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.

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.

"Haemophilus influenzae" produces beta-lactamases, and it is also able to modify its penicillin-binding proteins, so it has gained resistance to the penicillin family of antibiotics.

In severe cases, cefotaxime and ceftriaxone delivered directly into the bloodstream are the elected antibiotics, and, for the less severe cases, an association of ampicillin and sulbactam, cephalosporins of the second and third generation, or fluoroquinolones are preferred. (Fluoroquinolone-resistant "Haemophilus influenzae" have been observed.)

Macrolide antibiotics (e.g., clarithromycin) may be used in patients with a history of allergy to beta-lactam antibiotics. Macrolide resistance has also been observed.

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.

The serious complications of HiB are brain damage, hearing loss, and even death.

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 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.

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.

"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.

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.

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.

People with positive cultures for "Streptococcus pyogenes" should be treated with penicillin as long as allergy is not present. The use of antibiotics will not alter cardiac involvement in the development of rheumatic fever. Some suggest the use of benzathine benzylpenicillin.

Monthly injections of long-acting penicillin must be given for a period of five years in patients having one attack of rheumatic fever. If there is evidence of carditis, the length of therapy may be up to 40 years.

Another important cornerstone in treating rheumatic fever includes the continual use of low-dose antibiotics (such as penicillin, sulfadiazine, or erythromycin) to prevent recurrence.

While corticosteroids are often used, evidence to support this is poor. Salicylates are useful for pain.

Steroids are reserved for cases where there is evidence of an involvement of the heart. The use of steroids may prevent further scarring of tissue and may prevent the development of sequelae such as mitral stenosis.

High-dose antibiotics are administered by the intravenous route to maximize diffusion of antibiotic molecules into vegetation(s) from the blood filling the chambers of the heart. This is necessary because neither the heart valves nor the vegetations adherent to them are supplied by blood vessels. Antibiotics are typically continued for two to six weeks depending on the characteristics of the infection and the causative microorganisms.

In acute endocarditis, due to the fulminant inflammation empirical antibiotic therapy is started immediately after the blood has been drawn for culture. This usually includes vancomycin and ceftriaxone IV infusions until the microbial identification and susceptibility report with the minimum inhibitory concentration becomes available allowing for modification of the antimicrobial therapy to target the specific microorganism. It should be noted that the routine use of gentamicin to treat endocarditis has fallen out of favor due to the lack of evidence to support its use (except in infections caused by "Enterococcus" and nutritionally variant "streptococci") and the high rate of complications.

In subacute endocarditis, where patient's hemodynamic status is usually stable, antibiotic treatment can be delayed till the causative microorganism can be identified.

The most common organism responsible for infective endocarditis is "Staphylococcus aureus", which is resistant to penicillin in most cases. High rates of resistance to oxacillin are also seen, in which cases treatment with vancomycin is required.

Viridans group "streptococci" and "Streptococcus bovis" are usually highly susceptible to penicillin and can be treated with penicillin or ceftriaxone.

Relatively resistant strains of viridans group "streptococci" and "Streptococcus bovis" are treated with penicillin or ceftriaxone along with a shorter 2 week course of an aminoglycoside during the initial phase of treatment.

Highly penicillin resistant strains of viridans group "streptococci", nutritionally variant "streptococci" like "Granulicatella sp.", "Gemella sp." and "Abiotrophia defectiva", and "Enterococci" are usually treated with a combination therapy consisting of penicillin and an aminoglycoside for the entire duration of 4–6 weeks.

Selected patients may be treated with a relatively shorter course of treatment (2 weeks) with benzyl penicillin IV if infection is caused by viridans group "streptococci" or "Streptococcus bovis" as long as the following conditions are met:

- Endocarditis of a native valve, not of a prosthetic valve

- An MIC ≤ 0.12 mg/l

- Complication such as heart failure, arrhythmia, and pulmonary embolism occur

- No evidence of extracardiac complication like septic thromboembolism

- No vegetations > 5mm in diameter conduction defects

- Rapid clinical response and clearance of blood stream infection

Additionally oxacillin susceptible "Staphylococcus aureus" native valve endocarditis of the right side can also be treated with a short 2 week course of a beta-lactam antibiotic like nafcillin with or without aminoglycosides.

Surgical debridement of infected material and replacement of the valve with a mechanical or bioprosthetic artificial heart valve is necessary in certain situations:

- Patients with significant valve stenosis or regurgitation causing heart failure

- Evidence of hemodynamic compromise in the form of elevated end-diastolic left ventricular or left atrial pressure or moderate to severe pulmonary hypertension

- Presence of intracardiac complications like paravalvular abscess, conduction defects or destructive penetrating lesions

- Recurrent septic emboli despite appropriate antibiotic treatment

- Large vegetations (> 10 mm)

- Persistently positive blood cultures despite appropriate antibiotic treatment

- Prosthetic valve dehiscence

- Relapsing infection in the presence of a prosthetic valve

- Abscess formation

- Early closure of mitral valve

- Infection caused by fungi or resistant Gram negative bacteria.

The guidelines were recently updated by both the American College of Cardiology and the European Society of Cardiology. There was a recent meta-analysis published that showed surgical intervention at 7 days or less is associated with lower mortality .

Infective endocarditis is associated with 18% in-hospital mortality.

GBS is also an important infectious agent able to cause invasive infections in adults. Serious life-threatening invasive GBS infections are increasingly recognized in the elderly and in individuals compromised by underlying diseases such as diabetes, cirrhosis and cancer. GBS infections in adults include urinary tract infection, skin and soft-tissue infection (skin and skin structure infection) bacteremia without focus, osteomyelitis, meningitis and endocarditis.

GBS infection in adults can be serious, and mortality is higher among adults than among neonates.

In general, penicillin is the antibiotic of choice for treatment of GBS infections. Erythromycin or clindamycin should not be used for treatment in penicillin-allergic patients unless susceptibility of the infecting GBS isolate to these agents is documented. Gentamicin plus penicillin (for antibiotic synergy) in patients with life-threatening GBS infections may be used.

If the tonsillitis is caused by group A streptococcus, then antibiotics are useful, with penicillin or amoxicillin being primary choices. Cephalosporins and macrolides are considered good alternatives to penicillin in the acute setting. A macrolide such as erythromycin is used for people allergic to penicillin. Individuals who fail penicillin therapy may respond to treatment effective against beta-lactamase producing bacteria such as clindamycin or amoxicillin-clavulanate. Aerobic and anaerobic beta lactamase producing bacteria that reside in the tonsillar tissues can "shield" group A streptococcus from penicillins.

Intranasal corticosteroids are used to control symptoms associated with sneezing, rhinorrhea, itching, and nasal congestion. Steroid nasal sprays are effective and safe, and may be effective without oral antihistamines. They take several days to act and so must be taken continually for several weeks, as their therapeutic effect builds up with time.

In 2013, a study compared the efficacy of mometasone furoate nasal spray to betamethasone oral tablets for the treatment of people with seasonal allergic rhinitis and found that the two have virtually equivalent effects on nasal symptoms in people.

Systemic steroids such as prednisone tablets and intramuscular triamcinolone acetonide or glucocorticoid (such as betamethasone) injection are effective at reducing nasal inflammation, but their use is limited by their short duration of effect and the side-effects of prolonged steroid therapy.

Antihistamine drugs can be taken orally and nasally to control symptoms such as sneezing, rhinorrhea, itching, and conjunctivitis.

It is best to take oral antihistamine medication before exposure, especially for seasonal allergic rhinitis. In the case of nasal antihistamines like azelastine antihistamine nasal spray, relief from symptoms is experienced within 15 minutes allowing for a more immediate 'as-needed' approach to dosage.

Ophthalmic antihistamines (such as azelastine in eye drop form and ketotifen) are used for conjunctivitis, while intranasal forms are used mainly for sneezing, rhinorrhea, and nasal pruritus.

Antihistamine drugs can have undesirable side-effects, the most notable one being drowsiness in the case of oral antihistamine tablets. First-generation antihistamine drugs such as diphenhydramine cause drowsiness, but second- and third-generation antihistamines such as cetirizine and loratadine are less likely to cause this problem.

Pseudoephedrine is also indicated for vasomotor rhinitis. It is used only when nasal congestion is present and can be used with antihistamines. In the United States, oral decongestants containing pseudoephedrine must be purchased behind the pharmacy counter by law in effort to prevent the making of methamphetamine.

Though the introduction of national guidelines to screen pregnant women for GBS carriage and the use of IAP has significantly reduced the burden of GBS-EOD disease, it has had no effect on preventing either GBS-LOD in infants or GBS infections in adults. Because of this, if an effective vaccine against GBS were available, it would be an effective means of controlling not only GBS disease in infants, but also infections in adults. The capsular polysaccharide of GBS, which is an important virulence factor, is also an excellent candidate for the development of an effective vaccine. As early as 1976, low levels of maternal antibodies against the capsular polysaccharide were shown to be correlated with susceptibility to GBS-EOD and GBS-LOD. Maternal-specific antibodies, transferred from the mother to the newborn, were able to confer protection to babies against GBS infection.

Vaccination is considered an ideal solution to prevent not only GBS-EOD and GBS-LOD, but also infections in adults at risk. Nevertheless, though research and clinical trials for the development of an effective vaccine to prevent GBS infections are underway, no vaccine is available in 2016. At present, the licensing of GBS vaccines is difficult because of the challenge in conducting efficacy clinical trials in humans due to the low incidence of GBS neonatal diseases.

Chronic cases may be treated with tonsillectomy (surgical removal of tonsils) as a choice for treatment. Children have had only a modest benefit from tonsillectomy for chronic cases of tonsillitis.

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.

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.

For the allergic type, cool water poured over the face with the head inclined downward constricts capillaries, and artificial tears sometimes relieve discomfort in mild cases. In more severe cases, nonsteroidal anti-inflammatory medications and antihistamines may be prescribed. Persistent allergic conjunctivitis may also require topical steroid drops.

Viral conjunctivitis usually resolves on its own and does not require any specific treatment. Antihistamines (e.g., diphenhydramine) or mast cell stabilizers (e.g., cromolyn) may be used to help with the symptoms. Povidone iodine has been suggested as a treatment, but as of 2008 evidence to support it was poor.