Antibiotics

Definition

Antibiotics are drugs derived from molds or bacteria that inhibit the growth of other microorganisms. Even modern antibiotics that are chemically modified can be traced back to a substance originally found in a microorganism.

Description

A large number of antibiotics are available. They are classified by their chemical structure since drugs with similar chemical structures tend to have similar actions. Based on clinical experience, physicians may know that some types of infection normally respond to specific antibiotics, but if the infection fails to respond, or recurs, it may be necessary to do culture and sensitivity testing. Microorganisms develop resistance to antibiotics, and so there is no assurance that an antibiotic will retain its effectiveness against some types of infection.

Patterns of bacterial resistance also depend on the environment where the infection is acquired. In hospitals, where antibiotics are widely used, microorganisms are usually more resistant than those found outside the hospital. Infections developed by hospitalized patients often require different treatment from infections developed outside the hospital (community acquired).

Penicillins

• Penicillin G
• Penicillin V
• Nafcillin
• Oxacillin

• Ampicillin

  Antibiotics

  Brand name	Generic name
  (Illustration by GGS Information Services. Cengage Learning, Gale)
  Aminoglycosides
  Amikin	amikacin
  AK-Tob, Tobi, Tobrex	tobramycin
  Capastat Sulfate	capreomycin sulfate
  Garamycin, Gentak, Pred-G	gentamicin
  Kantrex	kanamycin
  Netromycin	netilmicin
  Carbapenems
  Invanz	ertapenem
  Merrem I.V.	meropenem
  Primaxin	imipenem/cilastatin
  Cephalosporins
  Ancef	cefazolin
  Ceclor	cefaclor
  Cedax	ceftibuten
  Ceftin, Zinacef	cefuroxime
  Cefzil	cefprozil
  Duricef	cefadroxil
  Fortaz, Tazicef	ceftazidime
  Keflex	cephalexin
  Mefoxin	cefoxitin
  Omnicef	cefdinir
  Rocephin	ceftriaxone
  Spectracef	cefditoren
  Suprax	cefixime
  Vantin	cefpodoxime
  Macrolides
  Biaxin, Biaxin XL	clarithromycin
  ERYC, Ery-Tab, EryDerm, EryGel, PCE	erythromycin
  Zithromax	azithromycin
  Penicillins
  Amoxil, Trimox	amoxicillin
  Bactocill	oxacillin
  Dicloxacillin Sodium	dicloxacillin sodium
  Pfizerpen	penicillin G
  Principen	ampicillin
  Timentin	ticarcillin (and clavulanate)
  Unipen	nafcillin
  V-Cillin K, Veetids	penicillin V
  Zosyn	piperacillin (and tazobactam)
  Polypeptides
  Baciim, Baci-Rx	bacitracin
  Coly-Mycin S	colistin sulfate
  Polymyxin B Sulfate	polymyxin b sulfate
  Quinolones
  Avelox, Vigamox	moxifloxacin hydrochloride
  Ciloxan, Cipro	ciprofloxacin hydrochloride
  Levaquin, Quixin	levofloxacin
  Maxaquin	lomefloxacin hydrochloride
  Noroxin	norfloxacin
  Tequin, Zymar	gatifloxacin
  Sulfonamides
  Azulfidine	sulfasalazine
  Bleph-10, Bleph-30, Cetamide, Isopto Cetamide, Ocusulf-10, Sulf-10	sulfacetamide sodium
  Gantanol	sulfamethoxazole
  Gantrisin	sulfisoxazole
  Silvadene	silver sulfadiazine
  Sulfamylon	mafenide acetate
  Thiosulfil Forte	sulfamethizole
  Tetracyclines
  Declomycin	demeclocycline
  Doryx, Monodox, Vibramycin, Vibra-Tabs	doxycycline hyclate
  Dynacin, Minocin	minocycline hydrochloride
  Sumycin	tetracycline hydrochloride
  Terramycin	oxytetracycline
  Miscellaneous
  Chloramphenicol	chloramphenicol
  Cleocin, Cleocin T, Clinda-Derm, Clindagel, Clindets, Clindesse	clindamycin
  Coly-Mycin M	colistimethate
  Flagyl, Flagyl ER, Flagyl I.V., Noritate, Metrog	metronidazole
  Furadantin, Macrobid	nitrofurantoin
  Monurol	fosfomycin tromethamine
  Myambutol	ethambutol
  Nydrazid	isoniazid
  Pyrazinamide	pyrazinamide
  Synercid	quinupristin/dalfopristin
  Trobicin	spectinomycin hydrochloride
  Vancocin	vancomycin hydrochloride
  Combination products
  Cortisporin, DexaSporin, Maxitrol, Neosporin Ophthalmic	bacitracin, neomycin, and polymyxin b sulfate
  Duac	clindamycin and benzoyl peroxide
  Helidac	tetracycline hydrochloride, metronidazole, and bismuth subsalicylate
  Prevpac	clarithromycin, amoxicillin, and lansoprazole
  Poly-Pred	neomycin, polymyxin b sulfate, and prednisolone
  Rifamate	isoniazid and rifampin
  Rifater	isoniazid, rifampin, and pyrazinamide
  TobraDex	Dexamethasone and tobramycin

  Amoxicillin

• Carbenicillin
• Piperacillin
• Ticarcillin

Penicillin was first discovered by Scottish researcher Sir Alexander Fleming (1881–1955) in 1928, and first used in treatment in the 1940s. Penicillin G is the original penicillin, and is still clinically valuable. Penicillin V is a chemical modification of penicillin with similar activity, but it is more stable in the acidic environment of the digestive tract. Penicillins G and V are effective against anaerobic bacteria (bacteria that live in the absence of air). Since anaerobic bacteria are common in the oral cavity, these two penicillins are widely used in dentistry.

Penicillins are bactericidal, meaning that they kill bacteria. They block the ability of bacteria to develop a cell wall. As a result, penicillins are most effective against bacteria that are actively multiplying.

Nafcillin and oxacillin are called penicillinase resistant penicillins because they are relatively resistant to the enzyme penicillinase produced by some bacteria. Penicillinase inactivates penicillin. The first penicillin in this class was methicillin. Although methicillin is no longer used, bacteria that have developed a resistance to this class of drugs are still referred to as methicillin resistant. The term methicillin-resistant Staphylococcus aureus (MRSA) applies to a strain of bacteria resistant to all penicillins.

Ampicillin and amoxicillin are aminopenicillins, which are effective against a wider range of bacteria than the original penicillins. Aminopenicillins are sensitive to penicillinase, but they can be combined with penicillinase inhibitors such as potassium clavulanate or sulbactam. The resulting combination is effective against penicillinase producing strains of bacteria.

Carbenicillin, piperacillin and ticarcillin are extended spectrum penicillins, and may be effective against some bacteria that are resistant to other penicillins.

Cephalosporins

Cephalosporins are chemically related to penicillins in that they have the same central ring structure, called the beta lactam ring. Some drugs in this group are not cephalosporins technically, but are considered together because they have similar structures, uses and activity. Cephalosporins are usually grouped by generation.

First generation cephalosporins are generally effective against simple infections of the skin and soft tissues. Cefazolin is widely used before surgery to prevent development of infections. Additional first generation cephalosporins are:

• Cefadroxil
• Cephalexin
• Cephradine

Second generation cephalosporins and the closely related cephamycins have a broader spectrum than the first generation drugs, and may be useful when an infection is caused by more than one organism. Cefoxitin and cefotetan are effective against anaerobic organisms, and may help treat infections of the intestines, decubitus ulcers or diabetic foot ulcers. Other second generation cephalosporins are:

• Cefaclor
• Cefprozil
• Cefuroxime

Third generation cephalosporins have a broader spectrum of action than the second generation drugs, and usually have better penetration into the central nervous system, making them useful for treatment of meningitis . It is often necessary to use third generation cephalosporins in combination with other antibiotics. Ceftazidime and cefoperazone are active against Pseudomonas aeruginosa, which is often resistant to other antibiotics. Some drugs in this group have relatively long durations of action and may require only one dose each day. Since these drugs are given intravenously, the drugs requiring fewer doses are good choices for home care . Third generation cephalosporins also include:

• Cefdinir
• Cefditoren
• Cefixime
• Cefotaxime
• Cefpodoxime
• Ceftibuten
• Ceftozoxime
• Ceftriaxone

Cefepime is sometimes called a fourth generation cephalosporin, but it is essentially the same as the third generation group.

Aminoglycosides

• Amikacin
• Gentamicin
• Neomycin
• Streptomycin
• Tobramycin

Streptomycin, the first of the aminoglycoside antibiotics, was isolated from soil bacteria by Russian American microbiologist Selman Waksman (1888–1973) in 1943. Drugs in this class are bactericidal and act by binding to proteins inside bacterial cells. These drugs are rarely used alone except for treating plague and tularemia. They are moe commonly used in hospitals in combination with beta-lactam antibiotics, for treatment of resistant infections. Even for that purpose, bacterial resistance has developed, leading some experts to advocate for replacing the aminoglycoside with a flouroquinolone in combination therapy. Amikacin, gentamicin and tobramycin are usually used in hospitals, and the selection is based on experience with the bacterial resistance patterns at the institution.

Streptomycin is used in combination with other drugs for treatment of tuberculosis . Neomycin and kanamycin are toxic, making their use limited. Neomycin is poorly absorbed through skin or mucous membranes, so it can be safely used as eye drops, ear drops, or for bowel cleansing before surgery. When swallowed, neomycin kills intestinal bacteria, but is not absorbed in large enough amounts to have any systemic effect.

Tetracyclines

• Tetracycline
• Demeclocycline
• Doxycycline
• Minocycline

There is some evidence that tetracycline was a byproduct of brewing and baking in ancient Egypt and that the antibacterial effects of beer were recognized and applied medicinally at that time. Several variants on tetracycline, including chlortetracycline and oxy-tetracycline, were discovered around the same period in the late 1940s. They all were found to have similar chemical structures and actions. Tetracyclines are bacteriostatic drugs—drugs that do not kill bacteria, but inhibit growth so that the normal immune response can destroy the pathogens. Tetracyclines are broad spectrum antibiotics, effective against a wider range of bacterial pathogens than any earlier antibiotics. Bacteriocidal drugs are generally preferred when available, but tetracycline and its derivatives are invaluable for treatment of Rocky Mountain Spotted Fever, Q Fever, chancroid and plague.

The tetracyclines have a broad spectrum, low toxicity, and good penetration into the skin, so they have been widely used for treatment of acne. Doxycycline has been recommended for prevention of traveler's diarrhea and some strains of malaria.

Flouroquinolones

• Ciprofloxacin
• Gatifloxacin
• Gemifloxacin
• Levofloxacin
• Moxifloxacin

• Norfloxacin

  Ofloxacin

• Trovafloxacin

Flouroquinolones are a newer group of antibiotics, and are relatively uniform in their actions and uses. They may be used in urinary tract infections, bacterial prostatitis, and most forms of infectious diarrhea. Ciprofloxacin has been useful in combination with a beta-lactam antibiotic against some resistant hospital acquired infections. It was also recommended for prevention against anthrax during the 2001 bio-terrorism alerts.

Flouroquinolones have been a major advance in antibiotic therapy, but their widespread use has resulted in bacterial resistance to some older members of this class of drugs.

Macrolides

• Azithromycin
• Clarithromycin
• Erythromycin
• Telithromycin

Erythromycin is used as an alternative to penicillin for patients who are allergic to the penicillin group. Although erythromycin is very similar in action and uses to penicillin G, it causes more stomach distress, and severe vein irritation when injected. Erythromycin is applied to the skin for treatment of acne.

Zithromycin and clarithromycin are relatively new, are more effective against many infections of the respiratory tract, and have a high degree of tolerability. They are particularly useful against Hemophilus influenzae and Mycobacterium avium complex. They are also useful against Legionnaire's Disease and other types of lung infections. Azithromycin is used for infections of the urethra and the cervix.

Telithromycin is a ketolide antibiotic, but is closely related to the macrolides. The unique chemical structure of this antibiotic makes it a broad spectrum antibiotic effective against penicillin- and macrolide-resistant pathogens. Telithromycin is primarily used to treat respiratory infections. The U.S. Food and Drug Administration (FDA) has issued warnings, and reduced the number of conditions telithromycin is approved to treat because of its toxicity. However, it remains useful for infections that are resistant to other antibiotics.

Other antibiotics

A large number of other antibiotics exist, but are less widely used than those just described.

Chloramphenicol is a broad spectrum antibiotic that is no longer considered the drug of choice for any infection, but is still used for serious infections that are resistant to other antibiotics.

Clindamycin has a spectrum of action similar to that of erythromycin, but is more useful in treatment of anaerobic infections.

Recommended dosage

The usual recommended doses for antibiotics may not apply to elderly patients due to unique problems typical for this age group. There is a normal age-related decline in kidney function and since most antibiotics are eliminated through the kidneys, lower doses may be necessary, particularly for those drugs that may themselves impair renal function. At the same time, because of age related declines in immune system function, higher blood levels of antibiotics may be required in elderly patients. Although some drugs have been studied in an elderly population and specific guidelines for dosing are available, these recommendations may be altered by the presence of coexisting diseases, and use of other medications at the same time. Whenever possible, infections in the elderly should be treated by physicians familiar with the specific needs of geriatric patients.

Precautions

Antibiotics may have special risks. The physician and pharmacist should discuss potential side effects and drug interactions with the patient. It is important that the patient tell their physician all medications they are using, both prescription and over-the-counter, as well as herbal preparations and other drugs.

Any side effects or adverse reactions should be reported to the physician immediately. Elderly patients may need guidance regarding what is and what is not a side effect.

In some cases, drug absorption can vary with the type of the food consumed. Patients should review the antibiotic label to determine if it should be taken with meals or on an empty stomach. Unless otherwise directed, store antibiotics in a cool, dry place. Do not store antibiotics in a medicine cabinet that may become steamy due to showering, or in a refrigerator.

Antibiotics have a limited shelf-life, and work only on specific organisms. It may be tempting to save extra doses and take them the next time there is evidence of an infection, but this is not safe because the drug may not be the right choice for the new infection, or it may have expired and will no longer be effective. Rarely, some antibiotics cause more severe allergic reactions when the drug passes its expiration date.

Side effects

All antibiotics have some side effects and adverse effects. The physician or pharmacist should discuss these with the patient when prescribing antibiotic medications.

Almost all antibiotics can cause diarrhea and hairy tongue. This occurs when the antibiotic kills some of the normal bacteria in the mouth and intestinal tract, leaving an overgrowth of resistant molds and fungi. The problem is more common with broad spectrum antibiotics, but has been reported with narrow spectrum drugs. Ampicillin causes diarrhea more frequently than does amoxicillin, although this advantage is seen more often in children than in adults.

Allergic reactions can be a serious problem with all antibiotics, but are particularly noted with the penicillins. Patients allergic to penicillin may also be allergic to cephalosporins. Because of the importance of these two classes of drugs in both treatment and prevention of infection, patients should describe all adverse reactions to penicillin in great detail. It is important to distinguish between a true allergic reaction, which is reason not to use these drugs, and a side effect such as upset stomach or mild dizziness .

Tetracyclines can cause photosensitization in which the skin becomes extra sensitive to sunlight. Demeclocycline is more prone to cause this problem than other tetracyclines. Persons taking tetracyclines should avoid excessive sun exposure. Some flour-oquinolones cause photosensitization, even with the use of sunblocks, or when light passes through glass.

Ruptures of the shoulder, hand, and Achilles tendons requiring surgical repair or resulting in prolonged disability have been reported with fluoroquinolones. Patients taking these drugs should report joint pain to their physician immediately. If tendon rupture is suspected, patients should avoid activity until a formal diagnosis has been made.

Telithromycin has been associated with severe liver toxicity.

Other potential adverse reactions to antibiotics include stomach upset, nausea, vomiting, nervousness, sleep disturbances, nervousness, anxiety and other problems. Rarely, antibiotics can affect critical organs including the liver and kidneys or cause convulsions and coma .

Interactions

The following interactions are of particular interest to seniors. Other interactions may also occur.

All antibiotics may increase the effects of warfarin, a medication used to prevent blood clots . Patients taking warfarin should have additional monitoring while taking antibiotics. Penicillins may interact with heparin to prolong bleeding time. Beta blockers may increase the risk of allergic reactions to penicillins.

QUESTIONS TO ASK YOUR PHARMACIST

• Is there a generic form of the name brand drug that was prescribed?
• Should this medication be taken with or without food?
• What adverse effects are most likely to occur? What are their symptoms?
• How should this medication be stored?
• Are there other medications or alternative treatments that should be avoided while I am taking this antibiotic?

Cefoperazone, cefazolin, cefmetazole and cefotetan have been reported to cause alcohol intolerance. Alcohol in any form should be avoided for 72 hours after receiving any of these drugs. Cefdinir should not be taken with iron supplements or foods rich in iron since this reduces their antibiotic effect. All cephalosporins should be used with caution in patients taking loop diuretics such as furosemide, since this may increase the risk of kidney damage. Do not take cephalosporins at the same time as antacids or histamine receptor blocking agents because they may reduce the effectiveness of the antibiotic.

Macrolides should not be taken with antacids. Clarithromyc and erythromycin may increase the effects of some anxiolytic drugs, including diazepam, alprazolam, triazolam and others. This may lead to unwanted sedation.

Tetracyclines should be taken with water, preferably on an empty stomach. They can interact with minerals such as calcium and sodium in dairy products, antacids and supplements. Combining these minerals with tetracycline results in some or all of their anti-infective activity being lost.

Caregiver concerns

Caregivers should discuss the selection of antibiotic with the physician. The caregiver can ensure the physician is aware of all medications, including over-the-counter drugs that the patient is taking.

To help with cost concerns, caregivers can ask if a generic drug is available for the brand name drug prescribed.

KEY TERMS

anaerobic —Not requiring oxygen. Anaerobic bacteria are commonly found in the mouth, intestines and vaginal area.

antibiotic —A chemical substance produced by a microorganism that kills or stops the growth of other microorganisms. The term includes antibiotics chemically modified from their original form, such as the semi-synthetic penicillins, but not the agents that come from sources other than microorganisms.

bacteria —The plural of bacterium; unicellular organisms that have a cell wall and multiply by cell fission. Some bacteria cause disease, while others are beneficial to human health. Still other have importance in commercial applications.

decubitus —This term refers to the position of a patient in a bed, but is rarely used that way. In common usage it applies to a bedsore; skin breakdown caused by continued pressure.

enzyme —An organic catalyst; a substance produced by an organism that acts as a catalyst to promote a chemical reaction.

fungus —A group of plants that lack chlorophyll and reproduce by spores.

infection —Invasion of the body by organisms that are able to cause disease.

mold —A term referring to both fungi and yeasts.

rupture —A tear in an organ or other tissue.

tendon —The connective tissue that holds muscle to a bone.

Most importantly, caregivers should be familiar with major adverse effects that the drug may cause, both in terms of severity and frequency. When reporting an adverse effect, describe it in as much detail as possible. Do not use the words “allergy” or “allergic” unless the reaction has been confirmed as a true immune response.

Resources

BOOKS

The Dispensatory of the United States of America, 25th edition, edited by A. Osol and G. Farrar. Philadelphia: J. B. Lippincott Co, 1955.

Martindale the Extra Pharmacopoeia, 30th edition, edited by J. Reynild. London: The Pharmaceutical Press, 1993.

PERIODICALS

Esposito, S., et al. “Antibiotic Resistance in Long-term Care Facilities.” New Microbiology 30, no. 3 (July 2007): 326–31.

Faulkner, C. M., H. L. Cox, and J. C. Williamson. “Unique Aspects of Antimicrobial Use in Older Adults.” Clinical Infectious Diseases 40, no. 7 (April 1, 2005): 997–1004.

Herring, A. R., and J. C. Williamson. “Principles of Anti-microbial Use in Older Adults.” Clinical Geriatric Medicine 23, no. 3 (August 2007): 481–97.

Niederman, M. S., and V. Brito. “Pneumonia in the Older Patient.” Clinics in Chest Medicine 28, no. 4 (December 2007): 751–71, vi.

Noreddin, A. M., and V. Haynes. “Use of Pharmacodynamic Principles to Optimize Dosage Regimens for Antibacterial Agents in the Elderly.” Drugs & Aging 24, no. 4 (2007): 275–92.

Razavi, B., A. Apisarnthanarak, and L. M. Mundy. “Clostridium difficile: Emergence of Hypervirulence and Fluoroquinolone Resistance.” Infection 35, no. 5 (October 2007): 300–7.

Trinh, C., and K. Prabhakar. “Diarrheal Diseases in the Elderly.” Clinical Geriatric Medicine 23, no. 4 (November 2007): 833–56, vii.

Woodmansey, E. J. “Intestinal Bacteria and Ageing.” Journal of Applied Microbiology 102, no. 5 (May 2007):1178–86.

OTHER

Information for Consumers. U.S. Food and Drug Administration: Center for Drug Evaluation and Research. [cited April 10, 2008]. http://www.fda.gov/cder/info/consumer.htm.

Rainbow, J. et al. “Emergence of Fluoroquinolone-Resistant Neisseria meningitides—Minnesota and North Dakota, 2007-2008.

” MMWR Weekly February 22, 2008 [cited April 10, 2008]. Centers for Disease Control. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5707a2.htm.

Sam Uretsky PharmD

Antibiotics

Definition

Antibiotics are drugs that are used to treat infections caused by bacteria and other organisms, including protozoa, parasites, and fungi.

Purpose

Many treatments for cancer destroy disease-fighting white blood cells, thereby reducing the body's ability to fight infection. For example, bladder, pulmonary, and urinary tract infections may occur with chemotherapy . Single-celled organisms called protozoa are rarely a problem for healthy individuals. However, they can cause serious infections in individuals with low white blood cell counts. Because of the dangers that infections present for cancer patients, antibiotic treatment often is initiated before the exact nature of the infection has been determined; instead, the choice of antibiotic may depend on the site of the infection and the organism that is likely to be the cause. Often, an antibiotic that kills a broad spectrum of bacteria is chosen and several antibiotics may be used together.

Description

The common antibiotics that are used during cancer treatment include:

• Atovaquone (Mapren): antiprotozoal drug used to prevent and treat a very serious type of pneumonia called Pneumocystis carinii pneumonia (PCP), in individuals who experience serious side effects with SMZ-TMP (Sulfamethoxazole/Trimethoprim, brand name Bactrim).
• Aztreonam (Azactam): monobactam antibiotic used to treat gram-negative bacterial infections of the urinary and lower respiratory tracts and the female organs, and infections that are present throughout the body (systemic infections or septicemia).
• Cefepime (Maxipime), ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime), and ceftriaxone sodium (Rocephin): members of a group of antibiotics called cephalosporins used to treat bacterial infections of the urinary and lower respiratory tracts, and infections of the skin, bones, joints, pelvis, and abdomen.
• Ciprofloxacin (Cipro): fluoroquinolone antibiotic used to treat certain gram-negative and gram-positive bacteria and some mycobacteria.
• Clindamycin phosphate (Cleocin): used to treat gram-positive and gram-negative bacterial infections and, in individuals who are allergic to sulfadiazine, toxoplasmosis caused by a parasitic protozoa.
• Gentamicin (gentamycin) sulfate (generic name product, Garamycin, G-Mycin, Jenamicin): aminoglycoside antibiotic used to treat serious infections by many gram-negative bacteria that cannot be treated with other medicines.
• Metronidazole hydrochloride (Flagyl, Metric 21, Metro I.V., Protostat): used for anaerobic bacteria and protozoa.
• Pentamidine (generic name product, Pentam 300): used to treat PCP if serious side effects develop with SMZTMP.
• Pyrimethamine (Daraprim): antiprotozoal medicine used together with sulfadiazine to treat toxoplasmosis; or in combination with other medicines for treating mild to moderate PCP, in individuals who cannot tolerate the standard treatment.
• Sulfadiazine (generic name product): sulfonamide antibiotic used with pyrimethamine to treat toxoplasmosis.
• Sulfamethoxazole-Trimethoprim (SMZ-TMP) (generic name product, Bactrim, Cofatrim Forte, Cotrim, Septra, Sulfatrim): the sulfonamide antibiotic, sulfamethoxazole, used in combination with trimethoprim, to prevent and treat PCP and bacterial infections, such as bronchitis and middle ear and urinary tract infections.
• Trimethoprim (generic name product, Proloprim, Trimpex): primarily used to prevent or treat urinary tract infections.
• Vancomycin hydrochloride (generic name product, Vancocin): glycopeptide antibiotic used to treat a variety of serious gram-positive bacterial infections for which other medicines are ineffective, including strains of Staphylococcus that are resistant to most oral antibiotics.

Most of these antibiotics kill bacteria by preventing them from making protein for their cell walls. Ciprofloxacin and metronidazole prevent bacteria from reproducing by interfering with their ability to make new DNA. All of these drugs are approved for prescription by the U.S. Food and Drug Administration.

Recommended dosage

Dosages of antibiotics depend on the individual, the infection that is being treated, and the presence of other medical conditions. For children, the dosage usually is based on body weight and is lower than the adult dosage. To be effective, an entire treatment with antibiotics must be completed, even if the symptoms of infection have disappeared. Furthermore, it is important to keep the level of antibiotic in the body at a constant level during treatment. Therefore, the drug should be taken on a regular schedule. If a dose is missed, it should be taken as soon as possible. If it is almost time for the next dose, the missed dose should be skipped. Doubling up doses is generally not recommended.

Average adult dosages of common antibiotics for cancer patients are as follows:

• Atovaquone: for PCP treatment, 750 mg oral suspension twice a day, or tablets three times per day, for 21 days; for PCP prevention, 1, 500 mg oral suspension, once a day; must be taken with balanced meals.
• Aztreonam: 1-2 gm every 6-12 hours, injected into a vein, over a 20-60 minute-period.
• Cefepime: 500 mg to 2 gm, injected into a vein or muscle, every 8-12 hours for 7-10 days.
• Ceftazidime: 250 mg to 2 gm, injected into a vein or muscle, every 8-12 hours.
• Ceftriaxone: 1-2 gm, injected into a vein or muscle, every 24 hours.
• Ciprofloxacin: 500-750 mg of the tablet or suspension, every 12 hours, for 3-28 days, taken two hours after meals with 8 oz of water; bone and joint infections usually are treated for at least 4-6 weeks; 200-400 mg injected every 8-12 hours.
• Clindamycin: 150-300 mg of capsule or solution, every six hours; 300-600 mg every six to eight hours or 900 mg every eight hours, injected into a vein or muscle.
• Gentamicin: dosage determined by body weight, every 8-24 hours for at least 7-10 days, injected into a vein or muscle.
• Metronidazole: for bacterial infections, 7.5 mg per kg (3.4 mg per lb) of body weight up to a maximum of 1 gm, every six hours for at least seven days (capsules or tablets); 15 mg per kg (6.8 mg per lb) for the first dose, followed by half that dosage every six hours for at least seven days (injected into a vein); for protozoal infections caused by amebas, 500-750 mg of oral medicine, three times per day for 5-10 days; for trichomoniasis, 2 gm for one day or 250 mg three times per day for seven days (oral medicine); extended-release tablets for vaginal bacterial infections, 750 mg once a day for seven days.
• Pentamidine: for treating PCP, 4 mg per kg (1.8 mg per lb) of body weight, once per day for 14-21 days, injected into a vein over one to two hours, while lying down.
• Pyrimethamine: for toxoplasmosis, 25-200 mg tablets, taken with other medicine, for several weeks.
• Sulfadiazine: for bacterial and protozoal infections, 2-4 gm for the first dose, followed by 1 gm every four to six hours (tablets).
• SMZ-TMP: 800 mg of sulfamethoxazole and 160 mg of trimethoprim, (tablet or oral suspension), every 12 hours for bacterial infections and every 24 hours for prevention of PCP; dosage based on body weight for PCP treatment; injections based on body weight, every six, eight or 12 hours for bacterial infections and every six hours for PCP treatment.
• Trimethoprim: 100 mg tablet every 12 hours for 10 days; for prevention of urinary tract infections, once a day for a long period.
• Vancomycin: 7.5 mg per kg (3.4 mg per lb) of body weight, or 500 mg-1 gram, injected or taken orally, every 6-12 hours.

Precautions

Stomach or intestinal problems or colitis (inflammation of the colon) may affect the use of:

• Atovaquone
• Cephalosporins
• Clindamycin

Kidney or liver disease may affect the use of:

• Aztreonam
• Cefepime
• Ceftazidime
• Ciprofloxacin
• Clindamycin
• Gentamicin
• Metronidazole
• Pentamidine
• Pyrimethamine
• Sulfadiazine
• SMZ-TMP
• Trimethoprim
• Vancomycin

Central nervous system or seizure disorders may affect the use of:

• Ciprofloxacin
• Metronidazole
• Pyrimethamine

Anemia (low red blood cell count) or other blood disorders may affect the use of:

• Metronidazole
• Pentamidine
• Pyrimethamine
• Sulfadiazine
• SMZ-TMP
• Trimethoprim

Ciprofloxacin may not be suitable for individuals with tendinitis or with skin sensitivities to sunlight. Gentamicin may not be suitable for people with hearing problems, myasthenia gravis , or Parkinson's disease. Metronidazole may not be suitable for individuals with heart disease, oral or vaginal yeast infections, or a history of alcoholism. Pentamidine may not be suitable for individuals with heart disease, bleeding disorders, or low blood pressure. Pentamidine may affect blood sugar levels, making control of diabetes mellitus or hypoglycemia (low blood sugar) difficult. Vancomycin may not be appropriate for individuals with hearing problems.

Many antibiotics should not be taken during pregnancy or while breast-feeding. Older individuals may be more susceptible to the side effects of sulfadiazine, SMZ-TMP, or trimethoprim.

Side effects

Some individuals may have allergic reactions to antibiotics. If symptoms of an allergic reaction (such as rash, shortness of breath, swelling of the face and neck), severe diarrhea , or abdominal cramping occur, the antibiotic should be stopped and the individual should seek medical advice.

Because antibiotics can affect bacteria that are beneficial, as well as those that are harmful, women may become susceptible to infections by fungi when taking antibiotics. Vaginal itching or discharge may be symptoms of such infections. All patients may develop oral fungal infections of the mouth, indicated by white plaques in the mouth.

Injected antibiotics may result in irritation, pain, tenderness, or swelling in the vein used for injection. Antibiotics used in cancer patients may have numerous side effects, both minor and severe; however, most side effects are uncommon or rare.

The more common side effects of atovaquone, aztreonam, cephalosporins, ciprofloxacin, clindamycin, gentamicin, metronidazole, and SMZ-TMP include:

• nausea and vomiting
• diarrhea
• loss of appetite

Eating active cultured yogurt may help counteract diarrhea, but if a patient has low white blood cells, this remedy is not recommended. For mild diarrhea with cephalosporins, only diarrhea medicines containing kaolin or attapulgite should be taken. With clindamycin, diarrhea medicines containing attapulgite should be taken several hours before or after the oral antibiotic. Diarrhea following antibiotics like clindamycin may indicate a bacterial infection that needs additional therapy, and a physician should be consulted.

Other side effects of atovaquone may include:

• fever
• skin rash
• cough
• headache
• insomnia

Other side effects of ciprofloxacin may include:

• abdominal pain
• increase in blood tests for kidney function
• dizziness or light-headedness
• inflammation or tearing of a tendon
• drowsiness
• insomnia

Other common side effects of clindamycin include abdominal pain and fever. Side effects may occur up to several weeks after treatment with this medicine.

Gentamicin and vancomycin may cause serious side effects, particularly in elderly individuals and newborn infants. These include kidney damage and damage to the auditory nerve that controls hearing. Other, more common side effects of gentamicin may include:

• changes in urination
• increased thirst
• muscle twitching or seizures
• headache
• lethargy

When gentamicin is injected into a muscle, vein, or the spinal fluid, the following side effects may occur:

• leg cramps
• skin rash
• fever
• seizures

Side effects from gentamicin may develop up to several weeks after the medicine is stopped.

More common side effects of metronidazole include:

• mouth dryness
• unpleasant or metallic taste
• dizziness or light-headedness
• headache
• stomach pain

Sugarless candy or gum, bits of ice, or a saliva substitute may relieve symptoms of dry mouth.

Pentamidine, pyrimethamine, sulfonamides, SMZTMP, and trimethoprim can lower the number of white blood cells, resulting in an increased risk of infection. These drugs also can lower the number of blood platelets that are important for blood clotting. Thus, there is an increased risk of bleeding or bruising while taking these drugs.

Serious side effects of pentamidine may include:

• heart problems
• low blood pressure
• high or low blood sugar
• other blood problems
• decrease in urination
• sore throat and fever
• sharp pain in upper abdomen

Some of these symptoms may not occur until several months after treatment with pentamidine.

Pyrimethamine and trimethoprim may lower the red blood cell count, causing anemia. Leucovorin or the vitamin folic acid may be prescribed for anemia.

Some individuals become more sensitive to sunlight when taking sulfonamides, SMZ-TMP, or trimethoprim. Other common side effects of sulfonamides and SMZTMP include:

• dizziness
• itching
• skin rash
• headache
• mouth sores or swelling of the tongue
• fatigue

If vancomycin is injected into a vein too quickly, it can cause flushing and a rash over the neck, face, and chest, wheezing or difficulty breathing, and a dangerous decrease in blood pressure.

Interactions

Many prescription and non-prescription medicines can interact with these antibiotics. Therefore, it is important to consult a complete list of known drug interactions. Among the more common or dangerous interactions:

• Antibiotics that lower the number of blood platelets, with blood thinners (anticoagulants), such as warfarin
• Aztreonam and metronidazole with alcohol; it is important not to consume alcohol until at least three days after treatment with these antibiotics
• Ciprofloxacin with antacids, iron supplements, or caffeine
• Pentamidine or pyrimethamine with previous treatments with x rays or cancer medicines (increased risk of blood cell damage)
• Trimethoprim with diuretics to remove excess fluid in the elderly

Many medicines can increase the risk of hearing or kidney damage from gentamicin. These include:

• cisplatin
• combination pain medicine with acetaminophen and aspirin or other salicylates (taken regularly in large amounts)
• cyclosporine
• inflammation or pain medicine, except narcotics
• lithium
• methotrexate
• other medicines for infection

The following drugs may increase the risk of liver effects with sulfadiazine or SMZ-TMP:

• acetaminophen, long-term, high-dose (eg Tylenol)
• birth control pills containing estrogens
• disulfiram (Antabuse)
• other medicines for infection

Resources

BOOKS

American Cancer Society. Consumers Guide to Cancer Drugs.Atlanta: Jones and Bartlett, 2000.

Drum, David. Making the Chemotherapy Decision, 2nd ed. Los Angeles: Lowell House, 1998.

OTHER

American Cancer Society. Cancer Drugs. Cancer Resource Center. 2000. 27 May 2001. <http://www2.cancer.org/drug_reference/index.cfm?ct=1&language=english>.

American Cancer Society. Infections in Individuals with Cancer. Cancer Resource Center. 30 Sep. 1999. 27 May 2001. <http://www3.cancer.org/cancerinfo/load_cont.asp?ct=1&doc=12>.

MEDLINEplus Drug Information. U.S. National Library of Medicine. 24 Jan. 2001. 22 May 2001. <http://www.nlm.nih.gov/medlineplus/druginfo/>.

Margaret Alic, Ph.D.

KEY TERMS

Gram-negative

—Types of bacteria that do not retain Gram stain.

Gram-positive

—Types of bacteria that retain Gram stain.

Mycobacteria

—Rod-shaped bacteria, some of which cause human diseases such as tuberculosis.

Pneumocystis carinii

pneumonia (PCP) —Serious type of pneumonia caused by the protozoan Pneumocystis carinii.

Protozoa

—Single-celled animals.

Toxoplasmosis

—Infection caused by the protozoan parasite Toxoplasma gondii, affecting animals and humans with suppressed immune systems.

Trichomoniasis

—Infection caused by a protozoan of the genus Trichomonas ; especially vaginitis caused by Trichomonas vaginalis

Antibiotic

The production of antibiotics has become a multibillion-dollar industry that continues to grow each year.

An antibiotic is a chemical substance made by a living microorganism (a living thing that is so small it can only be seen through a microscope), such as a fungus or mold, that is harmful to another microorganism that causes diseases. An antibiotic drug can stop the growth of harmful bacteria and other microorganisms, or destroy them. More than ten thousand antibiotic substances have been found. Scientists can also make antibiotics synthetically (artificially) from chemicals or from a combination of chemicals and natural substances (semisynthetic drugs). The production of antibiotics has become a multibillion-dollar industry that continues to grow each year.

Over 2,500 years old

Although the process by which antibiotics fight disease-causing bacteria was not discovered until the twentieth century, the Chinese had used antibiotics about 2,500 years ago. They discovered that applying the moldy curd of soybeans to the body could heal certain infections (conditions resulting from the body's invasion by disease-causing microorganisms).

Other cultures are also known to have used antibiotic-type substances to cure illnesses. The Sudanese-Nubian civilization used a type of tetracycline antibiotic as early as 350 c.e. (common era). In Europe during the Middle Ages (476–1453), crude plant extracts and cheese curds were used to fight infections.

Modern antibiotics

Modern antibiotics resulted from the work of several individuals who demonstrated that materials derived from certain microorganisms could be used to cure infectious diseases. In 1877, French chemist and microbiologist Louis Pasteur (1822–1895) discovered that disease-causing anthrax bacteria could be prevented from multiplying by Saprophyte bacteria living on dead and decaying organisms. Anthrax, a disease that dates back to biblical times, can be fatal, sometimes affecting a large number of animals. The disease also affects humans.

The first miracle drug

In 1928, Scottish bacteriologist Alexander Fleming (1881–1955) made one of the most important contributions to the field of antibiotics. While culturing (growing) Staphyloccus bacteria in a laboratory dish, Fleming made a remarkable discovery. He found that mold, which had grown on some bacteria, prevented their growth. Upon further investigation, Fleming found that a substance in the mold Penicillium notatum could destroy many disease-producing bacteria without harming healthy body cells.

However, Fleming was unable to develop penicillin for medical use. It was not until 1941 that Ernst Chain (1906–1979) and Howard Florey (1898–1968), continuing Fleming's work, developed the drug penicillin. Penicillin was later called the "miracle drug" because of its role in saving millions of human lives. Penicillin remains one of the effective treatments for such bacterial infections as pneumonia, strep throat, and syphilis.

Other antibiotics

Since the development of penicillin, other antibiotic substances have been found. In 1939, research began on identifying possible antibiotic materials from the soil bacteria Streptomyces. In 1943, Ukrainian-born American microbiologist Selman Waksman (1888–1973) developed the drug streptomycin from soil bacteria. It was the first antibiotic found effective in treating tuberculosis.

In 1941, Waksman coined the term antibiotic—from the Greek anti, meaning against, and bios, meaning life. The term describes the drug's function of fighting bacteria either by killing them or by preventing them from multiplying.

After World War II (1939–1945), the search for molds and other soil bacteria led to the development of other antibiotics, including erythromycin and cephalosporin that can each be used in patients allergic to penicillin. Quinolone, which was developed during the 1960s, has been used in treating urinary-tract infections and infectious diarrhea. Since the 1970s, most antibiotics produced have been the synthetic types.

How antibiotics work

Antibiotics fight harmful bacteria in different ways. Some antibiotics destroy bacteria by weakening their cell walls, causing the walls to burst. Certain antibiotics damage the exterior of bacterial cells, causing the contents of the cells to leak. Still other antibiotics interfere with the bacteria's metabolism, the chemical processes in the cells needed by the bacteria to multiply and function. For example, tetracycline interferes with the production of proteins, which not only make up structural parts of the bacteria but also perform important functions.

Raw Materials

Antibiotics are produced using a fermentation process. The substances that make up the fermentation broth are the raw materials needed to manufacture antibiotics. This broth contains all the ingredients needed to promote the growth of the specific antibiotic-producing microorganisms.

The fermentation broth typically contains a carbon source, such as molasses or soy meal, which are made up of lactose and glucose. These are the food sources for the microorganisms. Ammonia is added for its nitrogen, which the organisms need for metabolism. Trace elements are added for proper growth. They include phosphorus, sulfur, magnesium, zinc, iron, and copper. Anti-foaming substances are added to prevent foaming.

The Manufacturing Process

Although most antibiotics are found in nature, they do not normally occur in the amounts necessary to produce a great quantity. For this reason, a fermentation process has been developed. It involves collecting the microorganism whose antibiotic product is desired, promoting the increase in numbers of the culture (growth of the specific microorganism in a laboratory), and separating the excreted antibiotic product from the fermentation broth.

Starting the culture

1 Before fermentation can begin, the desired antibiotic-producing organism is collected and made to multiply. This is done by producing an initial, or sample, culture. This initial culture is cultivated in a dish with agar (a gelatin-like substance that acts as an environment in which organisms grow). Then, the initial culture is transferred into shake flasks (bottle-like containers) with growth-promoting nutrients added. The starter culture is allowed to multiply some more.

CONSUMERS LACK KNOWLEDGE OF ANTIBIOTIC USE

The misuse and overuse of antibiotics have encouraged the spread of bacterial resistance to antibiotics. Patients sometimes ask their doctors to prescribe antibiotics for the common cold and flu (influenza), which are caused by viruses and cannot be cured by antibiotics. Some doctors tend to prescribe antibiotics for all kinds of symptoms. For an antibiotic to work, the patient has to take the complete prescription. It is very common for patients to stop taking the prescription once the symptoms of the illness have disappeared. Some people do not know that even if they feel better after several days of medication, some of the bacteria that cause the infection live on and continue to multiply. Stopping the medication makes the surviving bacteria resistant to the drug. If the person develops the same illness in the future and is prescribed the same antibiotic, it may not work.

A 1998 survey of the American public by the American Society of Health-System Pharmacists, Bethesda, Maryland, found that:

Over one-third of Americans surveyed said they stopped taking their complete antibiotic prescription because they started feeling better.

About 1 out of 4 people said they saved antibiotics prescribed for one illness and then took them for another illness at a later time.

More than half thought antibiotics are the best medicine for viral infections.

2 The starter culture is transferred to seed tanks for further growth. The seed tanks are steel tanks filled with all the food and nutrients the specific microorganisms need to survive and grow. These include warm water, carbohydrate foods, such as lactose or glucose sugars, and nutrients like those found in the shake flasks. The tanks also contain carbon sources, such as acetic acid, alcohols, or hydrocarbons, as well as nitrogen sources, such as ammonia salts. Air that is sterilized (germ-free) and filtered (rid of impurities) is delivered into the tank, while mixers keep the mixture moving. After about twenty-four to twenty-eight hours, the mixture is transferred to fermentation tanks.

Fermentation

3 The fermentation tank is a bigger version of the seed tank and holds about 30,000 gallons. It is filled with the same ingredients found in the seed tank to encourage further growth of the microorganisms. The tank temperature is kept between 73 to 81 degrees Fahrenheit (23 to 27.2 degrees Centigrade). The mixture is constantly stirred, and sterilized, and filtered air is continuously pumped in. For this reason, antifoaming agents are periodically added. Acids or bases are added as needed to keep a pH balance that is ideal for growth. In this environment, the microorganisms continue to grow and multiply and excrete large quantities of the desired antibiotic.

Isolation and purification

4 After three to five days, when the maximum amount of antibiotic has been produced, the process of collecting the antibiotic from the broth starts. Different purification methods are used, depending on the type of antibiotic produced.

5 For antibiotics that are water-soluble (can be dissolved in water), an ion-exchange method is used. The antibiotic is separated from the waste materials in the fermentation broth. Then, it is separated from other water-soluble materials. For antibiotics that are oil-soluble (can be dissolved in oil), a solvent-extraction method is used. The fermentation broth is treated with butyl acetate or methyl isobutyl ketone, substances that can dissolve the antibiotic. The antibiotic is then collected using chemical means. These methods produce a purified powdered form of the antibiotic, which is further converted into different product forms.

Refining

6 Antibiotics can come in different forms. They can come in solutions for intravenous (given by injection) bags or syringes (needles) and in pill or gel-capsule form. They can be in the form of powders that are added to topical ointments (creams applied to a body part).

Based on the final form of the antibiotic, different refining steps are used. For intravenous bags, the crystalline antibiotic is dissolved in a solution and put in the bag, which is then hermetically sealed (tightly sealed so that air cannot get in). For gel capsules, powdered antibiotic is put into the capsule bottom; the top half of the capsule is then put in place. For topical ointments, the antibiotic is mixed into the ointment.

7 Finally, the antibiotic products are transported to the packaging stations. The products are stacked and put in boxes. They are loaded up on trucks and transported to hospitals, pharmacies, and various distributors.

Quality Control

A germ-free environment has to be maintained throughout the manufacturing process, so that other microorganisms do not contaminate (introduce impurities to) the culture. The culture medium and all the processing equipment are steam-sterilized. Moreover, frequent checks of the condition of the culture during fermentation are conducted. The finished product is further checked for its physical and chemical properties, including pH, melting point, and moisture content.

In the United States, the Food and Drug Administration (FDA) regulates the production of antibiotics. The amount of testing depends on the type of antibiotic and how it will be used. For example, the FDA might require that, for a particular antibiotic, it has to first check each batch for effectiveness and purity before giving its approval for sale to the public.

CLEVER GENES

Bacteria that are capable of resisting the action of an antibiotic may have resistance genes that produce enzymes, or proteins that chemically change the drug or make it powerless. Some resistance genes cause bacteria to mutate (change), leading to new characteristics that the antibiotic cannot attack.

The Future

Since the earliest use of antibiotics against disease-causing bacteria, some of these harmful microorganisms have developed drug resistance so that they cannot be killed or controlled by the antibiotic. Typically, an antibiotic destroys most bacteria that are making a person ill; however, a few bacteria may manage to survive. These bacteria develop resistance genes (basic units of hereditary materials) that are passed down to their offspring or transferred to others within the same species (a group of living things that have similar characteristics). Gene exchange is a common occurrence among organisms. Experts have found that resistant bacteria tend to fight off more than one antibiotic.

A renewed interest

According to the U.S. Centers for Disease Control and Prevention (CDC), cases of antibiotic resistance are increasing. Life-threatening diseases, such as tuberculosis, are on the rise. Realizing the threat to public health, drug companies all over the world are taking up the challenge of developing new antibiotics to fight microorganisms that are resistant to antibiotics.

One area of interest is sparked by the Human Genome Project, an international research program designed to understand the genomes of humans and organisms. (The genome is the complete collection of genes passed down from generation to generation.) For example, some scientists have been able to map out the genome of the bacterium that infects the lungs of cystic fibrosis patients. This antibiotic-resistant bacterium destroys the patient's lungs, eventually causing death. By studying the genome, scientists hope to develop an antibiotic that would target some part of the bacterium, thus destroying it. Researchers continue to look for newer types of antibiotics, as well as a combination of drugs to fight resistant bacteria. Scientists are also trying to develop vaccines to prevent bacterial infections.

agar:

A gelatin-like substance in which scientists grow organisms.

bacteria:

Small, one-celled organisms that can only be seen through a microscope.

culture:

A growth of microorganisms in nutrient.

infection:

Invasion of the body by disease-causing microorganisms.

ion-exchange method:

A method of purifying a water-soluble antibiotic that is collected after fermentation. The antibiotic is first separated from the waste materials in the fermentation broth, then sent through equipment that separates other water-soluble materials from the antibiotic.

microorganism:

A living thing that is so small it can only be seen through a microscope.

nutrient:

A food substance, such as carbohydrate, protein, fat, mineral, vitamin, water, or fiber needed for growth.

organism:

Any living thing.

pH:

A number that shows the acidity or alkalinity of a chemical substance.

semisynthetic antibiotic:

An antibiotic that is made from a combination of chemicals and natural substances.

solvent-extraction:

A method of purifying an oil-soluble antibiotic that is collected after fermentation. The fermentation broth is treated with substances that can dissolve the antibiotic, and the antibiotic is collected using chemical means.

starter culture:

A small growth of microorganisms used to start a larger growth to produce antibiotics.

synthetic antibiotic:

An antibiotic that is made artificially from chemicals.

virus:

A very tiny particle than can grow inside a living cell. Viruses attack the cells of other organisms to make copies of themselves. Outside a cell, viruses are lifeless. Viruses cause such illnesses as the flu, colds, and AIDS.

For More Information

Books

Gottfried, Ted. Alexander Fleming: Discoverer of Penicillin. New York, NY: Franklin Watts, 1997.

Levy, Stuart B. The Antibiotic Paradox: How the Misuse of Antibiotics Endangers TheirCurative Power. Cambridge, MA: Perseus Publishing, 2001.

Periodicals

Bren, Linda. "Antibiotic Resistance From Down on the Chicken Farm." FDA Consumer. (January-February 2001): pp. 10-11

Monroe, Judy. "Antibiotics vs. the Superbugs." Current Health 2. (October 2001): pp. 24-25.

Web Sites

"An Inside Look at FDA On-Site." Center for Drug Evaluation and Research, Food and Drug Administration.http://www.fda.gov/cder/about/whatwedo/testtube-7.pdf (accessed on July 22, 2002).

Antibiotic

Antibiotics are chemical substances that can inhibit the growth of, and even destroy, harmful microorganisms. They are derived from special microorganisms or other living systems, and are produced on an industrial scale using a fermentation process. Although the principles of antibiotic action were not discovered until the twentieth century, the first known use of antibiotics was by the Chinese over 2,500 years ago. Today, over 10,000 antibiotic substances have been reported. Currently, antibiotics represent a multibillion dollar industry that continues to grow each year.

Background

Antibiotics are used in many forms—each of which imposes somewhat different manufacturing requirements. For bacterial infections on the skin surface, eye, or ear, an antibiotic may be applied as an ointment or cream. If the infection is internal, the antibiotic can be swallowed or injected directly into the body. In these cases, the antibiotic is delivered throughout the body by absorption into the bloodstream.

Antibiotics differ chemically so it is under-standable that they also differ in the types of infections they cure and the ways in which they cure them. Certain antibiotics destroy bacteria by affecting the structure of their cells. This can occur in one of two ways. First, the antibiotic can weaken the cell walls of the infectious bacteria, which causes them to burst. Second, antibiotics can cause the contents of the bacterial cells to leak out by damaging the cell membranes. Another way in which antibiotics function is by interfering with the bacteria's metabolism. Some antibiotics such as tetracycline and erythromycin interfere with protein synthesis. Antibiotics like rifampin inhibit nucleic acid biosynthesis. Still other antibiotics, such as sulfonamide or trimethoprim have a general blocking effect on cell metabolism.

The commercial development of an antibiotic is a long and costly proposal. It begins with basic research designed to identify organisms, which produce antibiotic compounds. During this phase, thousands of species are screened for any sign of antibacterial action. When one is found, the species is tested against a variety of known infectious bacteria. If the results are promising, the organism is grown on a large scale so the compound responsible for the antibiotic effect can be isolated. This is a complex procedure because thousands of antibiotic materials have already been discovered. Often, scientists find that their new antibiotics are not unique. If the material passes this phase, further testing can be done. This typically involves clinical testing to prove that the antibiotic works in animals and humans and is not harmful. If these tests are passed, the Food and Drug Administration (FDA) must then approve the antibiotic as a new drug. This whole process can take many years.

The large-scale production of an antibiotic depends on a fermentation process. During fermentation, large amounts of the antibiotic-producing organism are grown. During fermentation, the organisms produce the antibiotic material, which can then be isolated for use as a drug. For a new antibiotic to be economically feasible, manufacturers must be able to get a high yield of drug from the fermentation process, and be able to easily isolate it. Extensive research is usually required before a new antibiotic can be commercially scaled up.

History

While our scientific knowledge of antibiotics has only recently been developed, the practical application of antibiotics has existed for centuries. The first known use was by the Chinese about 2,500 years ago. During this time, they discovered that applying the moldy curd of soybeans to infections had certain therapeutic benefits. It was so effective that it became a standard treatment. Evidence suggests that other cultures used antibiotic-type substances as therapeutic agents. The Sudanese-Nubian civilization used a type of tetracycline antibiotic as early as 350 a.d. In Europe during the Middle Ages, crude plant extracts and cheese curds were also used to fight infection. Although these cultures used antibiotics, the general principles of antibiotic action were not understood until the twentieth century.

The development of modern antibiotics depended on a few key individuals who demonstrated to the world that materials derived from microorganisms could be used to cure infectious diseases. One of the first pioneers in this field was Louis Pasteur. In 1877, he and an associate discovered that the growth of disease-causing anthrax bacteria could be inhibited by a saprophytic bacteria. They showed that large amounts of anthrax bacilli could be given to animals with no adverse affects as long as the saprophytic bacilli were also given. Over the next few years, other observations supported the fact that some bacterially derived materials could prevent the growth of disease-causing bacteria.

In 1928, Alexander Fleming made one of the most important contributions to the field of antibiotics. In an experiment, he found that a strain of green Penicillium mold inhibited the growth of bacteria on an agar plate. This led to the development of the first modern era antibiotic, penicillin. A few years later in 1932, a paper was published which suggested a method for treating infected wounds using a penicillin preparation. Although these early samples of penicillin were functional, they were not reliable and further refinements were needed. These improvements came in the early 1940s when Howard Florey and associates discovered a new strain of Penicillium, which produced high yields of penicillin. This allowed large-scale production of penicillin, which helped launch the modern antibiotics industry.

After the discovery of penicillin, other antibiotics were sought. In 1939, work began on the isolation of potential antibiotic products from the soil bacteria streptomyces. It was around this time that the term antibiotic was introduced. Selman Waxman and associates discovered streptomycin in 1944. Subsequent studies resulted in the discovery of a host of new, different antibiotics including actinomycin, streptothricin, and neomycin all produced by Streptomyces. Other antibiotics that have been discovered since include bacitracin, polymyxin, viomycin, chloramphenicol and tetracyclines. Since the 1970s, most new antibiotics have been synthetic modifications of naturally occurring antibiotics.

Raw Materials

The compounds that make the fermentation broth are the primary raw materials required for antibiotic production. This broth is an aqueous solution made up of all of the ingredients necessary for the proliferation of the microorganisms. Typically, it contains a carbon source like molasses, or soy meal, both of which are made up of lactose and glucose sugars. These materials are needed as a food source for the organisms. Nitrogen is another necessary compound in the metabolic cycles of the organisms. For this reason, an ammonia salt is typically used. Additionally, trace elements needed for the proper growth of the antibiotic-producing organisms are included. These are components such as phosphorus, sulfur, magnesium, zinc, iron, and copper introduced through water soluble salts. To prevent foaming during fermentation, anti-foaming agents such as lard oil, octadecanol, and silicones are used.

The Manufacturing
Process

Although most antibiotics occur in nature, they are not normally available in the quantities necessary for large-scale production. For this reason, a fermentation process was developed. It involves isolating a desired microorganism, fueling growth of the culture and refining and isolating the final antibiotic product. It is important that sterile conditions be maintained throughout the manufacturing process, because contamination by foreign microbes will ruin the fermentation.

Starting the culture

• 1 Before fermentation can begin, the desired antibiotic-producing organism must be isolated and its numbers must be increased by many times. To do this, a starter culture from a sample of previously isolated, cold-stored organisms is created in the lab. In order to grow the initial culture, a sample of the organism is transferred to an agar-containing plate. The initial culture is then put into shake flasks along with food and other nutrients necessary for growth. This creates a suspension, which can be transferred to seed tanks for further growth.
• 2 The seed tanks are steel tanks designed to provide an ideal environment for growing microorganisms. They are filled with the all the things the specific microorganism would need to survive and thrive, including warm water and carbohydrate foods like lactose or glucose sugars. Additionally, they contain other necessary carbon sources, such as acetic acid, alcohols, or hydrocarbons, and nitrogen sources like ammonia salts. Growth factors like vitamins, amino acids, and minor nutrients round out the composition of the seed tank contents. The seed tanks are equipped with mixers, which keep the growth medium moving, and a pump to deliver sterilized, filtered air. After about 24-28 hours, the material in the seed tanks is transferred to the primary fermentation tanks.

Fermentation

• 3 The fermentation tank is essentially a larger version of the steel, seed tank, which is able to hold about 30,000 gallons. It is filled with the same growth media found in the seed tank and also provides an environment inducive to growth. Here the microorganisms are allowed to grow and multiply. During this process, they excrete large quantities of the desired antibiotic. The tanks are cooled to keep the temperature between 73-81° F (23-27.2 ° C). It is constantly agitated, and a continuous stream of sterilized air is pumped into it. For this reason, anti-foaming agents are periodically added. Since pH control is vital for optimal growth, acids or bases are added to the tank as necessary.

Isolation and purification

• 4 After three to five days, the maximum amount of antibiotic will have been produced and the isolation process can begin. Depending on the specific antibiotic produced, the fermentation broth is processed by various purification methods. For example, for antibiotic compounds that are water soluble, an ion-exchange method may be used for purification. In this method, the compound is first separated from the waste organic materials in the broth and then sent through equipment, which separates the other water-soluble compounds from the desired one. To isolate an oil-soluble antibiotic such as penicillin, a solvent extraction method is used. In this method, the broth is treated with organic solvents such as butyl acetate or methyl isobutyl ketone, which can specifically dissolve the antibiotic. The dissolved antibiotic is then recovered using various organic chemical means. At the end of this step, the manufacturer is typically left with a purified powdered form of the antibiotic, which can be further refined into different product types.

Refining

• 5 Antibiotic products can take on many different forms. They can be sold in solutions for intravenous bags or syringes, in pill or gel capsule form, or they may be sold as powders, which are incorporated into topical ointments. Depending on the final form of the antibiotic, various refining steps may be taken after the initial isolation. For intravenous bags, the crystalline antibiotic can be dissolved in a solution, put in the bag, which is then hermetically sealed. For gel capsules, the powdered antibiotic is physically filled into the bottom half of a capsule then the top half is mechanically put in place. When used in topical ointments, the antibiotic is mixed into the ointment.
• 6 From this point, the antibiotic product is transported to the final packaging stations. Here, the products are stacked and put in boxes. They are loaded up on trucks and transported to various distributors, hospitals, and pharmacies. The entire process of fermentation, recovery, and processing can take anywhere from five to eight days.

Quality Control

Quality control is of utmost importance in the production of antibiotics. Since it involves a fermentation process, steps must be taken to ensure that absolutely no contamination is introduced at any point during production. To this end, the medium and all of the processing equipment are thoroughly steam sterilized. During manufacturing, the quality of all the compounds is checked on a regular basis. Of particular importance are frequent checks of the condition of the microorganism culture during fermentation. These are accomplished using various chromatography techniques. Also, various physical and chemical properties of the finished product are checked such as pH, melting point, and moisture content.

In the United States, antibiotic production is highly regulated by the Food and Drug Administration (FDA). Depending on the application and type of antibiotic, more or less testing must be completed. For example, the FDA requires that for certain antibiotics each batch must be checked by them for effectiveness and purity. Only after they have certified the batch can it be sold for general consumption.

The Future

Since the development of a new drug is a costly proposition, pharmaceutical companies have done very little research in the last decade. However, an alarming development has spurred a revived interest in the development of new antibiotics. It turns out that some of the disease-causing bacteria have mutated and developed a resistance to many of the standard antibiotics. This could have grave consequences on the world's public health unless new antibiotics are discovered or improvements are made on the ones that are available. This challenging problem will be the focus of research for many years to come.

Where to Learn More

Books

Crueger, W. Biotechnology: A Textbook of Industrial Microbiology. Sunderland: Sinauer Associates, Inc., 1989.

Kirk Othmer Encyclopedia of Chemical Technology. New York: John Wiley & Sons, 1992.

Periodicals

Morell, Virginia. "Antibiotic Resistance: Road of No Return." Science 278 (October 24, 1997): 575-576.

Stinson, Stephen. "Drug Firms Restock Antibacterial Arsenal." Chemical & Engineering News (September 23,1996): 75-100.

—PerryRomanowski

Antibiotics

Definition

Antibiotics are used for treatment or prevention of bacterial infection. They may be informally defined as the subgroup of anti-infectives that are derived from bacterial sources and are used to treat bacterial infections. Other classes of drugs, most notably the sulfonamides , may be effective antibacterials. Similarly, some antibiotics may have secondary uses, such as the use of demeclocycline (Declomycin, a tetracycline derivative) to treat the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Other antibiotics may be useful in treating protozoal infections.

Description

Classifications

Although there are several classification schemes for antibiotics, based on bacterial spectrum (broad versus narrow) or route of administration (injectable versus oral versus topical), or type of activity (bactericidal versus bacteriostatic), the most useful is based on chemical structure. Antibiotics within a structural class will generally show similar patterns of effectiveness, toxicity, and allergic potential.

PENICILLINS The penicillins are the oldest class of antibiotics and have a common chemical structure that they share with the cephalosporins. Classed as the betalactam antibiotics, the two groups are generally bacteriocidal, which means that they kill bacteria rather than simply inhibit its growth. The penicillins can be further subdivided. The natural penicillins are based on the original penicillin G structure; penicillinase-resistant penicillins, notably methicillin and oxacillin, are active even in the presence of the bacterial enzyme that inactivates most natural penicillins. Aminopenicillins such as ampicillin and amoxicillin have an extended spectrum of action compared with the natural penicillins; extended spectrum penicillins are effective against a wider range of bacteria. These generally include coverage for Pseudomonas aeruginosa.

CEPHALOSPORINS Cephalosporins and the closely related cephamycins and carbapenems, like the penicillins, contain a beta-lactam chemical structure. Consequently, there are patterns of cross-resistance and cross-allergenicity among the drugs in these classes. The "cepha" drugs are among the most diverse classes of antibiotics and are themselves subdivided into first, second, and third generations. Each generation has a broader spectrum of activity than the one before. In addition, cefoxitin, a cephamycin, is highly active against anaerobic bacteria, which offers utility in treatment of abdominal infections. The third generation drugs, cefotaxime, ceftizoxime, ceftriaxone, and others, cross the blood-brain barrier and may be used to treat meningitis and encephalitis . Cephalosporins are the usually preferred agents for surgical prophylaxis.

fluoroquinolones The fluoroquinolones are synthetic antibacterial agents and not derived from bacteria. They are included here because they can be readily interchanged with traditional antibiotics. An earlier, related class of antibacterial agents, the quinolones, drugs that were not well absorbed, could be used only to treat urinary tract infections. The fluoroquinolones, which are based on the older group, are broad-spectrum bacteriocidal drugs that are chemically unrelated to the penicillins or the cephalosporins. They are well distributed into bone tissue and so well absorbed that in general they are as effective by the oral route as by intravenous infusion.

TETRACYCLINES Tetracyclines got their name from the fact that they share a chemical structure that has four rings. They are derived from a species of Streptomyces bacteria. Broad-spectrum bacteriostatic agents, the tetracyclines may be effective against a wide variety of microorganisms, including rickettsia and amoebic parasites.

macrolides The macrolide antibiotics are derived from Streptomyces bacteria. Erythromycin, the prototype of this class, has a spectrum and use similar to penicillin. Newer members of the group, azithromycin and clarithromycin, are particularly useful for their high level of lung penetration. Clarithromycin has been widely used to treat Helicobacter pylori infections, the cause of stomach ulcers.

OTHERS Other classes of antibiotics include the aminoglycosides, which are particularly useful for their effectiveness in treating Pseudomonas aeruginosa infections, and the lincosamide drugs clindamycin and lincomycin, which are highly active against anaerobic pathogens. There are other, individual drugs which may have utility in specific infections.

General use

Antibiotics are used for treatment or prevention of bacterial infections. In most cases, they are prescribed for a short period of time to treat a specific infection. This period may range from three days to 10 days or more. More serious infections may require longer periods of treatment, up to several months or longer. Lower doses may be used over a long period of time to prevent the return of a serious infection.

Precautions

All antibiotics should be used as prescribed. These drugs will degrade over time and lose their potency. Not completing a prescribed course of treatment increases the probability that drug-resistant strains of organisms will develop.

Side effects

All antibiotics cause risk of overgrowth by non-susceptible bacteria. Manufacturers list other major hazards by class; however, the healthcare provider should review each drug individually to assess the degree of risk. Generally, breastfeeding may be continued while taking antibiotics, but nursing mothers should always check with their physician first. Excessive or inappropriate use may promote growth of resistant pathogens.

Hypersensitivity to penicillins may be common, and cross allergenicity with cephalosporins has been reported. (That is, those who are allergic to penicillin may also be allergic to cephalosporins.) Penicillins are classed as category B during pregnancy.

Several cephalosporins and related compounds have been associated with seizures. Cefmetazole, cefoperazone, cefotetan, and ceftriaxone may be associated with problems in poor blood clotting. Pseudomembranous colitis (an intestinal disorder) has been reported with cephalosporins and other broad spectrum antibiotics. Some drugs in this class may cause kidney toxicity. Cephalosporins are classed as category B during pregnancy.

Regarding fluoroquinolones, lomefloxacin has been associated with increased sensitivity to light. All drugs in this class have been associated with convulsions. Fluoroquinolones are classed as category C during pregnancy.

Of the tetracyclines, demeclocycline may cause increased photosensitivity. Minocycline may cause dizziness . Healthcare providers do not prescribe tetracyclines in children under the age of eight, and they specifically avoid doing so during periods of tooth development. Oral tetracyclines bind to anions such as calcium and iron. Although doxycycline and minocycline may be taken with meals, people must be advised to take other tetracycline antibiotics on an empty stomach and not to take the drugs with milk or other calcium-rich foods. Expired tetracycline should never be administered. These drugs have a pregnancy category D. Use during pregnancy may cause alterations in fetal bone development.

Of the macrolides, erythromycin may aggravate the weakness of people with myasthenia gravis. Azithromycin has, rarely, been associated with allergic reactions, including angioedema (swelling), anaphylaxis, and severe skin reactions. Oral erythromycin may be highly irritating to the stomach and when given by injection may cause severe phlebitis (inflammation of the veins). These drugs should be used with caution in people with liver dysfunction. Azithromycin and erythromycin are pregnancy category B. Clarithromycin, dirithromycin, and troleandomycin are pregnancy category C.

The aminoglycosides class of drugs causes kidney and ear problems. These problems can occur even with normal doses. Dosing should be based on kidney function, with periodic testing of both kidney function and hearing. These drugs are pregnancy category D.

Parental concerns

Parents should be sure to follow all dosage and label directions. This includes using all of a prescription at the time it is prescribed. Parents should also ensure that children cannot ingest any prescription medications by accident.

KEY TERMS

Bacteria —Singular, bacterium; tiny, one-celled forms of life that cause many diseases and infections.

Bacterial spectrum —The number of bacteria an antibiotic is effective against. Broad-spectrum antibiotics treat many different kinds of bacteria. Narrow-spectrum antibiotics treat fewer kinds.

Inflammation —Pain, redness, swelling, and heat that develop in response to tissue irritation or injury. It usually is caused by the immune system's response to the body's contact with a foreign substance, such as an allergen or pathogen.

Meningitis —An infection or inflammation of the membranes that cover the brain and spinal cord. It is usually caused by bacteria or a virus.

Microorganism —An organism that is too small to be seen with the naked eye, such as a bacterium, virus, or fungus.

Organism —A single, independent unit of life, such as a bacterium, a plant, or an animal.

Pregnancy category —A system of classifying drugs according to their established risks for use during pregnancy. Category A: Controlled human studies have demonstrated no fetal risk. Category B: Animal studies indicate no fetal risk, but no human studies, or adverse effects in animals, but not in well-controlled human studies. Category C: No adequate human or animal studies, or adverse fetal effects in animal studies, but no available human data. Category D: Evidence of fetal risk, but benefits outweigh risks. Category X: Evidence of fetal risk. Risks outweigh any benefits.

Resources

BOOKS

Antibiotics: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, CA: ICON Health Publications, 2003.

Archer, Gordon, and Ronald E. Polk. "Treatment and Prophylaxis of Bacterial Infections." In Harrison's Principles of Internal Medicine, 15th ed. Edited by Eugene Braunwald, et al. New York: McGraw-Hill, 2001, pp. 867-81.

Diasio, Robert B. "Principles of Drug Therapy." In Cecil Textbook of Medicine, 22nd ed. Edited by Lee Goldman, et al. Philadelphia: Saunders, 2003, pp. 124-34.

Scott, Geoffrey M. Handbook of Essential Antibiotics. New York: Gordon & Breach Publishing Group, 2004.

Sherman, Josepha. War against Germs. New York: Rosen Publishing Group, 2004.

PERIODICALS

Ashworth, M., et al. "Why has antibiotic prescribing for respiratory illness declined in primary care?" Journal of Public Health (Oxford) 26, no. 3 (2004): 268–74.

Carrat, F., et al. "Antibiotic treatment for influenza does not affect resolution of illness, secondary visits or lost workdays." European Journal of Epidemiology 19, no. 7 (2004): 703-5.

Dancer, S. J. "How antibiotics can make us sick: the less obvious adverse effects of antimicrobial chemotherapy." Lancet Infectious Diseases 4, no. 10 (2004): 611–9.

Simoes, J. A., et al. "Antibiotic resistance patterns of group B streptococcal clinical isolates." Infectious Diseases in Obstetrics and Gynecology 12, no. 1 (2004): 1–8.

ORGANIZATIONS

American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. Web site: <www.aafp.org/>.

American Academy of Pediatrics. 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. Web site: <www.aap.org/>.

American College of Emergency Physicians. PO Box 619911, Dallas, TX 75261-9911. Web site: <www.acep.org/>.

WEB SITES

"Antibiotic Guide." Johns Hopkins Point of Care Information Technology. Available online at <http://hopkinsabxguide.org/> (accessed December 19, 2004).

"Antibiotics: When They Can and Can't Help." American Academy of Family Physicians. Available online at <http://familydoctor.org/x2250.xml> (accessed December 19, 2004).

L. Fleming Fallon, Jr., MD, DrPH