Circular Letter No. 36

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Circular Letter No. 36

Penicillin Treats Bacterial Infections

Government document

Date: July 1, 1944

Source: E. Standlee. Report From Army Headquarters, Office of the Surgeon. North African Theater of Operations. Circular Letter No. 36. Available online at: Office of Medical History. 〈http://history.amedd.army.mil/default_index2.html〉 (accessed November 20, 2005).

About the Author: In 1942, Army Lieutenant Colonel Earle G. G. Standlee was designated chief medical purchasing and contracting officer for the Army Chief Surgeon's Office, European Theater of Operations. Within a year, he was reassigned to a similar position in North Africa, where he participated in writing Circular Letter No. 36. Standlee later retired from the Army as a major general and frequently reviewed military medical history publications for the Office of the Surgeon General.

INTRODUCTION

Antibiotics are naturally formed or synthetically made compounds that specifically kill bacteria. Viruses, whose structure differs from bacteria and which require the transcription machinery of bacteria or other host cells, are not affected by antibiotics. There are many different antibiotics that target different structures on the surface or inside of bacteria, or which disrupt select biochemical facets of bacterial operation.

Naturally occurring antibiotics are produced by bacteria and various eukaryotic organisms like plants. Their function is to allow the organism to outcompete other organisms for an ecological niche or to protect the organism from bacterial infection. Such compounds are detected by screening natural samples for antibacterial potency. In modern times this screening has been automated, enabling thousands of samples to be screened each day.

There are different classes of antibiotics, based on their structural chemistry and mode of action. Penicillin, for example, is a beta-lactam antibiotic, named for the ring structure that is a constituent of the molecule. Tetracyclines, aminoglycosides, rifamycins, quinolones, and sulphonamides are other classes of antibiotics.

Reflecting their different chemistries, the mode of action of the various antibiotics is different. Beta-lactam antibiotics disrupt the manufacture of peptidoglycan (the main stress-bearing meshwork in the bacterial cell wall) by blocking the construction of the peptidoglycan building blocks or preventing their incorporation into the existing peptidoglycan. Aminoglycoside antibiotics kill bacteria in a different way—by binding to a subunit of the ribosome and blocking the manufacture of protein. Aminoglycosides also can retard the movement of essential molecules from the outside to the inside of a bacterium. As a final example, quinolone antibiotics act by blocking the ability of an enzyme to uncoil the DNA double helix. This stops the DNA from replicating and is lethal to the bacterium.

Some antibiotics—known as narrow-spectrum antibiotics—act on only a few types of bacteria. Other antibiotics kill many kinds of bacteria, and so are described as having a broad-spectrum of activity.

Bacteria can be killed or weakened by agents other than antibiotics. Antiseptics, for example, are compounds that were originally conceived to control bacterial infections of the blood (sepsis; hence their name). Antiseptics prevent the growth of pathogenic (disease-causing) microorganisms. Organisms that are weakened by antiseptics can be rendered more susceptible to the defense mechanisms of the host.

The use of antimicrobial compounds dates back thousands of years. The black eye makeup—known as kohl—used by the ancient Arabs and Egyptians is an antiseptic mixture of copper and antimony. Indeed, present day treatment for trachoma (blindness caused by infection of the eyes by the bacterium Chlamydia trachomatis) utilizes medicine that is very similar to kohl.

While studying influenza viruses in his laboratory in 1928, the Scottish physician Alexander Fleming (1881–1955) noticed that a mold was growing by chance on a culture plate containing a staphylococcus bacteria, and that the mold had created a zone on the plate where the bacteria was not growing. With further experimentation, Fleming found that the mold contained a powerful anti-bacterial agent that could prevent the growth of staphylococci even when highly diluted. He named the agent penicillin. Over a decade later, in 1941, Oxford researchers Howard Florey (1898–1968) and Ernst Chain (1906–1979) found a way to purify and stabilize enough penicillin to administer to a human. All three scientists won the 1945 Nobel Prize in physiology or medicine for this accomplishment.

The Unites States Army made immediate use of penicillin in World War II (1941–1945). In hospitals near the front, the new therapeutic agent saved thousands of soldiers from post-battlefield wound infections, and proved an effective agent in treating many cases of syphilis and gonorrhea among the troops. American and British military hospitals served as a large-scale proving ground for the drug, and military physicians helped standardize dosage and administration procedures for penicillin. The following Army report summarizes the indications and usage for penicillin in treating soldiers wounded in North Africa in World War II.

PRIMARY SOURCE

                HEADQUARTERS
     NORTH AMERICAN THEATER OF OPERATIONS
            OFFICE OF THE SURGEON
                   APO 534
                 1 JULY 1944
            CIRCULAR LETTER NO. 36

SUBJECT: PENICILLIN THERAPY IN WOUND MANAGEMENT, SURGICAL DISEASE, BURNS, AND ANAEROBIC INFECTIONS

1. General. a. In World War II, two quite different policies have governed the use of chemotherapeutic agents in the management of wounds. Chemotherapy has been recommended: (1) as a substitute for adequate wound surgery, seeking to delay and minimize operative procedures; (2) as an adjunct to established and progressive surgical measures designed to achieve better results within an increased margin of safety. The latter has been and will continue to be the policy governing the management of the wounded in this theater.

b. The use of penicillin as an adjunct to surgery outlined in this circular is defined as therapy rather than prophylaxis. Routine immunization of troops with tetanus toxoid is a prophylactic measure. Administration of penicillin for contaminated wounds and established infection is a therapeutic measure. As with all therapy, if the desired goal is to be achieved, intelligent and precise professional supervision of every detail is essential.

2. Scope of Penicillin Therapy. a. Penicillin is accepted as the best available antibacterial agent for gram-positive bacteria and gram-negative diplococci. It is ineffective for gramnegative bacilli.

b. Penicillin does not sterilize dead, devitalized or avascular tissue, nor does it prevent the septic decomposition of contaminated blood clot. There is no evidence that it can neutralize preformed bacterial exotoxins or inhibit the locally necrotizing bacterial enzymes in undrained pus. These limitations demand that surgical wound management retain the principles of excision of devitalized tissue, dependent drainage of residual dead space, evacuation of pus and delayed or staged closure of contaminated wounds (see Circular Letter No. 26, Office of the Surgeon, Hq. NATOUSA).

c. The use of penicillin in an individual patient is based upon the decision that infection is probable or present.

d. It is recommended that parenteral administration be the basis of penicillin therapy. The local or topical use of penicillin is a supplement to systemic therapy only in lesions of the central nervous system, serous cavities and joints. The diffusion of the drug into these areas appears slow and limited.

3. Penicillin Therapy in Relation to Sulfonamide Therapy. a. Topical and oral administration of sulfonamides as first aid measures will be continued.

b. Intravenous sulfonamide prior to initial surgery will be replaced by parenteral administration of penicillin (par. 6, a).

c. At the conclusion of the initial wound operation, the decision will be made either to institute a postoperative course of penicillin therapy or to maintain chemotherapy with sulfonamides. It is recommended that the agents be used individually and not concomitantly. If a course of penicillin is elected, topical frosting of the wound with sulfonamide is omitted. The following observations will serve as a guide in this decision:

Clinical experience with penicillin has been greatest with wounds of the extremities and the thorax. The drug is recommended for these injuries.
The value of penicillin in craniocerebral wounds is well established, but an extensive experience has not been accumulated.
Cleanly debrided soft part wounds uncomplicated by fracture, extensive tissue destruction, or retained missiles are adequately handled by sulfonamide therapy.
Preliminary evaluation of penicillin therapy for fecal contamination of the peritoneal cavity is encouraging but at the present time is inadequate for comparison with sulfonamide therapy. In view of the difficulties in maintaining a fluid intake adequate to safeguard sulfonamide therapy in this group of cases, substitution of penicillin may be made at the discretion of time surgeon. Forcing of fluids is not necessary solely because of penicillin therapy and in fact, reduces the effective concentration of the drug by rapid urinary excretion.

4. Routes of Penicillin Administration. a. Intramuscular. This is the standard route for administration. The deltoid, gluteus and thigh muscles are recommended as the sites for injection. The same area may be used repeatedly. Subcutaneous administration is to be avoided.

b. Intravenous. The intravenous route is reserved for patients with shock or immediately life endangering infection. A single intravenous injection provides a therapeutic concentration of the drug that lasts for two hours. If intravenous therapy is indicated to span a longer period, the injection is repeated or constant drip administration instituted.

5. Dosage. a. Systemic therapy. Current practice dictates a dosage of 200,000 units in 24 hours, given as 25,000 units every three hours by the intramuscular route. Larger initial dosage or greater 24 hourly dosage have no demonstrable merit. Maintenance of full dosage schedules throughout the course of therapy is better than a graded terminal decrease in dosage.

b. Local therapy. The powdered sodium salt of penicillin is slightly acid and provokes a burning pain and serous discharge if applied to an open wound. A solution containing 10,000 units per c.c. is well tolerated as an intramuscular injection but may produce headache, meningismus and pleocytosis of the spinal fluid after intrathecal injection. The maximal effective local concentration is 250 to 500 units per c.c. The usual concentration employed chemically varies between 500 and 5,000 units per c.c. with predominate usage of a solution containing 1,000 units per c.c. The following dosage schedules are recommended for local instillation:

Intrathecal space: 7,500 units
Pleural cavity: 25,000 units
Peritoneal cavity: 50,000 units
Knee joint: 10,000 unitsLocal instillation of penicillin may be repeated at intervals of 12 to 48 hours in accordance within clinical indications. Needle aspiration and injection is preferable to inlying tubes.

6. Use of Penicillin in Mobile Hospitals. The following recommendations are made on the basis of procedures that have been found practical in Evacuation Hospitals:

a. Upon arrival in the shock or preoperative ward, the wounded will receive 25,000 units of penicillin intramuscularly, unless the wound is certainly of a trivial nature. If shock is present, an additional 25,000 units will be given intravenously.

b. Preoperative dosage is continued at 3 hourly intervals. It is more practical to give penicillin to every patient in a preoperative ward at the same time, than to keep each patient on a dosage schedule based on the time of arrival. There is no objection to a time interval of less than 3 hours between the first two injections.

c. The decision to continue penicillin or to substitute sulfonamide in the postoperative period is made when the operation is concluded and the nature and extent of the injury evaluated (see par. 3 c).

d. No patient will be held in a mobile hospital solely for the purpose of continuing penicillin therapy. The usual criteria based on the condition of the patient will determine the suitability for evacuation. In general, the drug is continued for 2 to 3 days beyond the period of clinical recovery from the hazard or subsidence of infection. A course of therapy may be associated with slight fever which disappears after the drug is stopped. Suitable periods of therapy are:

Soft part wounds: 5 to 7 days
Compound fractures: 10 to 12 days
Thoracic wounds: 8 to 10 days
Abdominal wounds: 8 to 10 days
Craniocerebral wounds: 8 to 10 days
Joint wounds: 7 to 14 days

e. Patients evacuated prior to completion of a course of therapy will carry a notation "On Penicillin" in the space provided under the designation "Special attention needed in transit, or other remarks" on the jacket of the Field Medical Record (Form 52d). This will indicate the need for continuation of therapy in holding stations, hospital ships and fixed hospitals.

7. Use of penicillin in Holding Stations or Hospital Ships. a. Form 52d will be examined in each case upon admission to identify those patients receiving penicillin therapy (par. 5 e).

b. 25,000 units of penicillin will be administered intramuscularly every 3 hours to all such designated patients.

8. Use of Penicillin in Fixed Hospitals. a. Patients designated as "On Penicillin" will have time course continued on admission to time hospital. Discontinuance of therapy will be time responsibility of a medical officer after lie has reviewed the status of time patient.

b. Secondary suture of cleanly debrided soft part wounds does not require penicillin therapy. Soft part wounds requiring delayed debridement or secondary debridement or within established infection may properly receive penicillin.

c. Reparative surgical procedures on wounds complicated by skeletal, joint, nerve, tendon or vascular injury require penicillin therapy.

d. Established wound infection is an indication for penicillin therapy.

e. Early secondary reparative operations through recently healed wounds require penicillin therapy.

9. Surgical Disease. a. Acute or chronic infections such as furuncles, carbuncles, felons, desert sores, tenosynovitis, etc. should be treated with penicillin whenever it is judged that loss of time from duty can be shortened….

For the SURGEON:
(S) E. STANDLEE
E. STANDLEE, Colonel, MC., Deputy Surgeon.

SIGNIFICANCE

Although penicillin was initially considered a war asset and war secret in the U.S. and Britain, by the end of 1945, commercial manufacturing plants were capable of producing enough penicillin so that physicians also could prescribe it to their civilian patients. Treatment protocols and dosage regimes that were perfected during wartime served the civilian population at the war's end. Penicillin was labeled a "miracle drug" after it also demonstrated its effectiveness in curing other bacterial infections including scarlet fever, meningitis, diphtheria, and bacteremia or septicemia (commonly known as blood poisoning).

In the decades following the discovery of penicillin, a flood of naturally occurring antibiotics was discovered, refined, and marketed. Antibiotics quickly became (and still are) a vital part of the treatment for infections and one of the major medical innovations of the twentieth century. Indeed, antibiotics were so effective that, by the 1970s, the conventional wisdom held that the threat of bacterial infectious diseases was ebbing. However, this heady hope proved to be shortsighted, and bacterial resistance to antibiotics began to concern scientists in the late 1980s.

Antibiotic development has become a race. New or altered antibiotics need to be developed to at least keep pace with the resistance acquired by clinically important bacteria. One strategy to keep antibiotics sensitive to the organisms they are intended to fight is to modify an existing antibiotic to restore its potency. Modifying an antibiotic slightly, such as by the addition of a different chemical group to alter the three dimensional structure of the compound, can work. Unfortunately, bacteria relatively quickly tend to develop resistance to the modified compound.

Misuse or overuse of antibiotics contributes to the development of bacterial resistance. For example, treatment of viral illnesses, such as a cold or the flu, with an antibiotic is a useless strategy, since antibiotics are ineffective against viruses. Yet, exposing any bacteria resident in the patient to the antibiotic can prompt the development of a more resistant and hardy bacteria.

Incomplete antibiotic therapy also is an example of misuse. If an antibiotic is used properly to treat an infection (i.e., taken as directed for the full length of time), the infectious bacterial population should be completely eliminated. However, the use of too low a concentration of an antibiotic or ending therapy too soon can leave bacterial survivors, which have the capacity to acquire resistance. If the resistance is governed by a genetic alteration, the genetic change may be passed on to subsequent generations of bacteria who also have resistance to the antibiotic.

As one example, many strains of the bacterium that causes tuberculosis are now resistant to one or more of the antibiotics routinely used to control this lung infection. Also, some strains of Staphylococcus aureus, a bacteria responsible for common infections, are resistant to almost all antibiotics.