The rise and fall of Ciprofloxacin (and other fluoroquinolones)

A spellbinding chronicle of the ignominious failures that culminated in a black box warning two decades too late, and how they bear remarkable parallels to our present times (bonus content at end)

Prologue

It has become well nigh impossible to watch 15 minutes of television these days without being molested by pharma commercials peddling miracle cures for bent carrot penises, bulging eyeballs, reptilian skin eczema, talking dogs complaining of itchy skin or the repeated refrains of “if its COVID, Paxlovid” followed by the perfunctory, breathlessly unintelligible concatenation of blood curdling side effects at speeds that would put champion auctioneering fast talkers to shame.

Have you ever wondered about the people that suffer these dreaded side effects?

What happens after someone’s life is permanently upended after that event?

Does the system of checks, balances and regulatory safeguards kick in to warn patients and prescribers after many people suffer an unexpected complication?

Consider the words in italics quoted verbatim from a 2021 Atlantic article by Olga Khazan:

“A few days ago, an unusual offer landed in my inbox. “Do you want to interview this man before he ends his life?” read the subject line of the message sent by Linda Martin, who, out of concerns for her safety, would tell me only that she is in her 60s and lives on the West Coast.

She said that John Fratti, a 50-year-old former pharmaceutical-sales representative, was “making plans to end his life in the next few weeks because he can no longer stand the pain caused by Fluoroquinolone Toxicity.” That’s the term Martin and others use to describe the side effects of fluoroquinolone antibiotics, a class of drugs that includes ciprofloxacin, sometimes called Cipro, and levofloxacin, or Levaquin, which are taken for severe bacterial infections. She added that Fratti had already obtained a powerful sedative that can be used in assisted suicide.”

Or take the case of Jill Cobb, who suffers from hip and shoulder pain so severe that she can barely walk. She describes insomnia and anxiety as devastating as the pain and says the psychological side effects began days after being prescribed Levaquin.

Heather McCarthy says her son Shay had no mental health issues until he was prescribed Levaquin as a preventative following a surgical procedure. Within months, Shay dropped out of Purdue University and wound up on drugs to treat bi-polar disorder. In 2013, he jumped out of a 2nd floor window and ran his car into a concrete barrier.

When Amy Moser had a simple urinary tract infection in her late 20s, her doctor prescribed Ciprofloxacin, a powerful antibiotic used to treat anthrax and some of the most fearsome bacterial infections. Nearly 2 weeks after she finished her treatment, her left kneecap dislocated while she was trying on a swimsuit at a retail store. Shortly afterward, she had painful ligament ruptures in her wrists, then her shoulder dislocated, followed by three Achilles tendon tears

There are countless such stories. But of course you won’t hear about them on TV. Because zero of the staggering $6.88 billion spent on US direct-to-consumer marketing of pharmaceuticals in 2021 was spent on things most crucial to informed consent.

What follows is a cautionary tale of just one drug family. And how lessons of the past, many not dissimilar, and some a startling facsimile of our current times are replaced by a collective amnesia and a fate consigned to repeat itself over and again.

The early years

Ciprofloxacin is an antibiotic that belongs to the fluoroquinolone family. It was patented in 1980 and approved by the FDA in 1987. It is on the World Health Organization's List of Essential Medicines and represented a significant leap in the therapeutic armamentarium of oral antibiotics for many bacterial infections, including pseudomonas, a bacteria naturally resistant to most antibiotics, which even to this day, several decades later, has no other oral antibiotics available to treat it.

It quickly achieved blockbuster status, and by 1999 was earning more than $1 billion in U.S. sales given its broad spectrum of activity and the convenience of availability in a pill form. But what really catapulted it to fame and national spotlight was a completely unexpected turn of events.

The Big Bang: Rise to fame

Mid to Late September, 2001, just weeks after the September 11 attacks, the United States experienced a deliberate act of bioterrorism. Anthrax spores were widely disseminated using the US postal service. Americans were gripped with fear and and a sense of panic not unlike that seen during COVID-19 swept the nation. The media went into overdrive. The 24/7 news cycle drummed up fears real and imagined, and news chyrons and anchors did their best to keep people glued to the unfolding drama.

At the beginning of the outbreak, Ciprofloxacin was the only drug approved by the FDA for post exposure prophylaxis. So naturally it became the centerpiece of media focus and was accorded the kind of monomaniacal idolatry usually reserved by stalkers, cult members and Taylor Swift and K-Pop fans for the objects of their attention.

The Guardian called ciprofloxacin “the world's most popular drug” and ran a fawning article entitled How Cipro beats anthrax.

NBC Nightly News anchor Tom Brokaw held a bottle of ciprofloxacin to the camera and said, "In Cipro we trust."

Time Magazine called it the “Drug of the Moment”

In the nine months leading up to September 25, 2001, there were just 13 media stories containing the words anthrax and Cipro. Over the next 40 days, the media pumped out an impressive 3,750 stories and articles.

Unsurprisingly then, Cipro became to Anthrax what toilet paper became to COVID. Everyone was stocking up on it. Sebastian Manciameli, a pharmacist at Zitomer Pharmacy on Manhattan's Upper East Side, said: ''We can't keep it in stock. I usually keep 100 tablets in stock, but this time I ordered 3,000 and sold out. One person bought 1,000 tablets.'' Read that again: one person, 1000 tablets.

Not to be left behind, the seedy underbelly of black market pharmaceuticals began cashing in on the cipro craze. Dozens of Web sites sprung up in less than two weeks promising to sell anthrax-treating Cipro packages without having to visit a doctor -- at a whopping $7 a pill. One study reported an “outbreak” of illegal Cipro sales. At least 59 Web sites selling ciprofloxacin without prescription—23 of which were created within 2 weeks after the anthrax outbreak. It was impossible to tell which websites sold the real thing and which ones sold spurious pills that contained, well, God only knows what.

Cipro seeking Americans even began flocking to Canada to procure the drug at cheaper prices while the Canadian government came very close to paying twice for the antibiotic after breaking its own drug patent rules when it ordered the drug from a generic drug manufacturer. Note that there were no confirmed bioterrorism anthrax cases in Canada. Bayer, the patent holder and manufacturer eventually donated a large amount of Cipro to Canada, which led the Canadian government to agree to acquire ciprofloxacin exclusively from Bayer for the duration of the patent agreement.

It was in the context of this feeding frenzy that ciprofloxacin, already a highly prescribed drug reached its sales apogee. By early November, 2001, approximately 32,000 people had initiated prophylaxis with ciprofloxacin or doxycycline. The average duration of prophylaxis is 60 days. Two months is an important number. Approximately 32,000 people took cipro or doxycycline for 2 months. There are very few situations in infectious diseases, if any, where perfectly healthy individuals take antibiotics for 2 months. Most clinical trials study antibiotic side effects for courses of 1-2 weeks. There are none for a 2 month duration. But this was a sales bonanza and Big Pharma wasn’t complaining.

At its peak, Cipro sales topped 2 billion euros in 2001. That is over 3 billion euros in inflation adjusted for 2023. For additional context, only 43 people tested positive for anthrax in 2001. Compare that to Paxlovid, which had sales of about $8 billion for COVID, a disease that infected millions.

The warning signs, The Black Box warnings and Beyond

Very shortly after approval, a trickle of warning signs began to appear. For example, as early as 1990, a report described reversible bilateral visual loss ascribed to ciprofloxacin. At the same time, a large 1989 study of nearly 9500 patients reported a 1.5 % discontinuation rate of the drug due to serious side effects, but called the drug “relatively safe” nonetheless.

Meanwhile, during approximately the same time, Temafloxacin, another fluoroquinolone antibiotic drug related to ciprofloxacin was withdrawn from sale in the United States just 4 months after its approval in 1992 because of serious adverse effects resulting in three deaths and concerning reactions in over a hundred patients. Which is all the more stunning when you consider that a year earlier, in 1991, a peer reviewed article in a high impact factor medical journal boasted that it was “safe” for high risk populations and even put it in the title: “Temafloxacin: A safe antibiotic for the elderly, patients with comorbidities, and other special populations”

By 1996, more than 130 reports of tendon inflammation (many involving rupture) and frequently involving the Achilles tendon in individuals taking fluoroquinolones had begun to flow in. And it wasn’t a goverment regulatory body that shed light on this safety signal, but a consumer advocacy group called Public Citizen’s Health Research Group. In fact, so alarmed were they by their findings that they petitioned the FDA to immediately add a warning label in bold type alerting the public and prescribers to the potential side effects of this class of drugs and to stop taking the medications if tendon pain occurred. The letter is phenomenally well documented and worth reading. It can be found here.

Thanks in no small part to the advocacy of public citizens health research group, the FDA finally issued a statement in the October 1996 issue of its Medical Bulletin to all manufacturers of fluoroquinolones requesting a revision of the package inserts to include a new paragraph in the “Warnings” section acknowledging the risk of tendonitis and tendon rupture with fluoroquinolone antibiotics.

In the aftermath of the anthrax attacks of 2001, a class action was filed against Bayer, the manufacturer of Ciprofloxacin on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the U.S. Capitol, who alleged they developed serious adverse effects from taking ciprofloxacin. The action alleged Bayer failed to warn class members of the potential side effects of the drug, thereby violating the Pennsylvania Unfair Trade Practices and Consumer Protection Laws. The class action was defeated and the litigation abandoned by the plaintiffs. A similar action was filed in 2003 in New Jersey by four New Jersey postal workers but was withdrawn for lack of grounds, as workers had been informed of the risks of ciprofloxacin when they were given the option of taking the drug.

In 2002, the FDA issued a warning to Bayer and other manufacturers of fluoroquinolone antibiotics that it had received numerous reports linking these drugs to an increased risk of peripheral neuropathy, a potentially serious nerve damage affecting the arms or legs. Recall, that the earlier warning involved tendon rupture, not nerve damage.

Then, in 2006, the same consumer group, Public Citizen’s Health Research Group, that petitioned the FDA in 1996, once again petitioned them; this time to add a “black box” warning, the strongest type available for prescription drugs, to fluoroquinolones given the risk of tendon injury and rupture. Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group wrote “The possibility of tendon rupture is now mentioned in the drug’s prescribing instructions, but the warning “is buried in a long list of possible adverse reactions and is far too easy to miss. The numbers are startling. Tendon ruptures associated with these drugs continue to occur at a disturbing rate but could be prevented if doctors and patients were more aware of early warning signals, such as the onset of tendon pain, and switched to other antibiotics,” Dr. Sidney Wolfe continued. “The FDA must act and require black box warnings and patient information guides.”

Public Citizen’s independent review of the FDA’s adverse event database showed 262 reported cases of tendon ruptures, 258 cases of tendonitis and 274 cases of other tendon disorders between November 1997 and Dec. 31, 2005, associated with the fluoroquinolone antibiotics, with 175 of those occurring since the beginning of 2003. Sixty-one percent of the ruptures were associated with Levaquin, which accounted for 45 percent of all fluoroquinolone prescriptions in the past four years, while 23 percent of the ruptures were associated with Cipro. (Ciprofloxacin and Levofloxacin belong to the same fluoroquinolone family of antibiotics). The entire letter can be read here.

Finally, in 2008, after over 2 decades since the drug was approved and a decade after the public citizens health research group implored them after countless cases of adverse events and a WHO survey in Australia showing fluoroquinolone use correlation in 90 percent of cases of tendon disorders, the FDA issued its first “black box warning” around the use of fluoroquinolones. Black box warnings are the highest safety-related warning that medications can have assigned by the Food and Drug Administration. These warnings are intended to bring the consumer’s attention to the major risks of the drug and are considered severe and frequent enough to have a significant public health impact.

Since 2008, as if awoken from a two decade coma, the FDA has doused the American public with a fire hose of warnings about fluoroquinolone use.

Below is the timeline of black box warnings:

• In 2008, the FDA first added a “black box” warning to fluoroquinolones, citing an increased risk of tendinitis and tendon rupture in patients prescribed these meds.

• In 2011, the agency required the warning label to include risks of worsening symptoms for those with myasthenia gravis, a chronic autoimmune disease that causes muscle weakness, vision problems, and speech problems.

• In 2013, regulators required updated labels noting the potential for irreversible peripheral neuropathy (serious nerve damage).

• In 2016, the FDA issued its strongest warning against the use of such antibiotics for simple bacterial infections – such as uncomplicated urinary tract infections (UTIs), acute sinusitis, and acute bronchitis – saying the “association of fluoroquinolones with disabling and potentially permanent side effects involving tendons, muscles, joints, nerves and the central nervous system … outweighs the benefits for patients.”

• In 2018, regulators required safety labeling changes to include warnings about the risks of aortic aneurysm – a life-threatening enlargement of the main vessel that delivers blood to the body – and mental health side effects and serious blood sugar disturbances.

A 2015 study in JAMA Internal Medicine found that people are twice as likely to suffer an aortic aneurysm or rupture within 60 days of using a fluoroquinolone. The FDA didn’t warn the public via safety label update until late 2018. (see last bullet above)

Since 2020, European regulators, namely the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) have been warning prescribers about an increased risk of leaking heart valves after the use of fluoroquinolones, based on a 2019 Journal of the American College of Cardiology paper linking valvular disease and fluoroquinolone use. While the Europeans have promulgated a cardiovascular safety safety update based on a journal paper written by Americans, conspicuously absent is any warning from the American regulator, the FDA.

Since the 1980s, more than 60,000 patients have reported hundreds of thousands of serious events linked to fluoroquinolones to the FDA, including 6,575 reports of deaths.

Fluoroquinolone makers have faced thousands of lawsuits from patients who claim that their injuries were caused by the drugs. J&J alone faced 3,400 lawsuits over Levaquin’s links to tendon problems and settled many of those cases. Since then, patients have sued over Levaquin’s potential to trigger peripheral neuropathy. And in January, another group of patients sued, claiming that J&J deliberately mislabeled and misbranded Levaquin, playing down harmful side effects for its own financial gain.

Epilogue

It took over 20 years from ciprofloxacin approval in 1987 to the appearance of the first fluoroquinolone black box warning in 2008. Two decades. Surely no one with a functioning brainstem thinks that the intervening decades pockmarked with lawsuits, journal publications and the constant exhortation by public advocacy groups were uneventful, placid and copasetic. But the gears of bureaucracy turn agonizingly slow.

The mechanism for collecting adverse events after approval of any drug is called “Postmarketing surveillance.” Its purpose is to identify previously unrecognized adverse effects as well as positive effects. Did this process fail in the case of fluoroquinolones? Or did the powers that be decide that it did not meet their safety threshold? This becomes even more baffling when you consider that Five fluoroquinolones were pulled off the US market for safety concerns before the 2008 black box warning.

Omniflox (temafloxacin)

Abbott withdrew the medication worldwide in 1992 because of blood cell destruction. More than four dozen people fell ill and at least three died.

Trovan (trovafloxacin)

The Pfizer drug was withdrawn in 2001 after it was linked to liver damage and liver failure only 3 years after approval.

Raxar (grepafloxacin)

Glaxo Wellcome pulled the medication from shelves worldwide in 1999 after the drug was linked to a certain type of potentially fatal heart rhythm.

Zagam (sparfloxacin)

The drug was pulled from the United States market because it caused toxic skin inflammation similar to a sunburn when people taking it were exposed to sunlight.

Tequin (gaitfloxacin)

Bristol-Myers Squibb stopped making the medication in 2006 after it caused dangerous fluctuations in blood sugar levels.

I want to be perfectly clear, this is not a demonization of fluoroquinolones, which are life-saving drugs, but only when used in the right circumstance, for the right indication, after comprehensive risk-benefit assessment, consideration of alternatives and with full disclosure and informed consent of the patient. This is about how human beings use these drugs. We seem to have forgotten the the dictum of the Renaissance physician Paracelsus (1493–1541) who famously said “What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison,” This centuries old tenet seems to have been erased from our collective psyche and replaced by the notion of a benign panacea, one that holds the promise of protecting an entire population but with none of the risks associated with indiscriminate use. If you still haven’t figured out, there is no such thing as perfectly “safe and effective” and the consequences of our self-imposed amnesia in pursuit of utopian ideals of safety are doomed to catastrophic outcomes every single time. This marketing catchphrase repeated to the point of absurdity, needs to be banished from the medical lexicon.

Safety and efficacy are relative. Consider these two extremes: Cancer drugs usually cause plethoric side effects, but still may not be “unsafe” because its safety and efficacy are weighted against certain death, which is the most unsafe outcome of untreated cancer. On the other hand, a toe nail fungus cure that carries a 1% chance of liver failure may still be unsafe. Because nobody dies of ugly nails, but not having a functioning liver can be fatal (“live” in name being a dead giveaway of its importance). This is why risk-benefit analysis is always an individual basis assessment and even then, an estimate and not a mathematical certainty. When you carpet bomb a population with a one-size-fits-all approach, its guaranteed to fit very few. So many of our public health measures are now analogous to tailoring legs to fit one safety pant instead of tailoring pants to fit different legs.

The story of fluoroquinolones is a cautionary tale many decades in the making whose lessons should’ve have been used as a template when formulating pandemic policy. Instead, its every instruction was forgotten and replaced by a hubris so inexplicable that it defies logic and reason. It takes several years, decades even, for the full range of side effects of a drug to fully manifest. And even then getting those in charge of regulating and warning to take notice is like swimming upstream during riptide with lead weights around your legs. A younger me used to be in awe of how many things were fixed through the miracle of modern medicine. The older me marvels at how many things can break because of it. The only certain things in life are death and taxes. The only certain thing in medicine is that what we think we know today ain’t so tomorrow. So maybe some humility is in order.

I first read Sir Robert Hutchinson's (1871-1960) most humble and intriguing petition to God, now known as "The Physician's Prayer," over three decades ago. It has since been the North Star of my personal medical credo.

From the inability to let well alone; 

From too much zeal for the new and contempt for what is old; 

From putting knowledge before wisdom, science before art, and cleverness before common sense; 

From treating patients as cases; 

And from making the cure of disease more grievous than the endurance of the same; 

Good Lord, deliver us.” 

Bonus for sticking around

Kudos to you for reading something this verbose. If you’d like to see even more paroxysms of verbosity from me, consider sharing it with your friends and show your support and encouragement by subscribing to my substack here:

In a bizarre twist of past is prologue, the use of ciprofloxacin for anthrax was rushed through FDA approval at the urging of the congress.

In the summer of 2000, after hearing testimony on bioterrorist threats, rattled lawmakers launched an investigation into U.S. preparedness. Two drugs were considered feasible treatments for anthrax: Penicillin and doxycycline. However . scientists feared that introducing massive amounts of penicillin into the general population could hasten the creation of mutant penicillin-resistant strains of bacteria. Some were concerned that terrorists had engineered strains of the anthrax bacteria resistant to both penicillin and doxycycline.

Lawmakers were told Ciprofloxacin was another option. Bayer was notified, and members of Congress urged the FDA to speed up drug approval. In August 2000, Cipro, which had demonstrated an anti-anthrax efficacy in tests on monkeys, was rushed through the approval process and dubbed the unequivocal drug of choice in the anthrax battle. No human testing was conducted for this indication. Fascinating isn’t it how we keep seeing the same movie over and again?

In the foaming sea of madness that the Anthrax bioterror had wrought upon public policy, one Washington Post writer offered a rare contrarian and remarkably prescient assessment in November 2001. He called it an 'Uncontrolled Experiment'

“Cipro had never been tested against anthrax in people. But based on its effectiveness against other bacteria and an animal study from 1993, regulators at the Food and Drug Administration designated Cipro the only medicine officially approved for inhalation anthrax…

The disparity between the imagined attack and the real one underscores the difficulty of formulating public health measures against little-known bioweapons, and the very real danger that some cures can cause more harm than the bioweapons themselves. For while the anthrax attack that has unfolded over the last three weeks has so far been much milder than the worst-case scenario, the consequences of over-aggressive treatment may not be mild at all.

The full impact of large numbers of people being put on Cipro by doctors -- and even larger numbers taking the medicine on their own -- will not be known for weeks or months. But already, patients with other illnesses who desperately need Cipro have been deprived of the medicine, and patients around the country taking the drug have begun reporting such side effects as dizziness, headaches, nausea and achy joints. Concerns are mounting that overusing Cipro will spawn the growth of resistant microbes, rendering ineffective a drug considered to be a last resort when no other antibiotics work.

..We have never faced the mass use of an antibiotic for 60 days; there's no precedent for that in medicine…

…When you start giving it for two months, that's a whole level of usage that hasn't been proven to be safe”

That’s a wrap folks. I spent countless hours researching and refining this. Hope you enjoyed reading as much as I did writing it. Feel free to share, subscribe and leave a comment. If you would like to reproduce any part of it, please give due credit.

Here is my original Twitter thread that was phenomenally well received. Follow me there for 240 character restricted cogitative refulgence.

See you soon.

Chabria @ShivenChabria

1. Ciprofloxacin, an antibiotic, was approved by the FDA in 1987. At its peak, ciprofloxacin sales crossed 2 billion euros in 2001. At one point it was one of the most frequently prescribed antibiotics and it remains a critically important lifesaving antibiotic today.