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.

"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.

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

While antibiotics with activity specifically against "M. pneumoniae" are often used (e.g., erythromycin, doxycycline), it is unclear if these result in greater benefit than using antibiotics without specific activity against this organism in those with an infection acquired in the community.

Antibiotics are the treatment of choice for bacterial pneumonia, with ventilation (oxygen supplement) as supportive therapy. The antibiotic choice depends on the nature of the pneumonia, the microorganisms most commonly causing pneumonia in the geographical region, and the immune status and underlying health of the individual. In the United Kingdom, amoxicillin is used as first-line therapy in the vast majority of patients acquiring pneumonia in the community, sometimes with added clarithromycin. In North America, where the "atypical" forms of community-acquired pneumonia are becoming more common, clarithromycin, azithromycin, or fluoroquinolones as single therapy have displaced the amoxicillin as first-line therapy.

Local patterns of antibiotic-resistance always need to be considered when initiating pharmacotherapy. In hospitalized individuals or those with immune deficiencies, local guidelines determine the selection of antibiotics.

"Streptococcus pneumoniae" — amoxicillin (or erythromycin in patients allergic to penicillin); cefuroxime and erythromycin in severe cases.

"Staphylococcus aureus" — flucloxacillin (to counteract the organism's β-lactamase).

Neuraminidase inhibitors may be used to treat viral pneumonia caused by influenza viruses (influenza A and influenza B). No specific antiviral medications are recommended for other types of community acquired viral pneumonias including SARS coronavirus, adenovirus, hantavirus, and parainfluenza virus. Influenza A may be treated with rimantadine or amantadine, while influenza A or B may be treated with oseltamivir, zanamivir or peramivir. These are of most benefit if they are started within 48 hours of the onset of symptoms. Many strains of H5N1 influenza A, also known as avian influenza or "bird flu", have shown resistance to rimantadine and amantadine. The use of antibiotics in viral pneumonia is recommended by some experts, as it is impossible to rule out a complicating bacterial infection. The British Thoracic Society recommends that antibiotics be withheld in those with mild disease. The use of corticosteroids is controversial.

Antibiotics improve outcomes in those with bacterial pneumonia. Antibiotic choice depends initially on the characteristics of the person affected, such as age, underlying health, and the location the infection was acquired. In the UK, treatment before culture results with amoxicillin is recommended as the first line for community-acquired pneumonia, with doxycycline or clarithromycin as alternatives. In North America, where the "atypical" forms of community-acquired pneumonia are more common, macrolides (such as azithromycin or erythromycin), and doxycycline have displaced amoxicillin as first-line outpatient treatment in adults. In children with mild or moderate symptoms, amoxicillin remains the first line. The use of fluoroquinolones in uncomplicated cases is discouraged due to concerns about side-effects and generating resistance in light of there being no greater clinical benefit.

For those who require hospitalization and caught their pneumonia in the community the use of a β-lactam such as cephazolin plus macrolide such as azithromycin or a fluoroquinolones is recommended. The addition of corticosteroids also appears to improve outcomes.

The duration of treatment has traditionally been seven to ten days, but increasing evidence suggests that shorter courses (three to five days) are similarly effective. Recommendations for hospital-acquired pneumonia include third- and fourth-generation cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and vancomycin. These antibiotics are often given intravenously and used in combination. In those treated in hospital, more than 90% improve with the initial antibiotics.

Treatment of CAP in children depends on the child's age and the severity of illness. Children under five are not usually treated for atypical bacteria. If hospitalization is not required, a seven-day course of amoxicillin is often prescribed, with co-trimaxazole an alternative when there is allergy to penicillins. Further studies are needed to confirm the efficacy of newer antibiotics. With the increase in drug-resistant Streptococcus pneumoniae, antibiotics such as cefpodoxime may become more popular. Hospitalized children receive intravenous ampicillin, ceftriaxone or cefotaxime, and a recent study found that a three-day course of antibiotics seems sufficient for most mild-to-moderate CAP in children.

Most newborn infants with CAP are hospitalized, receiving IV ampicillin and gentamicin for at least ten days to treat the common causative agents "streptococcus agalactiae", "listeria monocytogenes" and "escherichia coli". To treat the herpes simplex virus, IV acyclovir is administered for 21 days.

Usually initial therapy is empirical. If sufficient reason to suspect influenza, one might consider oseltamivir. In case of legionellosis, erythromycin or fluoroquinolone.

A third generation cephalosporin (ceftazidime) + carbapenems (imipenem) + beta lactam & beta lactamase inhibitors (piperacillin/tazobactam)

Treatment for meningitis is antibiotics. The particular drugs used are based off the infecting bacteria, but a mix of ampicillin, gentamicin, and cefotaxime is used for early-onset meningitis before identification of infection. A regimen of antistaphylococcal antibiotic, such as nafcillin or vancomycin, plus cefotaxime or ceftazidime with or without an aminoglycoside is recommended for late-onset neonatal meningitis. The aim for these treatments is to sterilize the CSF of any meningitis-causing pathogens. A repeated LP 24–48 hours after initial treatment should be used to declare sterilization.

Due to the importance of disease caused by "S. pneumoniae" several vaccines have been developed to protect against invasive infection. The World Health Organization recommend routine childhood pneumococcal vaccination; it is incorporated into the childhood immunization schedule in a number of countries including the United Kingdom, United States, and South Africa.

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

Prescribing antibiotics for laryngitis is not suggested practice. The antibiotics penicillin V and erythromycin are not effective for treating acute laryngitis. Erythromycin may improve voice disturbances after one week and cough after two weeks, however any modest subjective benefit is not greater than the adverse effects, cost, and the risk of bacteria developing resistance to the antibiotics. Health authorities have been strongly encouraging physicians to decrease the prescribing of antibiotics to treat common upper respiratory tract infections because antibiotic usage does not significantly reduce recovery time for these viral illnesses. Decreased antibiotic usage could also have prevented drug resistant bacteria. Some have advocated a delayed antibiotic approach to treating URIs which seeks to reduce the consumption of antibiotics while attempting to maintain patient satisfaction. Most studies show no difference in improvement of symptoms between those treated with antibiotics right away and those with delayed prescriptions. Most studies also show no difference in patient satisfaction, patient complications, symptoms between delayed and no antibiotics. A strategy of "no antibiotics" results in even less antibiotic use than a strategy of "delayed antibiotics".

Treatment for "Klebsiella" pneumonia is by antibiotics such as aminoglycosides and cephalosporins, the choice depending upon the person’s health condition, medical history and severity of the disease.

"Klebsiella" possesses beta-lactamase giving it resistance to ampicillin, many strains have acquired an extended-spectrum beta-lactamase with additional resistance to carbenicillin, amoxicillin, and ceftazidime. The bacteria remain susceptible to aminoglycosides and cephalosporins, varying degrees of inhibition of the beta-lactamase with clavulanic acid have been reported. Infections due to multidrug-resistant gram-negative pathogens in the ICU have invoked the re-emergence of colistin. However, colistin-resistant strains of "K. pneumoniae" have been reported in ICUs. In 2009, strains of "K. pneumoniae" with gene called New Delhi metallo-beta-lactamase ( NDM-1) that even gives resistance against intravenous antibiotic carbapenem, were discovered in India and Pakistan."Klebsiella" cases in Taiwan have shown abnormal toxicity, causing liver abscesses in people with diabetes mellitus (DM), treatment consists of third generation cephalosporins.

Patients with HCAP are more likely than those with community-acquired pneumonia to receive inappropriate antibiotics that do not target the bacteria causing their disease.

In 2002, an expert panel made recommendations about the evaluation and treatment of probable nursing home-acquired pneumonia. They defined probably pneumonia, emphasized expedite antibiotic treatment (which is known to improve survival) and drafted criteria for the hospitalization of willing patients.

For initial treatment in the nursing home, a fluoroquinolone antibiotic suitable for respiratory infections (moxifloxacin, for example), or amoxicillin with clavulanic acid plus a macrolide has been suggested. In a hospital setting, injected (parenteral) fluoroquinolones or a second- or third-generation cephalosporin plus a macrolide could be used. Other factors that need to be taken into account are recent antibiotic therapy (because of possible resistance caused by recent exposure), known carrier state or risk factors for resistant organisms (for example, known carrier of MRSA or presence of bronchiectasis predisposing to Pseudomonas aeruginosa), or suspicion of possible Legionella pneumophila infection (legionnaires disease).

In 2005, the American Thoracic Society and Infectious Diseases Society of America have published guidelines suggesting antibiotics specifically for HCAP. The guidelines recommend combination therapy with an agent from each of the following groups to cover for both "Pseudomonas aeruginosa" and MRSA. This is based on studies using sputum samples and intensive care patients, in whom these bacteria were commonly found.

- cefepime, ceftazidime, imipenem, meropenem or piperacillin–tazobactam; plus

- ciprofloxacin, levofloxacin, amikacin, gentamicin, or tobramycin; plus

- linezolid or vancomycin

In one observational study, empirical antibiotic treatment that was not according to international treatment guidelines was an independent predictor of worse outcome among HCAP patients.

Guidelines from Canada suggest that HCAP can be treated like community-acquired pneumonia with antibiotics targeting Streptococcus pneumoniae, based on studies using blood cultures in different settings which have not found high rates of MRSA or Pseudomonas.

Besides prompt antibiotic treatment, supportive measure for organ failure (such as cardiac decompensation) are also important. Another consideration goes to hospital referral; although more severe pneumonia requires admission to an acute care facility, this also predisposes to hazards of hospitalization such as delirium, urinary incontinence, depression, falls, restraint use, functional decline, adverse drug effects and hospital infections. Therefore, mild pneumonia might be better dealt with inside the long term care facility. In patients with a limited life expectancy (for example, those with advanced dementia), end-of-life pneumonia also requires recognition and appropriate, palliative care.

Among the categories of bacteria most known to infect patients are the category MRSA (resistant strain of "S. aureus"), member of gram-positive bacteria and "Acinetobacter" ("A. baumannii"), which is gram-negative. While antibiotic drugs to treat diseases caused by gram-positive MRSA are available, few effective drugs are available for "Acinetobacter". "Acinetobacter" bacteria are evolving and becoming immune to existing antibiotics, so in many cases, polymyxin-type antibacterials need to be used. "In many respects it’s far worse than MRSA," said a specialist at Case Western Reserve University.

Another growing disease, especially prevalent in New York City hospitals, is the drug-resistant, gram-negative "Klebsiella pneumoniae". An estimated more than 20% of the "Klebsiella" infections in Brooklyn hospitals "are now resistant to virtually all modern antibiotics, and those supergerms are now spreading worldwide."

The bacteria, classified as gram-negative because of their reaction to the Gram stain test, can cause severe pneumonia and infections of the urinary tract, bloodstream, and other parts of the body. Their cell structures make them more difficult to attack with antibiotics than gram-positive organisms like MRSA. In some cases, antibiotic resistance is spreading to gram-negative bacteria that can infect people outside the hospital. "For gram-positives we need better drugs; for gram-negatives we need any drugs," said Dr. Brad Spellberg, an infectious-disease specialist at Harbor-UCLA Medical Center, and the author of "Rising Plague", a book about drug-resistant pathogens.

One-third of nosocomial infections are considered preventable. The CDC estimates 2 million people in the United States are infected annually by hospital-acquired infections, resulting in 20,000 deaths. The most common nosocomial infections are of the urinary tract, surgical site and various pneumonias.

Alternatives to fosfomycin include nitrofurantoin, pivmecillinam, and co-amoxiclav in oral treatment of urinary-tract infections associated with extended-spectrum beta-lactamase.

In a separate study, CRE were treated with colistin, amikacin, and tigecycline, and emphasizes the importance of using gentamicin in patients undergoing chemotherapy or stem-cell therapy procedures.

While colistin had shown promising activity against carbapenemase-producing isolates, more recent data suggest a resistance to it is already emerging and it will soon become ineffective.

Using another antibiotic concomitantly with carbapenem can help prevent the development of carbapenem resistance. One specific study showed a higher rate of carbapenem resistance when using meropenem alone compared with combination therapy with moxifloxacin.

In addition, several drugs were tested to gauge their effectiveness against CRE infections. "In vitro" studies have shown that rifampin has synergistic activity against carbapenem-resistant "E. coli" and "K. pneumoniae". However, more data are needed to determine if rifampin is effective in a clinical setting.

Several new agents are in development. The main areas where scientists are focusing is new β-lactamase inhibitors with activity against carbapenemases. Some of these include MK-7655, NXL104, and 6-alkylidenepenam sulfones. The exact way they affect the carbapenemases is unknown. Another experimental agent with activity against CRE is eravacycline.

The Centers for Disease Control describe protocol for treating sinusitis while at the same time discouraging overuse of antibiotics:

- Target likely organisms with first-line drugs: Amoxicillin, Amoxicillin/Clavulanate

- Use shortest effective course: Should see improvement in 2–3 days. Continue treatment for 7 days after symptoms improve or resolve (usually a 10–14 day course).

- Consider imaging studies in recurrent or unclear cases: some sinus involvement is frequent early in the course of uncomplicated viral URI

Treatment comprises symptomatic support usually via analgesics for headache, sore throat and muscle aches. Moderate exercise in sedentary subjects with naturally acquired URTI probably does not alter the overall severity and duration of the illness. No randomized trials have been conducted to ascertain benefits of increasing fluid intake.

ILI occurs in some horses after intramuscular injection of vaccines. For these horses, light exercise speeds resolution of the ILI. Non-steroidal anti-inflammatory drugs (NSAIDs) may be given with the vaccine.

Gargling salt water is often suggested but evidence looking at its usefulness is lacking. Alternative medicines are promoted and used for the treatment of sore throats. However, they are poorly supported by evidence.

Tigecycline, a member of the glycylcyclines antibiotics, has proven to be an effective therapy against Enterobacteriaceae that typically display tetracycline resistance, because tigecycline has a higher binding affinity with ribosomal sites than tetracycline has. Tigecycline is capable of killing almost all of the ESBLs and multidrug-resistant (MDR) "E. coli" isolates and the large majority of ESBL and MDR isolates of "Klebsiella" species.

A 2008 review of 42 studies of "in vitro" susceptibility of bacteria to tigecycline showed that MDR "K. pneumoniae" and "E. coli", including those that were carbapenem resistant, were susceptible more than 90% of the time. A limited number of patients have been treated with tigecycline, but the FDA has approved it in certain cases with synergies of other drugs. The limited number of patients indicates that more trials are needed to determine the overall clinical effectiveness.

Although tigecycline is the one of the first lines of defense against carbapenemase-producing isolates, negative clinical outcomes with tigecycline have occurred. Both urinary tract and primary blood infections can make tigecycline ineffective, because it has limited penetration and rapid tissue diffusion after being intravenously infused, respectively.

The majority of time treatment is symptomatic. Specific treatments are effective for bacterial, fungal, and herpes simplex infections.

Evidence does not support the general use of antibiotics in acute bronchitis. While some evidence suggests antibiotics speed up resolution of the cough by about 12 hours there is a greater risk of gastrointestinal problems and no change in longer term outcomes. Antibiotics use also leads to the promotion of antibiotic-resistant bacteria, which increase morbidity and mortality.