at the ESCRS Congress in 2013. The 2014 survey had 490 participants, of whom about half were retained from the 2013 cohort.

Use of Intracameral Cefuroxime

“The 2014 results confirmed the results from the first year, and show consistency as only half the participants were the same,” Dr Cochener said.

Surgeons involved in both the 2013 and 2014 surveys were performing an average of about 520 cataract operations per year. Nearly all procedures were phacoemulsification (≥97.6%), and there was just a slight increase, from 0.5% to 1.1%, in the proportion performing femto-laser cataract surgery. However, the proportion of surgeons using a “mini” incision (1.8 to 2.1mm) increased significantly from 13% in 2013 to 18% in 2014.

Multiple questions probed practices for infection and inflammation prophylaxis before the patient arrived in the operating room (OR), during surgery, and after the patient left the OR. Highlighting some of the important findings, Dr Cochener noted that the proportion of antibiotic used before patients arrived in the OR decreased significantly from 42% in 2013 to 29% in 2014.

“We think this change is due to increased use of intracameral antibiotic at the end of surgery,” Dr Cochener said.

Only about one-third of surgeons were using an anti-inflammatory agent before the patient came to the OR, but there was evidence of growing preference for a fixed combination antibiotic-anti-inflammatory (NSAID or steroid) product accompanied by a decrease in NSAID. Use of ocular antiseptic decreased prior to patient arrival in the OR and increased in the OR, although Dr Cochener said the latter data may have been influenced by a wording improvement in this question.

Responses to questions asking about intracameral antibiotic showed it was

Figure 5

Use of Intracameral Cefuroxime

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used by more surgeons in 2014 than in 2013 (71% vs 66%); an increase in its use for all patients rather than in specific situations accounted for the change. Cefuroxime accounted for almost all intracameral antibiotic use in 2013 (88%) and 2014 (91%), and use of Aprokam as the cefuroxime of choice almost doubled from 35% in 2013 to 62% in 2014 (Figure 4).

“The increase in cefuroxime is expected because of the availability of Aprokam, which is approved for intracameral use,” said Dr Cochener.

A growing proportion of surgeons said it was important to have a commercially available broad-spectrum antibiotic licensed for direct intracameral injection (76% to 82%), and there was a dramatic increase in the proportion citing medicolegal protection as the reason (8% to 42%) (Figure 5).

Responses to questions examining medication use after the patient left the OR showed a global decrease in the proportion of surgeons prescribing antibiotics (44% to 34%) and no change in anti-inflammatory use (93%).

However, use of a fixed combination antibiotic+steroid was prevalent and growing, increasing from 43% in 2013 to 59% in 2014. Of concern was the fact that the majority of surgeons using the fixed combination were treating for more than two weeks, and almost half used a tapering regimen.

“These practices could favour bacterial resistance development in the future,” Dr Cochener cautioned.

Asked what guidelines they follow for cataract surgery, the surgeons cited local/hospital guidelines most frequently (41% in 2013, 38% in 2014).

Compared with the previous year, there were increases in 2014 in the proportion of surgeons who said they followed the ESCRS guidelines (13% to 17%) or scientific society guidelines (32% to 39%), and a decrease in adherence to national guidelines (32% to 25%).

“We are encouraged that the ESCRS guidelines are being progressively followed, but it seems they should be considered by even more surgeons,” Dr Cochener said.

A new question in 2014 aimed to gather data on personal endophthalmitis rates. Half of the surgeons said they had at least one case of endophthalmitis in the past five years.

“While the reported endophthalmitis rate is debatable, the fact that so many surgeons reported endophthalmitis in the last five years is quite significant, and especially considering that most were probably not using intracameral cefuroxime during this time,” Dr Cochener said.

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Answers to Key Questions Anders Behndig MD, Professor, Department of Clinical Sciences/Ophthalmology, Umeå University, Sweden

Peter Barry, Béatrice Cochener, Susanne Gardner

TOPICAL ANTIBIOTIC PROTOCOLS Is there justification for omitting topical antibiotics if we are using an intracameral agent for endophthalmitis prophylaxis?

Dr Behndig: An analysis of the Swedish registry data showed no significant benefit of using topical antibiotics before and/or after surgery as an add-on to intracameral cefuroxime in terms of reducing endophthalmitis rates [Friling E et al, J Cataract Refract Surg. 2013;39:15-21].

What is the recommended duration of postoperative antibiotic treatment?

Dr Barry: Based on the Swedish registry data, I believe that postoperative antibiotic use may be unnecessary.

However, I can’t be 100% confident about the postoperative integrity of the incision, and so I still use a topical antibiotic and continue it for one week. The antibiotic should not be used for more than 14 days. Such prolonged use is not necessary and will likely promote resistance. I would also emphasise that the antibiotic should not be tapered.

BACTERIAL RESISTANCE Do data from the Swedish National Cataract Register show any evidence of increased bacterial resistance to cefuroxime after such a long period of its intracameral use in Sweden?

Dr Behndig: The answer is no, and I think the explanation is that cefuroxime has less potential to drive resistance development than some other antibiotics, such as the fluoroquinolones. We do see that the proportion of infections caused by organisms that were always resistant to cefuroxime is increasing so that enterococci and coagulase-negative staphylococci now account for about 70% of pathogens in culture-positive cases. However, that information should be considered in the context of the current, very low overall endophthalmitis rate. In 2013, there were only 22 cases of endophthalmitis in over 100,000 cataract procedures, which is about one-fifth of what it was in early registry years. I doubt this decrease in endophthalmitis rates would be seen if bacterial resistance to cefuroxime was increasing over time.

However, it may also be difficult to investigate this issue in the Swedish registry data considering that during the prolonged period of intracameral cefuroxime use there have also been changes in the surgery and characteristics of patients undergoing surgery. Analyses from countries where surgeons are just now switching to intracameral cefuroxime may better answer this question.

Dr Barry: Didn’t Per Montan MD, and colleagues in Stockholm recently switch to using intracameral moxifloxacin to see if it might make a difference?

Dr Behndig: I stopped using a topical antibiotic postoperatively in the 1990s when I began routine use of intracameral cefuroxime.

I also want to comment about the tapering issue. The EurObsCat data showing many surgeons are using a tapering regimen is very concerning.

Dr Behndig: Yes, and according to some preliminary data, it does not appear to have affected the endophthalmitis rate. However, because the number of infections is so low, it is difficult to identify a difference if it existed.

Dr Cochener: I agree, and perhaps the message to surgeons is to not use antibiotic-steroid fixed combination products. I also would recommend not using the topical antibiotic for more than one week. Now, we have been using a macrolide with a “flash” therapy regimen involving twice-daily dosing for just three days.

Have you ever experienced an episode of TASS after using intracameral cefuroxime?

When do surgeons in your countries begin treatment with the topical antibiotic?

Dr Behndig: Swedish surgeons who use a topical antibiotic generally start on the day of surgery.

Dr Cochener: There is a lot of variability among surgeons within countries. That said, there may be a tendency in France towards using the “flash” regimen and starting it just after the patient leaves the operating theatre.

Dr Barry: In Ireland, the topical antibiotic is generally started on the first day after surgery, as was done in the ESCRS study. Some critics of the study, especially from North America, have questioned that delay and say the antibiotic should have been started sooner, on the day of surgery or even on the day before.

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INTRACAMERAL CEFUROXIME

SAFETY ISSUES

Dr Barry: Some minor TASS-like problems were encountered in the early days during the ESCRS study design period, and through our investigations to identify the cause, we found it was related to dilution or diluent errors in the majority of cases. Use of balanced salt solution rather than normal saline for powder reconstitution was one of the most common errors with the “kitchen pharmacy” preparation of the intracameral cefuroxime in cases where patients developed TASS-like symptoms.

Dr Behndig: Over the many years that intracameral cefuroxime has been used in Sweden, we have not seen much TASS. Should you inject intracameral cefuroxime in the setting of a torn posterior capsule or will it increase the risk for cystoid macular oedema?

Dr Gardner: In a rabbit model, intravitreal injection of cefuroxime 1mg did not cause any retinal toxicity, and there is an almost three-fold extra margin of safety in humans

Use of Intracameral Cefuroxime

given the larger size of the human eye. So, even in the worst case scenario where the entire 1mg of intracameral cefuroxime migrates into the back of the eye, available data indicate there is not a safety concern.

Dr Barry: Not only is it safe to use intracameral cefuroxime in that situation, but it is actually particularly critical because eyes with posterior capsule rupture are at a greatly increased risk for endophthalmitis.

However, there are also clinical data to show that it is safe. When switching to intracameral cefuroxime, Shorstein and colleagues first excluded patients with posterior capsule rupture [Shorstein N et al, J Cataract Refract Surg.

2013;39:8-14]. Their endophthalmitis rate decreased, but it dropped even further after they started to use intracameral cefuroxime in case of posterior capsule rupture.

Dr Behndig: In the Swedish registry, intracameral cefuroxime has been used in about 16,000 cases with a posterior capsule rupture. I think that experience supports its safety.

Should intracameral cefuroxime be used in patients with a history of penicillin or cephalosporin allergy?

Dr Barry: To my knowledge there are two cases in the world literature of an anaphylactic reaction after intracameral cefuroxime injection during cataract surgery, one from Spain [Villada JR et al, J Cataract Refract Surg.

2005;31:620-621] and one from Israel [Moisseiev E, Levinger E. J Cataract Refract Surg. 2013;39:14321434]. However, a cause and effect relationship cannot be established with certainty in either case.

The risk for cross-sensitivity with penicillin exists only for cephalosporins that share a side chain moiety with a penicillin. Cefuroxime does not, and the risk of there being a cross-reaction with its use in a penicillin allergic individual is essentially non-existent.

Dr Gardner: Early in the history of cephalosporin manufacturing, products contained trace amounts of penicillin, and that seemed to contribute to high rates of what seemed to be cross-sensitivity. Cephalosporin product contamination with penicillin has been eliminated through better manufacturing processes.

Dr Behndig: We ask our patients only about a history of allergy to a cephalosporin, not to penicillin, and patients with cephalosporin allergy are very rare because in recent years, cephalosporins have not been used much for systemic antibiotic therapy in Sweden. On that basis, I expect we will see even fewer patients with a cephalosporin allergy in the future.

Dr Cochener: In France, we also only ask about cephalosporin allergy.

APROKAM USE The reconstituted Aprokam vial contains 50 mg/5ml, but the dose administered is just 1 mg/0.1 ml. Does the remainder have to be discarded, or can it be used for other patients?

Dr Cochener: The product is marketed for single-use only, and for medicolegal reasons should not be used for multiple dosing.

Use of Intracameral Cefuroxime

Dr Barry: According to my regulatory authority, surgeons are prohibited from using a single-use product that is intended to prevent a rare event, such as endophthalmitis, for multiple dosing because that practice exchanges one risk for another.

However, aside from the legal and regulatory issues, I believe there are other differences in terms of materials between containers that are approved for single-use versus multi-use dosing.

Dr Gardner: That is true. The regulatory requirements for manufacture of vial closures on single-use versus multiple use vials may differ among countries. The vial closure materials may therefore be different, with the potential for incompatibility for multiple entries into vials intended for single use only. I agree that for medicolegal reasons, surgeons should not violate the instructions on a vial labeled for single-use only.

Given the excess amount of cefuroxime in the Aprokam vial, what is the margin of safety if the surgeon inadvertently delivers a volume greater than 0.1ml?

Dr Gardner: There is likely no increased risk because the concentration of cefuroxime delivered into the eye remains the same. However, there is potential for toxicity using a higher concentration of cefuroxime. In an animal study, toxicity occurred with a concentration of 100 mg/ml, just a 10-fold increase compared to the concentration of Aprokam.

This information mitigates against the use of extemporaneously compounded cefuroxime solution for intracameral administration.

Dr Behndig: These questions about dilution errors are surprising to me because at least to my knowledge, there have not been a prominent problem during the long history of intracameral cefuroxime use in Sweden.

However, I can imagine dose and dilution errors can occur if there is a change in surgical protocol, such as if surgeons switch from subconjunctival antibiotic injection to intracameral use and are relying on extemporaneous compounding.

Dr Barry: In Sweden you have operated with intracameral cefuroxime and kitchen pharmacy for many years without any problem because it is a routine that is familiar to all of the staff. However, if the protocols change, problems can arise if there is not good communication with and education of all personnel involved.

There is a published report from Finland describing eight patients who were blinded after receiving 50-100 mg/ ml intracameral cefuroxime [Olavi P. Acta Ophthalmol.

2012;90:e153-4]. The error occurred because when directions for preparing the solution were sent by the manufacturer, only two pages of the three page fax were received.

The take home message from this and other realworld examples is that surgeons who have access to Aprokam should seriously reconsider a decision to use anything else.

Dr Cochener: In some countries, including France, physicians can be prosecuted for using a product offlabel for a particular indication when there is an available alternative licensed for that use.

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