The side effects of penicillin can be altered by taking other medications at the same time. Taking oral contraceptives along with penicillin may lower the effects of the contraceptive. When probenecid is used concurrently with penicillin, kidney excretion of probenecid is increase resulting in higher blood levels of penicillin in the circulation. In some instances, this would be intended therapeutic effect. In other instances, this is an unintended side effect. Neomycin can lower the absorption of penicillin from the gastrointestinal tract resulting in lower than expected levels of penicillin in the circulation. This side effect may result in an ineffective therapeutic effect of penicillin. When methotrexate is administered with penicillin, toxicity may occur related to methotrexante.

When penicillin is used at high doses hypokalemia, metabolic acidosis, and hyperkalemia can occur. Developing hypernatremia after administering high doses of penicillin can be a serious side effect.

Antibiotics can cause severe reactions and add significantly to the cost of care. In the United States, antibiotics and anti-infectives are the leading cause of adverse effect from drugs. In a study of 32 States in 2011, antibiotics and anti-infectives accounted for nearly 24 percent of ADEs that were present on admission, and 28 percent of those that occurred during a hospital stay.

Prescribing by an infectious disease specialist compared with prescribing by a non-infectious disease specialist decreases antibiotic consumption and reduces costs.

Common situations in which antibiotics are overused include the following:

- Apparent viral respiratory illness in children should not be treated with antibiotics. If there is a diagnosis of bacterial infection, then antibiotics may be used.

- When children with ear tubes get ear infections, they should have antibiotic eardrops put into their ears to go to the infection rather than having oral antibiotics which are more likely to have unwanted side effects.

- Swimmer's ear should be treated with antibiotic eardrops, not oral antibiotics.

- Sinusitis should not be treated with antibiotics because it is usually caused by a virus, and even when it is caused by a bacteria, antibiotics are not indicated except in atypical circumstances as it usually resolves without treatment.

- Viral conjunctivitis should not be treated with antibiotics. Antibiotics should only be used with confirmation that a patient has bacterial conjunctivitis.

- Older persons often have bacteria in their urine which is detected in routine urine tests, but unless the person has the symptoms of a urinary tract infection, antibiotics should not be used in response.

- Eczema should not be treated with oral antibiotics. Dry skin can be treated with lotions or other symptom treatments.

- The use of topical antibiotics to treat surgical wounds does not reduce infection rates in comparison with non-antibiotic ointment or no ointment at all.

The chances of drug resistance can sometimes be minimized by using multiple drugs simultaneously. This works because individual mutations can be independent and may tackle only one drug at a time; if the individuals are still killed by the other drugs, then the mutations cannot persist. This was used successfully in tuberculosis. However, cross resistance where mutations confer resistance to two or more treatments can be problematic.

For antibiotic resistance, which represents a widespread problem nowadays, drugs designed to block the mechanisms of bacterial antibiotic resistance are used. For example, bacterial resistance against beta-lactam antibiotics (such as penicillins and cephalosporins) can be circumvented by using antibiotics such as nafcillin that are not susceptible to destruction by certain beta-lactamases (the group of enzymes responsible for breaking down beta-lactams). Beta-lactam bacterial resistance can also be dealt with by administering beta-lactam antibiotics with drugs that block beta-lactamases such as clavulanic acid so that the antibiotics can work without getting destroyed by the bacteria first. Recently, researchers have recognized the need for new drugs that inhibit bacterial efflux pumps, which cause resistance to multiple antibiotics such as beta-lactams, quinolones, chloramphenicol, and trimethoprim by sending molecules of those antibiotics out of the bacterial cell. Sometimes a combination of different classes of antibiotics may be used synergistically; that is, they work together to effectively fight bacteria that may be resistant to one of the antibiotics alone.

Destruction of the resistant bacteria can also be achieved by phage therapy, in which a specific bacteriophage (virus that kills bacteria) is used.

There is research being done using antimicrobial peptides. In the future, there is a possibility that they might replace novel antibiotics.

Epinephrine (adrenaline) is the primary treatment for anaphylaxis with no absolute contraindication to its use. It is recommended that an epinephrine solution be given intramuscularly into the mid anterolateral thigh as soon as the diagnosis is suspected. The injection may be repeated every 5 to 15 minutes if there is insufficient response. A second dose is needed in 16-35% of episodes with more than two doses rarely required. The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption. Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.

People on β-blockers may be resistant to the effects of epinephrine. In this situation if epinephrine is not effective intravenous glucagon can be administered which has a mechanism of action independent of β-receptors.

If necessary, it can also be given intravenously using a dilute epinephrine solution. Intravenous epinephrine, however, has been associated both with dysrhythmia and myocardial infarction. Epinephrine autoinjectors used for self-administration typically come in two doses, one for adults or children who weigh more than 25 kg and one for children who weigh 10 to 25 kg.

Throughout history treatment relied primarily on β-lactam antibiotics. In the 1960s nearly all strains of "S. pneumoniae" were susceptible to penicillin, but more recently there has been an increasing prevalence of penicillin resistance especially in areas of high antibiotic use. A varying proportion of strains may also be resistant to cephalosporins, macrolides (such as erythromycin), tetracycline, clindamycin and the quinolones. Penicillin-resistant strains are more likely to be resistant to other antibiotics. Most isolates remain susceptible to vancomycin, though its use in a β-lactam-susceptible isolate is less desirable because of tissue distribution of the drug and concerns of development of vancomycin resistance. More advanced beta-lactam antibiotics (cephalosporins) are commonly used in combination with other drugs to treat meningitis and community-acquired pneumonia. In adults recently developed fluoroquinolones such as levofloxacin and moxifloxacin are often used to provide empiric coverage for patients with pneumonia, but in parts of the world where these drugs are used to treat tuberculosis resistance has been described.

Susceptibility testing should be routine with empiric antibiotic treatment guided by resistance patterns in the community in which the organism was acquired. There is currently debate as to how relevant the results of susceptibility testing are to clinical outcome. There is slight clinical evidence that penicillins may act synergistically with macrolides to improve outcomes.

Antihistamines (both H1 and H2), while commonly used and assumed effective based on theoretical reasoning, are poorly supported by evidence. A 2007 Cochrane review did not find any good-quality studies upon which to base recommendations and they are not believed to have an effect on airway edema or spasm. Corticosteroids are unlikely to make a difference in the current episode of anaphylaxis, but may be used in the hope of decreasing the risk of biphasic anaphylaxis. Their prophylactic effectiveness in these situations is uncertain. Nebulized salbutamol may be effective for bronchospasm that does not resolve with epinephrine. Methylene blue has been used in those not responsive to other measures due to its presumed effect of relaxing smooth muscle.

The treatment of choice is penicillin, and the duration of treatment is around 10 days. Antibiotic therapy (using injected penicillin) has been shown to reduce the risk of acute rheumatic fever. In individuals with a penicillin allergy, erythromycin, other macrolides, and cephalosporins have been shown to be effective treatments.

Treatment with ampicillin/sulbactam, amoxicillin/clavulanic acid, or clindamycin is appropriate if deep oropharyngeal abscesses are present, in conjunction with aspiration or drainage. In cases of streptococcal toxic shock syndrome, treatment consists of penicillin and clindamycin, given with intravenous immunoglobulin.

For toxic shock syndrome and necrotizing fasciitis, high-dose penicillin and clindamycin are used. Additionally, for necrotizing fasciitis, surgery is often needed to remove damaged tissue and stop the spread of the infection.

No instance of penicillin resistance has been reported to date, although since 1985, many reports of penicillin tolerance have been made. The reason for the failure of penicillin to treat "S. pyogenes" is most commonly patient noncompliance, but in cases where patients have been compliant with their antibiotic regimen, and treatment failure still occurs, another course of antibiotic treatment with cephalosporins is common.

The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance).

The first major development was ampicillin in 1961. It offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant "Staphylococcus aureus" (MRSA) strains that subsequently emerged.

Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most important, the cephalosporins, still retain it at the center of their structures.

Antimicrobial stewardship teams in hospitals are encouraging optimal use of antimicrobials. The goals of antimicrobial stewardship are to help practitioners pick the right drug at the right dose and duration of therapy while preventing misuse and minimizing the development of resistance. Stewardship may reduce the length of stay by an average of slightly over 1 day while not increasing the risk of death.

Antibiotic stewardship programmes appear useful in reducing rates of antibiotic resistance.

Excessive antibiotic use has become one of the top contributors to the development of antibiotic resistance. Since the beginning of the antibiotic era, antibiotics have been used to treat a wide range of disease. Overuse of antibiotics has become the primary cause of rising levels of antibiotic resistance. The main problem is that doctors are willing to prescribe antibiotics to ill-informed individuals who believe that antibiotics can cure nearly all illnesses, including viral infections like the common cold. In an analysis of drug prescriptions, 36% of individuals with a cold or an upper respiratory infection (both viral in origin) were given prescriptions for antibiotics. These prescriptions accomplished nothing other than increasing the risk of further evolution of antibiotic resistant bacteria.

Antibiotics to combat the streptococcal infection are the mainstay of treatment for scarlet fever. Prompt administration of appropriate antibiotics decreases the length of illness. Peeling of the outer layer of skin however will happen despite treatment. One of the main goals of treatment is to prevent the child from developing one of the suppurative or nonsuppurative complications, especially acute rheumatic fever. As long as antibiotics are started within 9 days, it is very unlikely for the child to develop acute rheumatic fever. Antibiotic therapy has not been shown to prevent the development of poststreptococcal glomerulonephritis. Another important reason for prompt treatment with antibiotics is the ability to prevent transmission of the infection between children. An infected individual is most likely to pass on the infection to another person during the first 2 weeks. A child is no longer contagious (able to pass the infection to another child) after 24 hours of antibiotics.

The antibiotic of choice is penicillin V which is taken by mouth in pill form. Children who are not able to take pills can be given amoxicillin which comes in a liquid form and is equally effective. Duration of treatment is 10 days. Benzathine Penicillin G can be given as a one time intramuscular injection as another alternative if swallowing pills is not possible. If the patient is allergic to the family of antibiotics which both penicillin and amoxicillin are a part of (beta-lactam antibiotics), a first generation cephalosporin is used. Cephalosporin antibiotics however can still cause adverse reactions in patients whose allergic reaction to penicillin is a Type 1 Hypersensitivity reaction. In those cases it is appropriate to choose clindamycin or erythromycin instead.

Tonsillectomy, although once a reasonable treatment for recurrent streptococcal pharyngitis, is not indicated. This is due to the fact that a person can still be infected with group A streptococcus without their tonsils.

"S. pyogenes" infections are best prevented through effective hand hygiene. No vaccines are currently available to protect against "S. pyogenes" infection, although research has been conducted into the development of one. Difficulties in developing a vaccine include the wide variety of strains of "S. pyogenes" present in the environment and the large amount of time and number of people that will be needed for appropriate trials for safety and efficacy of the vaccine.

"S. pneumonia" can be treated with a combination of penicillin and ampicillin.

The antibiotic of choice in the United States for streptococcal pharyngitis is penicillin V, due to safety, cost, and effectiveness. Amoxicillin is preferred in Europe. In India, where the risk of rheumatic fever is higher, intramuscular benzathine penicillin G is the first choice for treatment.

Appropriate antibiotics decrease the average 3–5 day duration of symptoms by about one day, and also reduce contagiousness. They are primarily prescribed to reduce rare complications such as rheumatic fever and peritonsillar abscess. The arguments in favor of antibiotic treatment should be balanced by the consideration of possible side effects, and it is reasonable to suggest that no antimicrobial treatment be given to healthy adults who have adverse reactions to medication or those at low risk of complications. Antibiotics are prescribed for strep throat at a higher rate than would be expected from how common it is.

Erythromycin and other macrolides or clindamycin are recommended for people with severe penicillin allergies. First-generation cephalosporins may be used in those with less severe allergies and some evidence supports cephalosporins as superior to penicillin. Streptococcal infections may also lead to acute glomerulonephritis; however, the incidence of this side effect is not reduced by the use of antibiotics.

In cases of herpes simplex virus-derived meningitis, antiviral therapy (acyclovir or vidarabine) must be started immediately for a favorable outcome. Acyclovir is a better antiviral because it shows a similar effect on the infection as vidarabine and is safer to use in the neonate. The recommended dosage is 20 mg/kg every six hours for 21 days.

Treatment of AIT involves antibiotic treatment. Based on the offending organism found on microscopic examination of the stained fine needle aspirate, the appropriate antibiotic treatment is determined. In the case of a severe infection, systemic antibiotics are necessary. Empirical broad spectrum antimicrobial treatment provides preliminary coverage for a variety of bacteria, including "S. aureus" and "S. pyogenes." Antimicrobial options include penicillinase-resistant penicillins (ex: cloxacillin, dicloxacillin) or a combination of a penicillin and a beta-lactamase inhibitor. However, in patients with a penicillin allergy, clindamycin or a macrolide can be prescribed. The majority of anaerobic organisms involved with AIT are susceptible to penicillin. Certain Gram-negative bacilli (ex: "Prevotella", "Fusobacteria", and "Porphyromonas") are exhibiting an increased resistance based on the production of beta-lactamase. Patients who have undergone recent penicillin therapy have demonstrated an increase in beta-lactamase-producing (anaerobic and aerobic) bacteria. Clindamycin, or a combination of metronidazole and a macrolide, or a penicillin combined with a beta-lactamase inhibitor is recommended in these cases. Fungal thyroiditis can be treated with amphotericin B and fluconazole. Early treatment of AIT prevents further complications. However, if antibiotic treatment does not manage the infection, surgical drainage is required. Symptoms or indications requiring drainage include continued fever, high white blood cell count, and continuing signs of localized inflammation. The draining procedure is also based on clinical examination or ultrasound/CT scan results that indicate an abscess or gas formation. Another treatment of AIT involves surgically removing the fistula. This treatment is often the option recommended for children. However, in cases of an antibiotic resistant infection or necrotic tissue, a lobectomy is recommended. If diagnosis and/or treatment is delayed, the disease could prove fatal.

Penicillin is a secondary metabolite of certain species of "Penicillium" and is produced when growth of the fungus is inhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesis pathway of penicillin.

The by-product, -lysine, inhibits the production of homocitrate, so the presence of exogenous lysine should be avoided in penicillin production.

The "Penicillium" cells are grown using a technique called fed-batch culture, in which the cells are constantly subject to stress, which is required for induction of penicillin production. The available carbon sources are also important: Glucose inhibits penicillin production, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must also be carefully controlled.

The biotechnological method of directed evolution has been applied to produce by mutation a large number of "Penicillium" strains. These techniques include error-prone PCR, DNA shuffling, , and strand-overlap PCR.

Semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.

Pain medication such as NSAIDs and paracetamol (acetaminophen) helps in the management of pain associated with strep throat. Viscous lidocaine may also be useful. While steroids may help with the pain, they are not routinely recommended. Aspirin may be used in adults but is not recommended in children due to the risk of Reye syndrome.

Tetracyclines are a class of antibiotics that inhibit protein synthesis by binding to the 30s ribosomal subunit of bacterial cells, keeping transcription of the bacterial genome from occurring. Tetracyclines are bacteriostatic, which means that the growth of the bacterium will be slowed. Tetracyclines are not often recommended for the treatment of "N. gonorrhoeae" because the treatment regimen requires many doses, which may affect compliance and contribute to resistance. Tetracycline is still used as treatment for this infection in developing countries because the cost for the drug is low

As with the penicillin resistance, the "penB" (porin formation) and "mtr" (efflux pump formation) mutations mediate chromosomal resistance. These adaptations will also affect the ability of the antibiotic to get into, or stay in the bacterial cell. High level resistance of "N. gonorrhoeae" to tetracyclines was first reported in 1986 with the discovering of the "tetM" determinant. The mechanism of resistance is still unknown.

The standard treatment is with a minimum of four weeks of high-dose intravenous penicillin with an aminoglycoside such as gentamicin.

The use of high-dose antibiotics is largely based upon animal models.

Leo Loewe of Brooklyn Jewish Hospital was the first to successfully treat subacute bacterial endocarditis with penicillin. Loewe reported at the time seven cases of subacute bacterial endocarditis in 1944.

The Gonorrhea bacterium Neisseria gonorrhoeae has developed antibiotic resistance to many antibiotics.

The bacteria was first identified in 1879, although some Biblical scholars believe that references to the disease can be found as early as Parshat Metzora of the Old Testament.

In the 1940s effective treatment with penicillin became available, but by the 1970s resistant strains predominated. Resistance to penicillin has developed through two mechanisms: chromasomally mediated resistance (CMRNG) and penicillinase-mediated resistance (PPNG). CMRNG involves step wise mutation of penA, which codes for the penicillin-binding protein (PBP-2); mtr, which encodes an efflux pump that removes penicillin from the cell; and penB, which encodes the bacterial cell wall porins. PPNG involves the acquisition of a plasmid-borne beta-lactamase. "N. gonorrheoea" has a high affinity for horizontal gene transfer, and as a result, the existence of any strain resistant to a given drug could spread easily across strains.

Fluoroquinolones were a useful next-line treatment until resistance was achieved through efflux pumps and mutations to the gyrA gene, which encodes DNA gyrase. Third-generation cephalosporins have been used to treat gonorrhoea since 2007, but resistant strains have emerged. As of 2010, the recommended treatment is a single 250 mg intramuscular injection of ceftriaxone, sometimes in combination with azithromycin or doxycycline. However, certain strains of "N. gonorrhoeae" can be resistant to antibiotics usually that are normally used to treat it. These include: cefixime (an oral cephalosporin), ceftriaxone (an injectable cephalosporin), azithromycin, aminoglycosides, and tetracycline.

In addition, people should be given antibiotics, such as second- or third-generation cephalosporins, either alone or in combination with penicillin or ampicillin for streptococcal coverage. If allergy to penicillins is present, Co-trimoxazole or clindamycin is an alternative.

The Hib vaccine is very effective at preventing the disease.

In household contacts of any unvaccinated child infected with H. influenzae, rifampicin is used as prophylaxis.