Since their introduction over a decade ago, the fluoroquinolones have dramatically risen in importance, becoming an integral part of many therapeutic strategies. They offer effective treatment for serious infections as well as having a role treating more commonly encountered problems.

Ofloxacin has been one of the major fluoroquinolones, with excellent pharmacokinetic properties and a wide antibacterial spectrum. Investigation of ofloxacin’s racemic nature led to the discovery of a more active l-form, leading to the development of one of the latest and most advanced quinolones, levofloxacin. This compound offers all the advantages previously provided by ofloxacin, as well extra benefits of wider antibacterial coverage at a reduced dosage.

To discuss the use of fluoroquinolones in serious infections, with particular reference to levofloxacin, Penetration interviewed Dr. Ragnar Norrby, Visiting Professor in the Department of Microbiology, Prince of Wales Hospital, Hong Kong, and President of the International Society of Chemotherapy. Dr. Norrby, with his wide knowledge of infectious diseases, provides an insight into the latest developments in the field of infection, and the important role of fluoroquinolones and levofloxacin in this.

Questions

Q1. What do you see as the general directions for antimicrobial therapy in the future and the role of fluoroquinolones in this?

Q2. What role do you see for levofloxacin among the fluoroquinolones and what advantages does it offer?

Q3. Ofloxacin is well recognised as having less significant interactions than other fluoroquinolones, could you comment on levofloxacin in this regard and its safety profile?

Q4. Do you think these two major advantages would make levofloxacin the fluoroquinolone of choice in a number of situations?

Q5. What situations would you see levofloxacin being used clinically?

Q6. Could you comment on the role of levofloxacin in respiratory tract infections?

Q7. What role do you see levofloxacin having in tuberculosis?

Q8. What type of combination therapy would you recommend in those type of situations?

Q9. Could you give your views on the use of levofloxacin in genitourinary and obstetrical infections?

Q10. What dosage schedule would you use in those situations?

Q11. What duration of therapy do you recommend in urinary infections?

Q12. Could you comment on the use of self-medication for uncomplicated cystitis?

Q13. What about levofloxacin in the therapy of prostatitis?

Q14. Resistance development continues to be a major concern. Could you comment on this?

Q15. What of short-term prophylactic use, for example prior to surgery?

Q16. You have mentioned the use of fluoroquinolones in travellers’ diarrhea, what other types of gastrointestinal uses would you recommend?

Q17. Are there any other gastrointestinal indications?

Q18. Could you comment on the use of fluoroquinolones particularly ofloxacin and levofloxacin relating to cost effectiveness of treatment?

Q19. Could you comment on the use of once-daily therapy?

Q20. What other areas would you see fluoroquinolones, and particularly levofloxacin playing a role in?

Q21. Do you see a role for levofloxacin in immunocompromised patients?

Answers

Q1. What do you see as the general directions for antimicrobial therapy in the future and the role of fluoroquinolones in this?
A1. We are experiencing increasing problems with Gram-positive organisms, pneumococci, enterococci, and staphylococci. This is becoming more serious than we had expected. Gram-negatives are still a problem but one we can handle, especially using fluoroquinolones which I think hold a unique position in treating these infections.

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Q2. What role do you see for levofloxacin among the fluoroquinolones and what advantages does it offer?
A2. Levofloxacin is very interesting due to its enantiomorphic nature and is fundamentally an improved version of ofloxacin. It offers the good pharmacokinetics of ofloxacin (Table 1)(1), plus an improved antibacterial spectrum, and is more active so that it can be given in lower doses. I think that these factors allow pharmaceutical companies to develop levofloxacin for indications where ofloxacin has not been very strong.

Table 1. Comparison of pharmacokinetic parameters for levofloxacin and ofloxacin after a single oral administrationa (reference 1)

Levofloxacin is approximately twice active as ofloxacin. By combining this increase in activity added to its better pharmacokinetics, an advantage ofloxacin has always had over ciprofloxacin, I believe that levofloxacin will now be at the same level as ciprofloxacin. Until now ciprofloxacin has been the preferred quinolone because it has an excellent spectrum as well as activity against Pseudomonas, but now levofloxacin surpasses this.

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Q3. Ofloxacin is well recognised as having less significant interactions than other fluoroquinolones, could you comment on levofloxacin in this regard and its safety profile? 
A3. Levofloxacin has the major advantage of not having any significant drug-drug interactions since it does not have a major P-450 metabolism. I see two major safety advantages with ofloxacin and levofloxacin: lack of drug-drug interactions, particularly important being its lack of interaction with theophylline (Table 2)(2) and lack of phototoxicity potential. By having less phototoxicity, levofloxacin offers significant advantages over other quinolones as we have seen the problems encountered with lomefloxacin, and we are seeing them now with sparfloxacin.

Table 2. Interactions between quinolones and theophylline (reference 2)

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Q4. Do you think these two major advantages would make levofloxacin the fluoroquinolone of choice in a number of situations?
A4. Yes, it would have to be considered to be equal, and in some ways better, than ciprofloxacin. Previously, although very similar in many ways, ciprofloxacin had the advantage over ofloxacin with its better Pseudomonas activity. However levofloxacin now overcomes this and thus offers all the advantages of ciprofloxacin but also some additional advantages.

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Q5. What situations would you see levofloxacin being used clinically?
A5. The main indications should be Gram-negative infections, particularly in the genitourinary tract and enteric infections. There is also a potential role in the pediatric field, and I believe that we are now able to legitimately do prospective controlled trials in children, using a reasonably high dose and relatively short treatment times. I think all studies so far published have indicated that quinolones are safe in children and they are certainly needed in this population.
In addition there is a role in some specific Gram-positive infections but that depends very much on what happens to the prophylactic use and emergence of resistance. Levofloxacin is a very good therapeutic drug in some hospital situations, but I think should it not be used in neutropenic patients prophylactically due to reasons I will outline later.

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Q6. Could you comment on the role of levofloxacin in respiratory tract infections?
A6. The two major areas where I see levofloxacin being most useful in the respiratory field are hospital-acquired pneumonia and acute exacerbations of chronic bronchitis. Hospital-acquired pneumonia is predominantly a Gram-negative infection and if faced with Gram-positive etiology it is most probably Staphylococcus aureus, pneumococci are extremely rare in hospital-acquired pneumonia.
I don’t think that there is a role for any quinolone in community-acquired pneumonia. We have recently finished a trial in over 100 patients where we compared a new fluoroquinolone (fleroxacin) to doxycycline for the treatment of atypical pneumonia using very stringent diagnostic criteria. There was a statistically significant difference favoring doxycycline in terms of clinical efficacy for atypical pneumonia. However, it is possible that in the future quinolones may have a role to play in treating pnemonia in which the pathogen is either a penicillin-resistant S. pneumoniae, or one that is not susceptible to ß-lactams.

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Q7. What role do you see levofloxacin having in tuberculosis?
A7. Levofloxacin is a good candidate for tuberculosis treatment. In Hong Kong, the Mecca of tuberculosis, we use ofloxacin as one of the drugs for multi-drug resistant tuberculosis (MDR) and obviously everything that ofloxacin does, levofloxacin will do better (Table 3)(3). That is the key message with the drug, that it will be a better drug than ofloxacin, there is no doubt about that.

Table 3. Activity of quinolones and macrolides against Mycobacterium tuberculosis (reference 3)

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Q8. What type of combination therapy would you recommend in those type of situations?
A8. MDR is always very difficult. We now give multi-drug treatment when we suspect an MDR — that is, cases who are recurrences or don’t respond to initial conservative treatment. Normally we add ofloxacin, a macrolide, clarithromycin and we add ethambutol if it has not already been given because ethambutol seems to be a potent synergistic agent.

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Q9. Could you give your views on the use of levofloxacin in genitourinary and obstetrical infections?
A9. I think there is no doubt that in pyelonephritis a quinolone is the first line drug. For oral treatment there is nothing that beats a fluoroquinolone and I would prefer to see quinolones as the only first line drug in this situation. Levofloxacin has been studied in S. aureus pyelonephritis in mice, and shown to be more active than ciprofloxacin in vitro (Figure)(4).

Figure. Therapeutic efficacies of levoflaxin in Staphylococcus aureus pyelonephritis in mice.(reference 4)

Similarly I would see them as the first line alternative for recurrent and complicated cystitis. I prefer not to see them as first line treatment for uncomplicated sporadic cystitis, because that would probably add to the problems of resistance that such countries as France, with 30-40% resistance in Escherichia coli, are facing.

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Q10. What dosage schedule would you use in those situations? 
A10. There are pharmacodynamic studies which indicate that similar to aminoglycosides, quinolones should be dosed at high doses with long intervals, which is contrary to the penicillins and cephalosporins. I would tend to use levofloxacin 400-800 mg once a day rather than spaced.

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Q11. What duration of therapy do you recommend in urinary infections?
A11. Three days in cystitis, and two weeks is normal treatment time in pyelonephritis. There are studies showing that single dose treatment is similar in efficacy to three days using fluoroquinolones, however this depends on efficacy criteria used. Certainly there is little difference in clinical efficacy between shorter duration schedules, but there is a difference in bacteriological efficacy which is still the end point drug regulators require.

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Q12. Could you comment on the use of self-medication for uncomplicated cystitis?
A12. If I were to investigate one use of a drug like levofloxacin in uncomplicated cystitis it would be looking at very early, single dose, self-treatment at home compared to traditional strategies. This would be on prescription, not over-the-counter, for women who have recurrent cystitis and are easily able to recognise their symptoms. Experience we have gained from very well controlled studies of travellers’ diarrhea shows that if you start treatment very early the results are far better than if started 24 hours or later after onset of symptoms. This is due to limitation of mucosal damage, allowing recovery to occur much faster.

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Q13. What about levofloxacin in the therapy of prostatitis?
A13. Fluoroquinolones, I believe, are first line drugs for prostatitis. There is no doubt about that and levofloxacin may have added advantages giving it an edge there because of its better activity against some of the STDs and improved chlamydial activity.

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Q14. Resistance development continues to be a major concern. Could you comment on this?
A14. The emergence of resistance, particularly among the Gram-positives has been a problem (Table 4)(5). One reason leading to this is the use of fluoroquinolone prophylactically in neutropenic patients. Prophylaxis promotes resistance so I think this is one area where fluoroquinolones should not be used. If you introduce one drug on a regular low dose schedule for a prolonged period of time in neutropenic patients, resistance will develop. And this is being seen now with the antifungals. When it comes to fluoroquinolone prophylaxis I think that is one of the reasons why we have seen this shift towards more Gram-positive and less Gram-negative infections. Levofloxacin may have some advantage in this area. There has been a study which reports that levofloxacin and ofloxacin may have less potential in selecting for resistance. This is possibly due to the longer half-life of ofloxacin and levofloxacin compared to ciprofloxacin, as well as via a secondary mechanism of action they appear to have against non-dividing organisms. Such a feature of levofloxacin, if validated, would be a significant advantage, but this has not been tested in the clinical situation and needs further study.
The other reason why we see so much drug resistance in some areas is over the counter availability, which is a fact in most of southern Europe, all of Latin America, and most of Asia.

Table 4. Minimum inhibitory concentration (MIC) susceptibility testing results of 1,200 Gram-positive cocci, 1,300 Enterobacteriaceae species, and 700 other Gram-negative organisms tested at five medical centers in the USA and Canada versus 12 antimicrobial agents(reference 5)

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Q15. What of short-term prophylactic use, for example prior to surgery?
A15. Fluoroquinolones are good drugs prior to prostatectomy, and in some other surgical procedures. They are excellent drugs for prophylaxis against enteric infections allowing early self-treatment for problems such as travellers’ diarrhea.

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Q16. You have mentioned the use of fluoroquinolones in travellers’ diarrhea, what other types of gastrointestinal uses would you recommend?
A16. Definitely in Shigella, all cases of paratyphoid and typhoid, and septic cases of salmonellosis. I think those are the cases where you would use it from a therapeutic point of view. A recent very large trial in Vietnam compared ceftriaxone to a fluoroquinolone in children in a typhoid outbreak and the fluoroquinolone certainly came out much better than ceftriaxone. You would also use quinolones in cholera although the effect is more epidemiological, allowing the patients to become carrier free very quickly. While the clinical benefits of using antibiotics in cholera are debatable the enormous gain is that the patient is not a carrier. Quinolones are also useful in treating E. coli enteritis, hemorrhagic syndromes and all enteropathogenic E. coli. However shigellosis and typhoid remain the two important indications, although resistance is now rampant in virtually all of Asia. However I believe that in Pakistan and Vietnam there is a lot of chloramphenicol resistant Salmonella typhi, and more than 80% co-trimoxazole resistance, but no resistance to quinolones.

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Q17. Are there any other gastrointestinal indications?
A17. Yes, biliary tract infections are a potential indication. Very little research has been done on this which is surprising as the most common source of Gram-negative bacteremia in Hong Kong is cholangitis. This accounts for 40% of all community-acquired Gram-negative bacteremias, making it a more common source than urinary tract.

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Q18. Could you comment on the use of fluoroquinolones particularly ofloxacin and levofloxacin relating to cost effectiveness of treatment?
A18. They are cost-effective in that they offer the possibility of using the same drug parenterally and then switching to oral administration. The problem that we have seen, especially with ciprofloxacin, is pricing. Ciprofloxacin was originally priced to be given at a very low intravenous dose. However much higher doses were usually given for the serious infections being treated, thus making it extremely expensive when used clinically. This was not such a problem for ofloxacin, although I think, if intravenous ofloxacin had been priced at 50% of what it is now it would have been a blockbuster.

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Q19. Could you comment on the use of once-daily therapy?
A19. The pharmacodynamics of levofloxacin allow it to be administered in a range of infections on a once-daily schedule. Although useful, I do not think there is a big difference in compliance between once- or twice-daily therapy.

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Q20. What other areas would you see fluoroquinolones, and particularly levofloxacin playing a role in?
A20. I use fluoroquinolones in some situations when treating MRSA patients, although in general quinolones are not primarily Gram-positive drugs. They are good drugs for a range of problems, including osteomyelitis, where long-term treatment is needed. An area that requires further data is the activity of quinolones against anaerobes. There was one study presented at ICAAC where a blind loop was made in rabbit gut, emptied and when all the fecal contents were emptied it was demonstrated that ofloxacin was very effective in eradicating anaerobes from the gut. I would like to see more studies in this area, and it may be a possible advantage offered by ofloxacin and levofloxacin.

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Q21. Do you see a role for levofloxacin in immunocompromised patients?
A21. Yes, provided that you can demonstrate that you do not have a resistance problem in the hospital environment. Levofloxacin certainly offers an alternative but needs to be properly evaluated in a very large trial against one of the standard treatments. If you wanted to use a fluoroquinolone to treat a bacterial infection in an HIV patient I would certainly prefer to use one which has a minimum of drug-drug interactions and doesn’t involve the cytochrome P-450 system. This would probably favor ofloxacin or levofloxacin over the other fluoroquinolones.

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References

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